Nitric oxide contributes to learning and memory deficits observed in hypothyroid rats during neonatal and juvenile growth

array:24 ["pii" => "S1807593222029052" "issn" => "18075932" "doi" => "10.1590/S1807-59322010001100021" "estado" => "S300" "fechaPublicacion" => "2010-01-01" "aid" => "2905" "copyright" => "CLINICS" "copyrightAnyo" => "2010" "documento" => "article" "crossmark" => 0 "licencia" => "https://creativecommons.org/licenses/by-nc/3.0/" "subdocumento" => "fla" "cita" => "Clinics. 2010;65:1175-81" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "itemSiguiente" => array:19 [ "pii" => "S1807593222029064" "issn" => "18075932" "doi" => "10.1590/S1807-59322010001100022" "estado" => "S300" "fechaPublicacion" => "2010-01-01" "aid" => "2906" "copyright" => "CLINICS" "documento" => "article" "crossmark" => 0 "licencia" => "https://creativecommons.org/licenses/by-nc/3.0/" "subdocumento" => "fla" "cita" => "Clinics. 2010;65:1183-7" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "BASIC RESEARCH" "titulo" => "The role of central mechanisms in the anti-inflammatory effect of amitriptyline on carrageenan-induced paw edema in rats" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "1183" "paginaFinal" => "1187" ] ] "contieneResumen" => array:1 [ "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig3-cln_65p1183" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 316 "Ancho" => 498 "Tamanyo" => 11702 ] ] "descripcion" => array:1 [ "en" => "Lack of effect of intrathecal injection of amitriptyline on carrageenan-induced paw edema in the rats. Amitriptyline or the vehicle was administrated intrathecally 30 min prior to carrageenan (1%) injection, and the rats were evaluated for paw edema 4 h post-carrageenan. The values represent the mean variation in the paw volume ± S.D. (n = 6)." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Valiollah Hajhashemi, Hossein Sadeghi, Mohsen Minaiyan, Ahmad Movahedian, Ardeshir Talebi" "autores" => array:5 [ 0 => array:2 [ "nombre" => "Valiollah" "apellidos" => "Hajhashemi" ] 1 => array:2 [ "nombre" => "Hossein" "apellidos" => "Sadeghi" ] 2 => array:2 [ "nombre" => "Mohsen" "apellidos" => "Minaiyan" ] 3 => array:2 [ "nombre" => "Ahmad" "apellidos" => "Movahedian" ] 4 => array:2 [ "nombre" => "Ardeshir" "apellidos" => "Talebi" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1807593222029064?idApp=UINPBA00004N" "url" => "/18075932/0000006500000011/v1_202212010805/S1807593222029064/v1_202212010805/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S1807593222029040" "issn" => "18075932" "doi" => "10.1590/S1807-59322010001100020" "estado" => "S300" "fechaPublicacion" => "2010-01-01" "aid" => "2904" "copyright" => "CLINICS" "documento" => "article" "crossmark" => 0 "licencia" => "https://creativecommons.org/licenses/by-nc/3.0/" "subdocumento" => "fla" "cita" => "Clinics. 2010;65:1167-73" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "BASIC RESEARCH" "titulo" => "Phagocytic responses of peritoneal macrophages and neutrophils are different in rats following prolonged exercise" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "1167" "paginaFinal" => "1173" ] ] "contieneResumen" => array:1 [ "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig2-cln_65p1167" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 604 "Ancho" => 662 "Tamanyo" => 41430 ] ] "descripcion" => array:1 [ "en" => "Total number and phagocytic capacity of peritoneal macrophages and neutrophils. A, macrophage study. B, neutrophil study. The results are expressed as the average number of peritoneal macrophages and neutrophils and the percentage of phagocytosis ± standard error of the average. ∗ p ≤ 0.05 for exercise groups submitted to low- and moderate-intensity exercise (unadapted low intensity = EXAGL; moderate intensity = EXAGM and corresponding preadapted groups, EXADL and EXADM) as compared to the control group (C); # p ≤ 0.05 for comparisons made among the groups." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Clílton K O Ferreira, Jonato Prestes, Felipe F Donatto, Rozangela Verlengia, James W Navalta, Cláudia R Cavaglieri" "autores" => array:6 [ 0 => array:2 [ "nombre" => "Clílton K O" "apellidos" => "Ferreira" ] 1 => array:2 [ "nombre" => "Jonato" "apellidos" => "Prestes" ] 2 => array:2 [ "nombre" => "Felipe F" "apellidos" => "Donatto" ] 3 => array:2 [ "nombre" => "Rozangela" "apellidos" => "Verlengia" ] 4 => array:2 [ "nombre" => "James W" "apellidos" => "Navalta" ] 5 => array:2 [ "nombre" => "Cláudia R" "apellidos" => "Cavaglieri" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1807593222029040?idApp=UINPBA00004N" "url" => "/18075932/0000006500000011/v1_202212010805/S1807593222029040/v1_202212010805/en/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "BASIC RESEARCH" "titulo" => "Nitric oxide contributes to learning and memory deficits observed in hypothyroid rats during neonatal and juvenile growth" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "1175" "paginaFinal" => "1181" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Mahmoud Hosseini, Samaneh Sadat Dastghaib, Houshang Rafatpanah, Mosa Al-Reza Hadjzadeh, Hossein Nahrevanian, Ismaeil Farrokhi" "autores" => array:6 [ 0 => array:4 [ "nombre" => "Mahmoud" "apellidos" => "Hosseini" "email" => array:1 [ 0 => "hosseinim@MUMS.ac.ir" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "I," "identificador" => "af1-cln_65p1175" ] 1 => array:2 [ "etiqueta" => "II" "identificador" => "af2-cln_65p1175" ] 2 => array:2 [ "etiqueta" => "*" "identificador" => "c1-cln_65p1175" ] ] ] 1 => array:3 [ "nombre" => "Samaneh Sadat" "apellidos" => "Dastghaib" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "I" "identificador" => "af1-cln_65p1175" ] ] ] 2 => array:3 [ "nombre" => "Houshang" "apellidos" => "Rafatpanah" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "III" "identificador" => "af3-cln_65p1175" ] ] ] 3 => array:3 [ "nombre" => "Mosa Al-Reza" "apellidos" => "Hadjzadeh" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "I," "identificador" => "af1-cln_65p1175" ] 1 => array:2 [ "etiqueta" => "II" "identificador" => "af2-cln_65p1175" ] ] ] 4 => array:3 [ "nombre" => "Hossein" "apellidos" => "Nahrevanian" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "IV" "identificador" => "af4-cln_65p1175" ] ] ] 5 => array:3 [ "nombre" => "Ismaeil" "apellidos" => "Farrokhi" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "I" "identificador" => "af1-cln_65p1175" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Neuroscience Research Center, Mashhad University of Medical Sciences (MUMS), Mashhad, Iran" "etiqueta" => "I" "identificador" => "af1-cln_65p1175" ] 1 => array:3 [ "entidad" => "Department of Physiology, School of Medicine, Mashhad University of Medical Sciences (MUMS), Mashhad, Iran" "etiqueta" => "II" "identificador" => "af2-cln_65p1175" ] 2 => array:3 [ "entidad" => "Immunology Research Center, Buali Institute, Mashhad University of Medical Sciences (MUMS), Mashhad, Iran" "etiqueta" => "III" "identificador" => "af3-cln_65p1175" ] 3 => array:3 [ "entidad" => "Department of Parasitology, Pasteur Institute of Iran, Tehran, Iran" "etiqueta" => "IV" "identificador" => "af4-cln_65p1175" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "c1-cln_65p1175" "etiqueta" => "*" "correspondencia" => "Tel.: 0511-8828564-5" ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig3-cln_65p1175" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 313 "Ancho" => 498 "Tamanyo" => 16353 ] ] "descripcion" => array:1 [ "en" => "Comparison of the length of the swimming path (cm) between methimazole-treated animals and controls using a repeated measure ANOVA. The length of the swimming path in the offspring of the methimazole group was significantly higher than that of controls (P<0.001). Data are shown as mean ± SEM of seven animals per group." ] ] ] "textoCompleto" => "INTRODUCTIONMany studies have shown a significant role for thyroid hormones in the development and maturation of the mammalian central nervous system.<a class="elsevierStyleCrossRefs" href="#bib1">1,2</a> These hormones regulate axonal and dendritic growth and synapse formation.<a class="elsevierStyleCrossRef" href="#bib3">3</a> Growth retardation and severe cognitive impairment are known complications following thyroid hormone deficiency in the prenatal and neonatal periods.<a class="elsevierStyleCrossRef" href="#bib4">4</a> It has been shown that hypothyroidism is associated with changes in gene expression in both the central and peripheral nervous system.<a class="elsevierStyleCrossRef" href="#bib5">5</a> The inability to produce long-term potentiation (LTP) in the rat hippocampus and impaired learning and memory in both rats and humans are among the functional consequences of hypothyroidism.<a class="elsevierStyleCrossRef" href="#bib6">6</a> Other studies have suggested that hypothyroidism affects behavioral conditions and is accompanied by emotional symptoms, including lethargy and dysphoria.<a class="elsevierStyleCrossRefs" href="#bib7">7-11</a> The results of other studies have shown that several cognitive deficits, including attention and memory processing deficits, general intelligence and visual-spatial skills, are induced by hypothyroidism.<a class="elsevierStyleCrossRefs" href="#bib9">9,10</a> Hypothyroidism has a lesser effect on auditory attention, motor skills, language and set-shifting.<a class="elsevierStyleCrossRefs" href="#bib7">7,10,12</a> In addition, there is evidence indicating that even subclinical hypothyroidism is associated with depressive symptoms and cognitive impairment.<a class="elsevierStyleCrossRef" href="#bib13">13</a>Nitric oxide (NO), a free radical gas, is known to play critical roles in biologic systems;<a class="elsevierStyleCrossRef" href="#bib14">14</a> It acts like a diffusible intercellular signaling molecule in the brain and spinal cord.<a class="elsevierStyleCrossRef" href="#bib15">15</a> NO synthase (NOS) is the enzyme that produces NO from l-arginine. NO can act as an important mediator in synaptic plasticity, LTP and the consolidation of LTP.<a class="elsevierStyleCrossRefs" href="#bib16">16-18</a> In addition, there are reports that suggest a relationship between NMDA (N-methyl-D-aspartate)receptors and the NO system in learning and memory.<a class="elsevierStyleCrossRefs" href="#bib19">19,20</a> Several studies have shown that NOS inhibitors impair the consolidation of memory<a class="elsevierStyleCrossRefs" href="#bib21">21,22</a> and block the induction of LTP.<a class="elsevierStyleCrossRefs" href="#bib21">21-24</a> There is, however, some evidence showing that l-arginine, an NO precursor, improves memory formation and reverses the effect of NOS inhibition.<a class="elsevierStyleCrossRef" href="#bib25">25</a> There are also reports indicating that NO donors activate both LTP and long-term depression.<a class="elsevierStyleCrossRefs" href="#bib23">23,26</a> These results suggest the involvement of NO in learning and memory processes.The relationship between thyroid hormones and the NO system has been well documented.<a class="elsevierStyleCrossRefs" href="#bib23">23,26-28</a> There is evidence that thyroid hormones are involved in regulating NO synthase gene expression in the brain. Considering the aforementioned findings, this study aimed to investigate the effect of hypothyroidism induced during the neonatal and juvenile periods on learning and memory of offspring and on NO metabolite concentrations in the hippocampus.MATERIALS AND METHODSAnimals and treatmentsTwenty pregnant female Wistar rats (8 weeks old and weighing 200 ± 20 g) were kept in separate cages at 22 ± 2 °C in a room with a 12 h light/dark cycle (light on at 7:00 am). Offspring were randomly divided into two groups and treated according to the experimental protocol from the first day after birth through the first two months of life. Rats in the control group received normal drinking water, whereas the second group received the same drinking water supplemented with 0.03% methimazole (Sigma, USA) to induce hypothyroidism.<a class="elsevierStyleCrossRef" href="#bib29">29</a> After 60 days, seven male offspring of each group were randomly selected and tested in the Morris water maze (MWM).In the methimazole group, hypothyroidism was confirmed by testing serum thyroxine concentration levels using the radioimmunoassay method (Daisource, T4- RIA - CT).Animal handling and all related procedures were carried out in accordance with the rules set by the Mashhad University of Medical Sciences Ethical Committee.Morris water maze apparatus and proceduresA circular black pool (136 cm diameter, 60 cm high, 30 cm deep) was filled with water (20–24 °C). A circular platform (10 cm diameter, 28 cm high) was placed within the pool and was submerged approximately 2 cm below the surface of the water in the center of the southwest quadrant. Outside the maze, fixed visual cues were present at various locations around the room (i.e., a computer, hardware and posters). An infrared camera was mounted above the center of the maze and an infrared LED was attached to each rat for motion tracking. Before each experiment, each rat was handled daily for 3 days and habituated to the water maze for 30 sec without a platform. The animals performed four trials on each of the eight consecutive days, and each trial began with the rat being placed in the pool and released facing the side wall at one of four positions (the boundaries of the four quadrants, labeled North (N), East (E), South (S) and West (W). Release positions were randomly predetermined. For each trial, the rat was allowed to swim until it found and remained on the platform for 15 seconds. If 60 seconds had passed and the animal had not found the platform, it was guided to the platform by the experimenter and allowed to stay on the platform for 15 sec. The rat was then removed from the pool, dried and placed in its holding bin for 5 min. The time latency to reach the platform and the length of the swimming path were recorded by a video tracking system.<a class="elsevierStyleCrossRefs" href="#bib29">29,32-34</a> On the ninth day, the platform was removed, and the animals were allowed to swim for 60 s. The time spent in the target quadrant (Q1) and the traveled path were compared between groups. All measurements were performed during the first half of the light cycle.Biochemical assessmentAfter the last session of the MWM test, blood samples were taken from all rats to determine hypothyroidism status and to measure the NO metabolites NO2 and NO3 (Griess reagent method). The animals were then sacrificed, and hippocampi were removed and submitted to NO metabolite measurements in the tissue. The Griess reaction was adapted to assay nitrates as previously described.<a class="elsevierStyleCrossRef" href="#bib35">35</a> Briefly, standard curves for nitrates (Sigma, St. Louis, Missouri, USA) were prepared, and samples (50 µl plasma and 100 µl tissue suspension) were added to the Griess reagent. The proteins were subsequently precipitated by the addition of 50 µl of 10% trichloroacetic acid (Sigma). The contents were then vortex-mixed and centrifuged, and the supernatants were transferred to a 96-well flat-bottomed microplate. Absorbance was read at 520 nm using a microplate reader, and final values were calculated from standard calibration plots.<a class="elsevierStyleCrossRef" href="#bib36">36</a>Statistical analysisAll data are expressed as mean ± SEM. Swim time latency and the length of the traveled path over the eight training days were analyzed by repeated measures analysis of variance ANOVA. The time spent in the target quadrant (Q1) and the length of the swimming path in this quadrant was compared using unpaired t-tests. Comparison of serum thyroxin levels and plasma levels of NO metabolites was carried out using unpaired t-tests. The criterion for statistical significance was P<0.05.RESULTSThe serum thyroxine concentration in methimazole-treated animals was significantly lower compared to that of control animals (P<0.01; <a class="elsevierStyleCrossRef" href="#fig1-cln_65p1175">Fig. 1</a>). In addition, the time latency and the length of the swimming path over the eight training days were significantly higher in offspring of the methimazole group (P<0.001; <a class="elsevierStyleCrossRefs" href="#fig2-cln_65p1175">Figs. 2 and 3</a>, respectively). In the probe trial, the time spent in the target quadrant (Q1) by the offspring of the methimazole group was significantly lower compared to controls (P<0.001; <a class="elsevierStyleCrossRef" href="#fig4-cln_65p1175">Fig. 4A</a>). Furthermore, the length of the traveled path in Q1 by animals in the methimazole group was shorter than for those in the control group (P<0.001; <a class="elsevierStyleCrossRef" href="#fig4-cln_65p1175">Fig. 4B</a>). There were no significant differences in the time spent or the length of the swim path in the other quadrants between the two groups. In addition, there were no significant differences between the plasma concentrations of NO2 or NO3; however, the concentration of NO metabolites in the hippocampi of the methimazole group offspring was higher than that of the control animals (P<0.05; <a class="elsevierStyleCrossRef" href="#fig5-cln_65p1175">Figs. 5A and 5B</a>, respectively).<elsevierMultimedia ident="fig1-cln_65p1175"></elsevierMultimedia><elsevierMultimedia ident="fig2-cln_65p1175"></elsevierMultimedia><elsevierMultimedia ident="fig3-cln_65p1175"></elsevierMultimedia><elsevierMultimedia ident="fig4-cln_65p1175"></elsevierMultimedia><elsevierMultimedia ident="fig5-cln_65p1175"></elsevierMultimedia>DISCUSSIONNeonatal hypothyroidism has been clearly shown to be related to cognitive dysfunction.<a class="elsevierStyleCrossRefs" href="#bib9">9-11,37,38</a> For example, studies in humans have shown that a temporal deficiency in thyroid hormones during developmental periods impairs cognitive functions such as attention, learning and memory.<a class="elsevierStyleCrossRef" href="#bib39">39</a> Experimental hypothyroidism in developing rats has also been shown to result in impaired learning and memory.<a class="elsevierStyleCrossRefs" href="#bib40">40,41</a> In this study we induced hypothyroidism in rats, resulting in impaired learning and memory during the neonatal and juvenile periods.Hypothyroidism impairs hippocampal-dependent learning and short- and long-term memory.<a class="elsevierStyleCrossRefs" href="#bib42">42,43</a> In addition, hypothyroidism impairs early and late phases of LTP.<a class="elsevierStyleCrossRef" href="#bib44">44</a> The exact mechanisms underlying the induced deficits in memory and LTP have not been elucidated. Many studies have demonstrated that cognitive dysfunction in hypothyroidism is likely due to abnormal brain development, diminished inter-neuronal connectivity and, in particular, impaired synaptic plasticity in the hippocampus.<a class="elsevierStyleCrossRef" href="#bib45">45</a> It has been shown that maturation and function of the hippocampus are dependent on thyroid hormones.<a class="elsevierStyleCrossRef" href="#bib43">43</a> Transient hypothyroidism has even been shown to impair synaptic transmission and plasticity in the adult hippocampus.<a class="elsevierStyleCrossRefs" href="#bib46">46,47</a> It has also been reported that impairment of LTP and memory due to hypothyroidism correlates with changes in c-jun and c-fos protein expression and extracellular signal regulated kinases (ERKs) levels in the hippocampus during crucial periods of brain development.<a class="elsevierStyleCrossRefs" href="#bib48">48,49</a> Changes in the expression of other proteins such as synapsin I, synaptotagmin I, and syntaxin may also be involved in hypothyroidism-induced memory deficits.<a class="elsevierStyleCrossRef" href="#bib50">50</a> It has also been suggested that thyroid hormone deficiency results in changes in brain regions such as the dorsal hippocampal-mPFC pathway and changes in the glutamate release, which can lead to cognitive disturbances.<a class="elsevierStyleCrossRefs" href="#bib51">51-53</a> Moreover, hypothyroidism has been shown to induce oxidative stress in the hippocampus.<a class="elsevierStyleCrossRef" href="#bib54">54</a>The relationship between oxidative stress, neuronal damage and cognitive dysfunction has been well documented.<a class="elsevierStyleCrossRefs" href="#bib55">55-58</a> In addition, it is well known that neonatal hypothyroidism is accompanied by a delay in myelinogenesis and a decrease in the number of myelinated axons.<a class="elsevierStyleCrossRefs" href="#bib59">59,60</a> In the present study, we have shown that a deficiency of thyroid hormones during lactation and in the neonatal period could impair learning of offspring in the MWM test. The animals in the hypothyroid group had significantly higher time latency to find the platform during every day of training (<a class="elsevierStyleCrossRef" href="#fig2-cln_65p1175">Fig. 2</a>), indicating a deleterious effect of the lack of thyroid hormones on spatial learning processes. The results presented here also confirm that methimazole-induced hypothyroidism during the neonatal and juvenile periods impairs spatial memory given that the animals in the hypothyroid group spent less time in the target quadrant compared to the control group when tested on the ninth day (probe trial; <a class="elsevierStyleCrossRef" href="#fig4-cln_65p1175">Fig. 4</a>). The results of the present study are consistent with findings from our previous study, in which we found an impairment in the MWM in adult rats with methimazole-induced hypothyroidism over a 180-day period.<a class="elsevierStyleCrossRef" href="#bib29">29</a> It has also been reported that treatment of thyroidectomized adult rats with thyroxine improved radial arm water maze tasks and LTP in the CA1 area of the hippocampus.<a class="elsevierStyleCrossRef" href="#bib61">61</a> These researchers showed that cyclic-AMP response element binding protein (CREB) and mitogen-activated protein kinases (MAPKs) may contribute to the impairment of hippocampal-dependent learning and memory; however, the authors suggested that calcium-calmodulin-dependent NOS and brain-derived neurotrophic factor (BDNF) may not have roles in this process.<a class="elsevierStyleCrossRef" href="#bib61">61</a>The free radical gas NO has been associated with different forms of learning and memory and in several forms of synaptic plasticity thought to be involved in memory formation. This association has been widely confirmed via pharmacological studies, which have utilized a variety of substances and methods to inhibit NO synthase. Results from knockout studies in mice have revealed that mice deficient in eNOS and nNOS expression exhibit impaired LTP.<a class="elsevierStyleCrossRefs" href="#bib20">20,61-65</a> It has also been reported that nitrergic neurons, the neurons that produce NO, increase in number after spatial learning in rats, which can be interpreted as upregulation induced by behavioral training.<a class="elsevierStyleCrossRef" href="#bib63">63</a> This evidence implies that NO participates in the memory process.<a class="elsevierStyleCrossRef" href="#bib63">63</a> In contrast to these results, which indicate a positive role for NO in learning and memory, it has been shown that inhibition of NOS does not prevent the induction of LTP or impair spatial memory. Thus, these findings suggest that NO does not play an important role in memory and learning.<a class="elsevierStyleCrossRef" href="#bib66">66</a> Here, we have examined the relationship between NO and hypothyroidism. We found that both hypothyroidism and impaired MWM performance were present in the methimazole group.We also found a significant increase in hippocampal NO metabolites in the methimazole-treated group. The association between hypothyroidism and increased NO levels in the brain has been previously investigated. One study indicated that maternal thyroid hormone deficiency during the early gestational period resulted in a significant elevation in neuronal nitric oxide synthase (nNOS) expression with associated neuronal death in the embryonic rat neocortex.<a class="elsevierStyleCrossRef" href="#bib67">67</a> It has also been shown that nNOS acts as a negative regulator of neurogenesis.<a class="elsevierStyleCrossRefs" href="#bib67">67-69</a> The inhibitory effect of NO on neurogenesis may be due to a reduction in the proliferative potential of neural precursor cells<a class="elsevierStyleCrossRef" href="#bib70">70</a> or a defect in the survival of newly generated neurons after differentiation.<a class="elsevierStyleCrossRef" href="#bib71">71</a> There is evidence showing that thyroid hormone deficiency increases cell death.<a class="elsevierStyleCrossRef" href="#bib67">67</a> The relationship between nNOS and poor survival of neurons and thyroid hormone deprivation has also been suggested.<a class="elsevierStyleCrossRef" href="#bib67">67</a> It has been shown that even a moderate and transient decrease in maternal thyroxine significantly increases nNOS expression, which is reversible by hormone replacement.<a class="elsevierStyleCrossRefs" href="#bib67">67,72</a> In contrast, another report showed that propylthiouracil (PTU)-treated animals exhibited reduced NOS activity that could be rescued by T4 administration.<a class="elsevierStyleCrossRef" href="#bib72">72</a>It has also been shown that hypothyroidism changes the pattern of NOS activity in a tissue-dependent manner. NOS activity was significantly increased in both the right and left ventricles, but it was significantly reduced in the aorta, whereas in the vena cava, renal cortex and medulla, the enzyme activity was non-significantly higher compared to controls.<a class="elsevierStyleCrossRef" href="#bib73">73</a> The results of the present study also showed no difference in NO metabolites between the hypothyroid group and controls in peripheral blood samples. It might be suggested that an increase in NO in the hippocampus is due to stimulatory effects of thyroid hormone deprivation on nNOS activity. Although some studies have suggested NO to be a neurotransmitter that plays an important role in enhancing memory, others have claimed that its excess in the hippocampus may result in memory deficits.<a class="elsevierStyleCrossRef" href="#bib74">74</a> NO has been shown to have bidirectional effects. Under normal physiological conditions, it acts as an important neuronal messenger; however, when NO increases to high concentrations, it has a toxic effect that can lead to neuronal death.<a class="elsevierStyleCrossRefs" href="#bib75">75-77</a> A common example of the toxic effect of NO in the CNS is due to glutamate neurotransmission and the activation N-methyl-D-aspartate (NMDA) receptors, which leads to significant increases in intracellular calcium, followed by stimulation of neuronal NOS.<a class="elsevierStyleCrossRefs" href="#bib77">77,78</a>Finally, other findings have suggested selective enhancement of reactive oxygen species (ROS) and lipid peroxidation in the amygdala and hippocampus of rats after three weeks of treatment with methimazole. These authors showed a significant increase in NOS activity,<a class="elsevierStyleCrossRef" href="#bib54">54</a> suggesting a correlation between increased NOS activity and elevated oxidative stress. It may therefore be suggested that increased NO production in the hippocampus during hypothyroidism acts as an oxidative stressor, which may explain the deficits in learning and memory observed here.CONCLUSIONSIn this study, we found that hypothyroidism induced during the neonatal and juvenile periods resulted in impaired learning and memory of rats tested in the Morris water maze. In addition, we found an increase in NO metabolites in the hippocampus, suggesting that the impairment of memory in hypothyroidism may be due to increases in NOS and NO." "textoCompletoSecciones" => array:1 [ "secciones" => array:8 [ 0 => array:2 [ "identificador" => "xpalclavsec1581421" "titulo" => "KEYWORDS" ] 1 => array:2 [ "identificador" => "cesec10" "titulo" => "INTRODUCTION" ] 2 => array:3 [ "identificador" => "cesec20" "titulo" => "MATERIALS AND METHODS" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "cesec30" "titulo" => "Animals and treatments" ] 1 => array:2 [ "identificador" => "cesec40" "titulo" => "Morris water maze apparatus and procedures" ] 2 => array:2 [ "identificador" => "cesec50" "titulo" => "Biochemical assessment" ] 3 => array:2 [ "identificador" => "cesec60" "titulo" => "Statistical analysis" ] ] ] 3 => array:2 [ "identificador" => "cesec70" "titulo" => "RESULTS" ] 4 => array:2 [ "identificador" => "cesec80" "titulo" => "DISCUSSION" ] 5 => array:2 [ "identificador" => "cesec90" "titulo" => "CONCLUSIONS" ] 6 => array:2 [ "identificador" => "xack638839" "titulo" => "ACKNOWLEDGEMENTS" ] 7 => array:1 [ "titulo" => "REFERENCES" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2010-05-02" "fechaAceptado" => "2010-08-23" "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "KEYWORDS" "identificador" => "xpalclavsec1581421" "palabras" => array:5 [ 0 => "Hypothyroidism" 1 => "Learning" 2 => "Memory" 3 => "Nitric Oxide" 4 => "Offspring" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:2 [ "resumen" => "INTRODUCTION:Severe cognitive impairment follows thyroid hormone deficiency during the neonatal period. The role of nitric oxide (NO) in learning and memory has been widely investigated. METHODS:This study aimed to investigate the effect of hypothyroidism during neonatal and juvenile periods on NO metabolites in the hippocampi of rats and on learning and memory. Animals were divided into two groups and treated for 60 days from the first day of lactation. The control group received regular water, whereas animals in a separate group were given water supplemented with 0.03% methimazole to induce hypothyroidism. Male offspring were selected and tested in the Morris water maze. Samples of blood were collected to measure the metabolites of NO, NO2, NO3 and thyroxine. The animals were then sacrificed, and their hippocampi were removed to measure the tissue concentrations of NO2 and NO3. DISCUSSION:Compared to the control group's offspring, serum thyroxine levels in the methimazole group's offspring were significantly lower (P<0.01). In addition, the swim distance and time latency were significantly higher in the methimazole group (P<0.001), and the time spent by this group in the target quadrant (Q1) during the probe trial was significantly lower (P<0.001). There was no significant difference in the plasma levels of NO metabolites between the two groups; however, significantly higher NO metabolite levels in the hippocampi of the methimazole group were observed compared to controls (P<0.05). CONCLUSION:These results suggest that the increased NO level in the hippocampus may play a role in the learning and memory deficits observed in childhood hypothyroidism; however, the precise underlying mechanism(s) remains to be elucidated." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "ceabs10" "titulo" => "INTRODUCTION:" ] 1 => array:2 [ "identificador" => "ceabs20" "titulo" => "METHODS:" ] 2 => array:2 [ "identificador" => "ceabs30" "titulo" => "DISCUSSION:" ] 3 => array:2 [ "identificador" => "ceabs40" "titulo" => "CONCLUSION:" ] ] ] ] "multimedia" => array:5 [ 0 => array:7 [ "identificador" => "fig1-cln_65p1175" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 221 "Ancho" => 478 "Tamanyo" => 13979 ] ] "descripcion" => array:1 [ "en" => "Serum thyroxine concentrations (µg/dl) in offspring of methimazole and control groups. The animals in the control group received regular drinking water, whereas the methimazole group received the water supplemented with 0.03% methimazole. Data are shown as mean ± SEM (n = 7 in each group). ∗∗P<0.01 compared to controls." ] ] 1 => array:7 [ "identificador" => "fig2-cln_65p1175" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 366 "Ancho" => 531 "Tamanyo" => 16872 ] ] "descripcion" => array:1 [ "en" => "Comparison of swim time latency (sec) to find the platform between offspring of the methimazole and control groups. The latency was significantly higher in offspring of rats in the methimazole group compared to controls (P<0.001). Data are shown as mean ± SEM of seven animals per group." ] ] 2 => array:7 [ "identificador" => "fig3-cln_65p1175" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 313 "Ancho" => 498 "Tamanyo" => 16353 ] ] "descripcion" => array:1 [ "en" => "Comparison of the length of the swimming path (cm) between methimazole-treated animals and controls using a repeated measure ANOVA. The length of the swimming path in the offspring of the methimazole group was significantly higher than that of controls (P<0.001). Data are shown as mean ± SEM of seven animals per group." ] ] 3 => array:7 [ "identificador" => "fig4-cln_65p1175" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 618 "Ancho" => 441 "Tamanyo" => 41725 ] ] "descripcion" => array:1 [ "en" => "The results of the time (sec) spent (4A) and the length of the swimming path (cm) (4B) in each quadrant during the probe trial on day 9 (24 h after the last secession of learning). Data are shown as mean ± SEM of seven animals per group. The platform was removed, and the time spent and the length of the swim path in the target quadrant (Q1) was compared between the groups. The time spent and the length of the swim path in Q1 by the offspring of the methimazole group was significantly lower compared to controls. ∗∗∗P<0.001 compared to controls." ] ] 4 => array:7 [ "identificador" => "fig5-cln_65p1175" "etiqueta" => "Figure 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr5.jpeg" "Alto" => 475 "Ancho" => 431 "Tamanyo" => 34881 ] ] "descripcion" => array:1 [ "en" => "Comparison of plasma NO metabolite levels (A) and the concentrations of these metabolites in hippocampal tissue (B) between offspring of the methimazole and control groups. Data are shown as mean ± SEM of seven animals per group. There were no significant differences between the plasma concentrations of NO2 or NO3; however, the concentration of NO metabolites in the hippocampi of the methimazole group offspring was higher than that of the control animals. ∗P<0.05 compared to controls." ] ] ] "bibliografia" => array:2 [ "titulo" => "REFERENCES" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "cebibsec10" "bibliografiaReferencia" => array:78 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Thyroid hormones and nervous system development" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => """ PS Timiras \n \t\t\t\t\t\t\t\t """ 1 => """ EU Nzekwe \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1159/000242941" "Revista" => array:6 [ "tituloSerie" => "Biol Neonate" "fecha" => "1989" "volumen" => "55" "paginaInicial" => "376" "paginaFinal" => "385" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2663092" "web" => "Medline" ] ] ] ] 1 => array:2 [ "doi" => "10.1159/000242941" "WWW" => array:1 [ "link" => "10.1159/000242941" ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib2" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "T3 administration in adult hypothyroid mice modulates expression of proteins involved in striatal synaptic plasticity and improves motor behavior" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => """ J Vallortigara \n \t\t\t\t\t\t\t\t """ 1 => """ S Alfos \n \t\t\t\t\t\t\t\t """ 2 => """ J Micheau \n \t\t\t\t\t\t\t\t """ 3 => """ P Higueret \n \t\t\t\t\t\t\t\t """ 4 => """ V Enderlin \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1016/j.nbd.2008.05.015" "Revista" => array:6 [ "tituloSerie" => "Neurobiol Dis" "fecha" => "2008" "volumen" => "31" "paginaInicial" => "378" "paginaFinal" => "385" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18585460" "web" => "Medline" ] ] ] ] 1 => array:2 [ "doi" => "10.1016/j.nbd.2008.05.015" "WWW" => array:1 [ "link" => "10.1016/j.nbd.2008.05.015" ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib3" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Thyroid hormone enhances the formation of synapses between cultured neurons of rat cerebral cortex" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => """ R Hosoda \n \t\t\t\t\t\t\t\t """ 1 => """ K Nakayama \n \t\t\t\t\t\t\t\t """ 2 => """ M Kato-Negishi \n \t\t\t\t\t\t\t\t """ 3 => """ M Kawahara \n \t\t\t\t\t\t\t\t """ 4 => """ K Muramoto \n \t\t\t\t\t\t\t\t """ 5 => """ Y Kuroda \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:2 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Cell Mol Neurobiol" "fecha" => "2003" "volumen" => "23" "paginaInicial" => "895" "paginaFinal" => "906" ] ] 1 => array:1 [ "WWW" => array:1 [ "link" => "10.1023/B:CEMN.0000005318.53810.de" ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib4" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The role of thyroid hormones in prenatal and neonatal neurological development–current perspectives" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => """ SP Porterfield \n \t\t\t\t\t\t\t\t """ 1 => """ CE Hendrich \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/edrv-14-1-94" "Revista" => array:6 [ "tituloSerie" => "Endocr Rev" "fecha" => "1993" "volumen" => "14" "paginaInicial" => "94" "paginaFinal" => "106" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8491157" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib5" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effects of hypothyroidism induced by perinatal exposure to PTU on rat behavior and synaptic gene expression" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ K Kobayashi \n \t\t\t\t\t\t\t\t """ 1 => """ R Tsuji \n \t\t\t\t\t\t\t\t """ 2 => """ T Yoshioka \n \t\t\t\t\t\t\t\t """ 3 => """ M Kushida \n \t\t\t\t\t\t\t\t """ 4 => """ S Yabushita \n \t\t\t\t\t\t\t\t """ 5 => """ M Sasaki \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1016/j.tox.2005.04.012" "Revista" => array:6 [ "tituloSerie" => "Toxicology" "fecha" => "2005" "volumen" => "212" "paginaInicial" => "135" "paginaFinal" => "147" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15941614" "web" => "Medline" ] ] ] ] 1 => array:2 [ "doi" => "10.1016/j.tox.2005.04.012" "WWW" => array:1 [ "link" => "10.1016/j.tox.2005.04.012" ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib6" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Thyroid hormone regulation of N-methyl-D-aspartic acid receptor subunit mRNA expression in adult brain" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => """ PR Lee \n \t\t\t\t\t\t\t\t """ 1 => """ D Brady \n \t\t\t\t\t\t\t\t """ 2 => """ JI Koenig \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1046/j.1365-2826.2003.00959.x" "Revista" => array:6 [ "tituloSerie" => "J Neuroendocrinol" "fecha" => "2003" "volumen" => "15" "paginaInicial" => "87" "paginaFinal" => "92" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12535174" "web" => "Medline" ] ] ] ] 1 => array:2 [ "doi" => "10.1046/j.1365-2826.2003.00959.x" "WWW" => array:1 [ "link" => "10.1046/j.1365-2826.2003.00959.x" ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib7" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hypothyroidism and cognition: preliminary evidence for a specific defect in memory" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => """ LA Burmeister \n \t\t\t\t\t\t\t\t """ 1 => """ M Ganguli \n \t\t\t\t\t\t\t\t """ 2 => """ HH Dodge \n \t\t\t\t\t\t\t\t """ 3 => """ T Toczek \n \t\t\t\t\t\t\t\t """ 4 => """ ST DeKosky \n \t\t\t\t\t\t\t\t """ 5 => """ RD Nebes \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1089/10507250152741037" "Revista" => array:6 [ "tituloSerie" => "Thyroid" "fecha" => "2001" "volumen" => "11" "paginaInicial" => "1177" "paginaFinal" => "1185" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12186506" "web" => "Medline" ] ] ] ] 1 => array:2 [ "doi" => "10.1089/10507250152741037" "WWW" => array:1 [ "link" => "10.1089/10507250152741037" ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib8" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "[Is cognitive change related to hypothyroidism reversible with replacement therapy?]" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ C Capet \n \t\t\t\t\t\t\t\t """ 1 => """ A Jego \n \t\t\t\t\t\t\t\t """ 2 => """ P Denis \n \t\t\t\t\t\t\t\t """ 3 => """ D Noel \n \t\t\t\t\t\t\t\t """ 4 => """ I Clerc \n \t\t\t\t\t\t\t\t """ 5 => """ AC Cornier \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1016/s0248-8663(00)80022-3" "Revista" => array:6 [ "tituloSerie" => "Rev Med Interne" "fecha" => "2000" "volumen" => "21" "paginaInicial" => "672" "paginaFinal" => "678" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10989492" "web" => "Medline" ] ] ] ] 1 => array:2 [ "doi" => "10.1016/s0248-8663(00)80022-3" "WWW" => array:1 [ "link" => "10.1016/S0248-8663(00)80022-3" ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib9" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Thyroid hormones, brain function and cognition: a brief review" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => """ JW Smith \n \t\t\t\t\t\t\t\t """ 1 => """ AT Evans \n \t\t\t\t\t\t\t\t """ 2 => """ B Costall \n \t\t\t\t\t\t\t\t """ 3 => """ JW Smythe \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1016/s0149-7634(01)00037-9" "Revista" => array:6 [ "tituloSerie" => "Neurosci Biobehav Rev" "fecha" => "2002" "volumen" => "26" "paginaInicial" => "45" "paginaFinal" => "60" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11835983" "web" => "Medline" ] ] ] ] 1 => array:2 [ "doi" => "10.1016/s0149-7634(01)00037-9" "WWW" => array:1 [ "link" => "10.1016/S0149-7634(01)00037-9" ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib10" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Neurocognitive aspects of hypothyroidism" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => """ AT Dugbartey \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1001/archinte.158.13.1413" "Revista" => array:6 [ "tituloSerie" => "Arch Intern Med" "fecha" => "1998" "volumen" => "158" "paginaInicial" => "1413" "paginaFinal" => "1418" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9665349" "web" => "Medline" ] ] ] ] 1 => array:2 [ "doi" => "10.1001/archinte.158.13.1413" "WWW" => array:1 [ "link" => "10.1001/archinte.158.13.1413" ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib11" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Subclinical hypothyroidism: a review of neuropsychiatric aspects" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ JJ Haggerty Jr \n \t\t\t\t\t\t\t\t """ 1 => """ JC Garbutt \n \t\t\t\t\t\t\t\t """ 2 => """ DL Evans \n \t\t\t\t\t\t\t\t """ 3 => """ RN Golden \n \t\t\t\t\t\t\t\t """ 4 => """ C Pedersen \n \t\t\t\t\t\t\t\t """ 5 => """ JS Simon \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.2190/ADLY-1UU0-1A8L-HPXY" "Revista" => array:6 [ "tituloSerie" => "Int J Psychiatry Med" "fecha" => "1990" "volumen" => "20" "paginaInicial" => "193" "paginaFinal" => "208" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2203696" "web" => "Medline" ] ] ] ] 1 => array:2 [ "doi" => "10.2190/ADLY-1UU0-1A8L-HPXY" "WWW" => array:1 [ "link" => "10.2190/ADLY-1UU0-1A8L-HPXY" ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib12" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Verbal memory retrieval deficits associated with untreated hypothyroidism" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ KJ Miller \n \t\t\t\t\t\t\t\t """ 1 => """ TD Parsons \n \t\t\t\t\t\t\t\t """ 2 => """ PC Whybrow \n \t\t\t\t\t\t\t\t """ …3 ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1176/jnp.2007.19.2.132" "Revista" => array:6 [ "tituloSerie" => "J Neuropsychiatry Clin Neurosci" "fecha" => "2007" "volumen" => "19" "paginaInicial" => "132" "paginaFinal" => "136" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib13" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Subclinical hypothyroidism is mild thyroid failure and should be treated" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1210/jcem.86.10.7959" "Revista" => array:6 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "2001" "volumen" => "86" "paginaInicial" => "4585" "paginaFinal" => "4590" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.1210/jcem.86.10.7959" "WWW" => array:1 [ "link" => "10.1210/jc.86.10.4585" ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib14" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "7-Nitroindazole, a neuronal nitric oxide synthase inhibitor, impairs passive-avoidance and elevated plus-maze memory performance in rats" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ …6] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1016/j.pbb.2007.05.019" "Revista" => array:6 [ "tituloSerie" => "Pharmacol Biochem Behav" "fecha" => "2007" "volumen" => "87" "paginaInicial" => "434" "paginaFinal" => "443" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.1016/j.pbb.2007.05.019" "WWW" => array:1 [ "link" => "10.1016/j.pbb.2007.05.019" ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib15" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Nitric oxide and memory" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ …4] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1177/1073858403261226" "Revista" => array:6 [ "tituloSerie" => "Neuroscientist" "fecha" => "2004" "volumen" => "10" "paginaInicial" => "153" "paginaFinal" => "162" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.1177/1073858403261226" "WWW" => array:1 [ "link" => "10.1177/1073858403261226" ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib16" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The pharmacodynamics of L-arginine" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ …1] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/jn/137.6.1650S" "Revista" => array:7 [ "tituloSerie" => "J Nutr" "fecha" => "2007" "volumen" => "137" "numero" => "6 Suppl 2" "paginaInicial" => "1650S" "paginaFinal" => "1655S" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib17" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Changes in NMDA receptor/nitric oxide signaling pathway in the brain with aging" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1002/(SICI)1097-0029(19981001)43:1<68::AID-JEMT10>3.0.CO;2-W" "Revista" => array:6 [ "tituloSerie" => "Microsc Res Tech" "fecha" => "1998" "volumen" => "43" "paginaInicial" => "68" "paginaFinal" => "74" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.1002/(SICI)1097-0029(19981001)43:1<68::AID-JEMT10>3.0.CO;2-W" "WWW" => array:1 [ "link" => "10.1002/(SICI)1097-0029(19981001)43:1<68::AID-JEMT10>3.0.CO;2-W" ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib18" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Long-term deprivation of oestrogens by ovariectomy potentiates beta-amyloid-induced working memory deficits in rats" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:2 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Br J Pharmacol" "fecha" => "1999" "volumen" => "128" "paginaInicial" => "419" "paginaFinal" => "427" ] ] 1 => array:1 [ "WWW" => array:1 [ "link" => "10.1038/sj.bjp.0702811" ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib19" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Glutamate, nitric oxide and cell-cell signalling in the nervous system" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ …1] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1016/0166-2236(91)90022-m" "Revista" => array:6 [ "tituloSerie" => "Trends Neurosci" "fecha" => "1991" "volumen" => "14" "paginaInicial" => "60" "paginaFinal" => "67" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.1016/0166-2236(91)90022-m" "WWW" => array:1 [ "link" => "10.1016/0166-2236(91)90022-M" ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib20" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Nitric oxide as modulator of neuronal function" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1016/s0301-0082(00)00044-7" "Revista" => array:6 [ "tituloSerie" => "Prog Neurobiol" "fecha" => "2001" "volumen" => "64" "paginaInicial" => "51" "paginaFinal" => "68" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.1016/s0301-0082(00)00044-7" "WWW" => array:1 [ "link" => "10.1016/S0301-0082(00)00044-7" ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib21" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "NO synthesis inhibition decreases cortical ACh release and impairs retention of a conditioned response" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1016/s0006-8993(00)03148-6" "Revista" => array:6 [ "tituloSerie" => "Brain Res" "fecha" => "2001" "volumen" => "894" "paginaInicial" => "141" "paginaFinal" => "144" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.1016/s0006-8993(00)03148-6" "WWW" => array:1 [ "link" => "10.1016/S0006-8993(00)03148-6" ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib22" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effects of nitric oxide on passive avoidance learning in rats" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] "host" => array:2 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Int J Neurosci" "fecha" => "2004" "volumen" => "114" "paginaInicial" => "597" "paginaFinal" => "606" ] ] 1 => array:1 [ "WWW" => array:1 [ "link" => "10.1080/00207450490430471" ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib23" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Possible involvement of nitric oxide in long-term potentiation" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1016/0014-2999(91)90505-k" "Revista" => array:6 [ "tituloSerie" => "Eur J Pharmacol" "fecha" => "1991" "volumen" => "199" "paginaInicial" => "379" "paginaFinal" => "381" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.1016/0014-2999(91)90505-k" "WWW" => array:1 [ "link" => "10.1016/0014-2999(91)90505-K" ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib24" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "On the role of nitric oxide in hippocampal long-term potentiation" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1523/JNEUROSCI.23-05-01941.2003" "Revista" => array:6 [ "tituloSerie" => "J Neurosci" "fecha" => "2003" "volumen" => "23" "paginaInicial" => "1941" "paginaFinal" => "1948" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib25" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Involvement of hippocampal nitric oxide in spatial learning in the rat" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ …4] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1016/j.nlm.2008.04.010" "Revista" => array:6 [ "tituloSerie" => "Neurobiol Learn Mem" "fecha" => "2008" "volumen" => "90" "paginaInicial" => "413" "paginaFinal" => "419" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.1016/j.nlm.2008.04.010" "WWW" => array:1 [ "link" => "10.1016/j.nlm.2008.04.010" ] ] ] ] ] ] 25 => array:3 [ "identificador" => "bib26" "etiqueta" => "26" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Endogenous nitric oxide release required for long-term synaptic depression in the cerebellum" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1038/349326a0" "Revista" => array:6 [ "tituloSerie" => "Nature" "fecha" => "1991" "volumen" => "349" "paginaInicial" => "326" "paginaFinal" => "328" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.1038/349326a0" "WWW" => array:1 [ "link" => "10.1038/349326a0" ] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib27" "etiqueta" => "27" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Plasma concentration of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, is elevated in hyperthyroid patients" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:2 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "2002" "volumen" => "87" "paginaInicial" => "5636" "paginaFinal" => "5640" ] ] 1 => array:1 [ "WWW" => array:1 [ "link" => "10.1210/jc.2002-020905" ] ] ] ] ] ] 27 => array:3 [ "identificador" => "bib28" "etiqueta" => "28" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hypothalamic nitric oxide synthase gene expression is regulated by thyroid hormones" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ …4] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1210/endo.136.10.7545100" "Revista" => array:6 [ "tituloSerie" => "Endocrinology" "fecha" => "1995" "volumen" => "136" "paginaInicial" => "4182" "paginaFinal" => "4187" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.1210/endo.136.10.7545100" "WWW" => array:1 [ "link" => "10.1210/en.136.10.4182" ] ] ] ] ] ] 28 => array:3 [ "identificador" => "bib29" "etiqueta" => "29" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The beneficial effects of olibanum on memory deficit induced by hypothyroidism in adult rats tested in Morris water maze" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:2 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Arch Pharm Res" "fecha" => "2010" "volumen" => "33" "paginaInicial" => "463" "paginaFinal" => "468" ] ] 1 => array:1 [ "WWW" => array:1 [ "link" => "10.1007/s12272-010-0317-z" ] ] ] ] ] ] 29 => array:3 [ "identificador" => "bib30" "etiqueta" => "30" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of hypothyroidism on beta-adrenoceptor-mediated relaxation in the rat thoracic aortae. A time-dependent study" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1016/s1537-1891(02)00166-0" "Revista" => array:6 [ "tituloSerie" => "Vascul Pharmacol" "fecha" => "2002" "volumen" => "38" "paginaInicial" => "149" "paginaFinal" => "155" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.1016/s1537-1891(02)00166-0" "WWW" => array:1 [ "link" => "10.1016/S1537-1891(02)00166-0" ] ] ] ] ] ] 30 => array:3 [ "identificador" => "bib31" "etiqueta" => "31" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hypothyroidism and hyperthyroidism modulates Ras-MAPK intracellular pathway in rat thyroids" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:2 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Endocrine" "fecha" => "2007" "volumen" => "31" "paginaInicial" => "174" "paginaFinal" => "178" ] ] 1 => array:1 [ "WWW" => array:1 [ "link" => "10.1007/s12020-007-0029-4" ] ] ] ] ] ] 31 => array:3 [ "identificador" => "bib32" "etiqueta" => "32" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Vitamins E and C pretreatment prevents ovariectomy-induced memory deficits in water maze" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1016/j.nlm.2005.08.002" "Revista" => array:6 [ "tituloSerie" => "Neurobiol Learn Mem" "fecha" => "2005" "volumen" => "84" "paginaInicial" => "192" "paginaFinal" => "199" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.1016/j.nlm.2005.08.002" "WWW" => array:1 [ "link" => "10.1016/j.nlm.2005.08.002" ] ] ] ] ] ] 32 => array:3 [ "identificador" => "bib33" "etiqueta" => "33" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The effect of L-Arginin on Morris water maze tasks of ovariectomized rats" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ …6] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1556/APhysiol.97.2010.2.8" "Revista" => array:6 [ "tituloSerie" => "Acta Physiol Hung" "fecha" => "2010" "volumen" => "97" "paginaInicial" => "216" "paginaFinal" => "223" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.1556/APhysiol.97.2010.2.8" "WWW" => array:1 [ "link" => "10.1556/APhysiol.97.2010.2.8" ] ] ] ] ] ] 33 => array:3 [ "identificador" => "bib34" "etiqueta" => "34" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effects of treadmill running on mid-term memory and swim speed in the rat with Morris water maze test" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1016/j.jbmt.2007.05.004" "Revista" => array:6 [ "tituloSerie" => "J Bodyw Mov Ther" "fecha" => "2008" "volumen" => "12" "paginaInicial" => "72" "paginaFinal" => "75" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.1016/j.jbmt.2007.05.004" "WWW" => array:1 [ "link" => "10.1016/j.jbmt.2007.05.004" ] ] ] ] ] ] 34 => array:3 [ "identificador" => "bib35" "etiqueta" => "35" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Nitric oxide and reactive nitrogen intermediates during lethal and nonlethal strains of murine malaria" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1046/j.1365-3024.2001.00406.x" "Revista" => array:6 [ "tituloSerie" => "Parasite Immunol" "fecha" => "2001" "volumen" => "23" "paginaInicial" => "491" "paginaFinal" => "501" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.1046/j.1365-3024.2001.00406.x" "WWW" => array:1 [ "link" => "10.1046/j.1365-3024.2001.00406.x" ] ] ] ] ] ] 35 => array:3 [ "identificador" => "bib36" "etiqueta" => "36" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Antileishmanial effects of trinitroglycerin in BALB/C mice infected with Leishmania major via nitric oxide pathway" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ …6] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.3347/kjp.2009.47.2.109" "Revista" => array:6 [ "tituloSerie" => "Korean J Parasitol" "fecha" => "2009" "volumen" => "47" "paginaInicial" => "109" "paginaFinal" => "115" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.3347/kjp.2009.47.2.109" "WWW" => array:1 [ "link" => "10.3347/kjp.2009.47.2.109" ] ] ] ] ] ] 36 => array:3 [ "identificador" => "bib37" "etiqueta" => "37" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Motor and cognitive development in children with congenital hypothyroidism: a long-term evaluation of the effects of neonatal treatment" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ …6] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1016/s0022-3476(05)83178-6" "Revista" => array:6 [ "tituloSerie" => "J Pediatr" "fecha" => "1994" "volumen" => "124" "paginaInicial" => "903" "paginaFinal" => "909" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.1016/s0022-3476(05)83178-6" "WWW" => array:1 [ "link" => "10.1016/S0022-3476(05)83178-6" ] ] ] ] ] ] 37 => array:3 [ "identificador" => "bib38" "etiqueta" => "38" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Age-dependent alterations of long-term synaptic plasticity in thyroid-deficient rats" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:2 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Hippocampus" "fecha" => "2003" "volumen" => "13" "paginaInicial" => "816" "paginaFinal" => "825" ] ] 1 => array:1 [ "WWW" => array:1 [ "link" => "10.1002/hipo.10132" ] ] ] ] ] ] 38 => array:3 [ "identificador" => "bib39" "etiqueta" => "39" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Syndrome of resistance to thyroid hormone: insights into thyroid hormone action" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3181/00379727-211-43951" "Revista" => array:6 [ "tituloSerie" => "Proc Soc Exp Biol Med" "fecha" => "1996" "volumen" => "211" "paginaInicial" => "49" "paginaFinal" => "61" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 39 => array:3 [ "identificador" => "bib40" "etiqueta" => "40" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hyperactivity and spatial maze learning impairment of adult rats with temporary neonatal hypothyroidism" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ …4] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1016/0892-0362(91)90077-a" "Revista" => array:6 [ "tituloSerie" => "Neurotoxicol Teratol" "fecha" => "1991" "volumen" => "13" "paginaInicial" => "317" "paginaFinal" => "322" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.1016/0892-0362(91)90077-a" "WWW" => array:1 [ "link" => "10.1016/0892-0362(91)90077-A" ] ] ] ] ] ] 40 => array:3 [ "identificador" => "bib41" "etiqueta" => "41" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "An unliganded thyroid hormone receptor causes severe neurological dysfunction" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1073/pnas.051454698" "Revista" => array:6 [ "tituloSerie" => "Proc Natl Acad Sci U S A" "fecha" => "2001" "volumen" => "98" "paginaInicial" => "3998" "paginaFinal" => "4003" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.1073/pnas.051454698" "WWW" => array:1 [ "link" => "10.1073/pnas.051454698" ] ] ] ] ] ] 41 => array:3 [ "identificador" => "bib42" "etiqueta" => "42" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Adverse effect of the combination of hypothyroidism and chronic psychosocial stress on hippocampus-dependent memory in rats" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1016/j.bbr.2004.04.003" "Revista" => array:6 [ "tituloSerie" => "Behav Brain Res" "fecha" => "2004" "volumen" => "155" "paginaInicial" => "77" "paginaFinal" => "84" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.1016/j.bbr.2004.04.003" "WWW" => array:1 [ "link" => "10.1016/j.bbr.2004.04.003" ] ] ] ] ] ] 42 => array:3 [ "identificador" => "bib43" "etiqueta" => "43" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hypothyroidism impairs late LTP in CA1 region but not in dentate gyrus of the intact rat hippocampus: MAPK involvement" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] "host" => array:2 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Hippocampus" "fecha" => "2004" "volumen" => "14" "paginaInicial" => "40" "paginaFinal" => "45" ] ] 1 => array:1 [ "WWW" => array:1 [ "link" => "10.1002/hipo.10165" ] ] ] ] ] ] 43 => array:3 [ "identificador" => "bib44" "etiqueta" => "44" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Nicotine reverses adult-onset hypothyroidism-induced impairment of learning and memory: Behavioral and electrophysiological studies" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ …4] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1002/jnr.21014" "Revista" => array:6 [ "tituloSerie" => "J Neurosci Res" "fecha" => "2006" "volumen" => "84" "paginaInicial" => "944" "paginaFinal" => "953" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.1002/jnr.21014" "WWW" => array:1 [ "link" => "10.1002/jnr.21014" ] ] ] ] ] ] 44 => array:3 [ "identificador" => "bib45" "etiqueta" => "45" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Thyroid hormone and development of the rat hippocampus: cell acquisition in the dentate gyrus" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1016/0306-4522(86)90134-x" "Revista" => array:6 [ "tituloSerie" => "Neuroscience" "fecha" => "1986" "volumen" => "19" "paginaInicial" => "1207" "paginaFinal" => "1216" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.1016/0306-4522(86)90134-x" "WWW" => array:1 [ "link" => "10.1016/0306-4522(86)90134-X" ] ] ] ] ] ] 45 => array:3 [ "identificador" => "bib46" "etiqueta" => "46" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Alterations in synaptic transmission and plasticity in area CA1 of adult hippocampus following developmental hypothyroidism" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ …1] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1016/j.devbrainres.2003.09.018" "Revista" => array:6 [ "tituloSerie" => "Brain Res Dev Brain Res" "fecha" => "2004" "volumen" => "148" "paginaInicial" => "11" "paginaFinal" => "18" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.1016/j.devbrainres.2003.09.018" "WWW" => array:1 [ "link" => "10.1016/j.devbrainres.2003.09.018" ] ] ] ] ] ] 46 => array:3 [ "identificador" => "bib47" "etiqueta" => "47" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Propylthiouracil (PTU)-induced hypothyroidism in the developing rat impairs synaptic transmission and plasticity in the dentate gyrus of the adult hippocampus" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1016/s0165-3806(03)00191-3" "Revista" => array:6 [ "tituloSerie" => "Brain Res Dev Brain Res" "fecha" => "2003" "volumen" => "145" "paginaInicial" => "19" "paginaFinal" => "29" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.1016/s0165-3806(03)00191-3" "WWW" => array:1 [ "link" => "10.1016/S0165-3806(03)00191-3" ] ] ] ] ] ] 47 => array:3 [ "identificador" => "bib48" "etiqueta" => "48" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Congenital iodine deficiency and hypothyroidism impair LTP and decrease C-fos and C-jun expression in rat hippocampus" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ …6] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1016/j.neuro.2005.03.003" "Revista" => array:6 [ "tituloSerie" => "Neurotoxicology" "fecha" => "2005" "volumen" => "26" "paginaInicial" => "417" "paginaFinal" => "426" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.1016/j.neuro.2005.03.003" "WWW" => array:1 [ "link" => "10.1016/j.neuro.2005.03.003" ] ] ] ] ] ] 48 => array:3 [ "identificador" => "bib49" "etiqueta" => "49" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Impairment in short-term but enhanced long-term synaptic potentiation and ERK activation in adult hippocampal area CA1 following developmental thyroid hormone insufficiency" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1093/toxsci/kfi095" "Revista" => array:6 [ "tituloSerie" => "Toxicol Sci" "fecha" => "2005" "volumen" => "85" "paginaInicial" => "647" "paginaFinal" => "656" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.1093/toxsci/kfi095" "WWW" => array:1 [ "link" => "10.1093/toxsci/kfi095" ] ] ] ] ] ] 49 => array:3 [ "identificador" => "bib50" "etiqueta" => "50" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Thyroid hormone regulates neurotransmitter release in neonatal rat hippocampus" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ …4] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1016/s0306-4522(01)00541-3" "Revista" => array:6 [ "tituloSerie" => "Neuroscience" "fecha" => "2002" "volumen" => "110" "paginaInicial" => "19" "paginaFinal" => "28" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.1016/s0306-4522(01)00541-3" "WWW" => array:1 [ "link" => "10.1016/S0306-4522(01)00541-3" ] ] ] ] ] ] 50 => array:3 [ "identificador" => "bib51" "etiqueta" => "51" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Decreased glutamate release during hypothyroidism may contribute to protection in cerebral ischemia" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1006/exnr.1994.1135" "Revista" => array:6 [ "tituloSerie" => "Exp Neurol" "fecha" => "1994" "volumen" => "128" "paginaInicial" => "260" "paginaFinal" => "265" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.1006/exnr.1994.1135" "WWW" => array:1 [ "link" => "10.1006/exnr.1994.1135" ] ] ] ] ] ] 51 => array:3 [ "identificador" => "bib52" "etiqueta" => "52" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Adult-onset hypothyroidism impairs paired-pulse facilitation and longterm potentiation of the rat dorsal hippocampo-medial prefrontal cortex pathway in vivo" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1016/j.brainres.2006.04.042" "Revista" => array:6 [ "tituloSerie" => "Brain Res" "fecha" => "2006 22" "volumen" => "1096" "paginaInicial" => "53" "paginaFinal" => "60" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.1016/j.brainres.2006.04.042" "WWW" => array:1 [ "link" => "10.1016/j.brainres.2006.04.042" ] ] ] ] ] ] 52 => array:3 [ "identificador" => "bib53" "etiqueta" => "53" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Expression of vesicular glutamate transporter-2 in gonadotropin-releasing hormone neurons of the adult male rat" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ …4] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1210/en.2004-0589" "Revista" => array:6 [ "tituloSerie" => "Endocrinology" "fecha" => "2004" "volumen" => "145" "paginaInicial" => "4018" "paginaFinal" => "4021" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.1210/en.2004-0589" "WWW" => array:1 [ "link" => "10.1210/en.2004-0589" ] ] ] ] ] ] 53 => array:3 [ "identificador" => "bib54" "etiqueta" => "54" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hypothyroidism induces selective oxidative stress in amygdala and hippocampus of rat" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1007/s11011-008-9099-0" "Revista" => array:6 [ "tituloSerie" => "Metab Brain Dis" "fecha" => "2008" "volumen" => "23" "paginaInicial" => "275" "paginaFinal" => "287" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.1007/s11011-008-9099-0" "WWW" => array:1 [ "link" => "10.1007/s11011-008-9099-0" ] ] ] ] ] ] 54 => array:3 [ "identificador" => "bib55" "etiqueta" => "55" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Biomarkers in Alzheimer's disease: past, present and future" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.2217/bmm.09.86" "Revista" => array:6 [ "tituloSerie" => "Biomark Med" "fecha" => "2010" "volumen" => "4" "paginaInicial" => "15" "paginaFinal" => "26" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.2217/bmm.09.86" "WWW" => array:1 [ "link" => "10.2217/bmm.09.86" ] ] ] ] ] ] 55 => array:3 [ "identificador" => "bib56" "etiqueta" => "56" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Oxidative damage and cognitive dysfunction: antioxidant treatments to promote healthy brain aging" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ …1] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1007/s11064-008-9808-4" "Revista" => array:6 [ "tituloSerie" => "Neurochem Res" "fecha" => "2009" "volumen" => "34" "paginaInicial" => "670" "paginaFinal" => "678" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.1007/s11064-008-9808-4" "WWW" => array:1 [ "link" => "10.1007/s11064-008-9808-4" ] ] ] ] ] ] 56 => array:3 [ "identificador" => "bib57" "etiqueta" => "57" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pathophysiology of neuronal energy crisis in Alzheimer's disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ …1] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1159/000113681" "Revista" => array:6 [ "tituloSerie" => "Neurodegener Dis" "fecha" => "2008" "volumen" => "5" "paginaInicial" => "126" "paginaFinal" => "132" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.1159/000113681" "WWW" => array:1 [ "link" => "10.1159/000113681" ] ] ] ] ] ] 57 => array:3 [ "identificador" => "bib58" "etiqueta" => "58" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Recent advances in our understanding of neurodegeneration" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ …1] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1007/s00702-009-0240-y" "Revista" => array:6 [ "tituloSerie" => "J Neural Transm" "fecha" => "2009" "volumen" => "116" "paginaInicial" => "1111" "paginaFinal" => "1162" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.1007/s00702-009-0240-y" "WWW" => array:1 [ "link" => "10.1007/s00702-009-0240-y" ] ] ] ] ] ] 58 => array:3 [ "identificador" => "bib59" "etiqueta" => "59" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "2′3′Cyclic nucleotide 3′phosphodiesterase immunohistochemistry shows an impairment on myelin compaction in hypothyroid rats" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1016/s0736-5748(00)00028-9" "Revista" => array:6 [ "tituloSerie" => "Int J Dev Neurosci" "fecha" => "2000" "volumen" => "18" "paginaInicial" => "887" "paginaFinal" => "892" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.1016/s0736-5748(00)00028-9" "WWW" => array:1 [ "link" => "10.1016/S0736-5748(00)00028-9" ] ] ] ] ] ] 59 => array:3 [ "identificador" => "bib60" "etiqueta" => "60" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The development of the anterior commissure in normal and hypothyroid rats" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:2 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Brain Res Dev Brain Res" "fecha" => "1994" "volumen" => "81" "paginaInicial" => "293" "paginaFinal" => "308" ] ] 1 => array:1 [ "WWW" => array:1 [ "link" => "10.1016/0165-3806(94)90315-8" ] ] ] ] ] ] 60 => array:3 [ "identificador" => "bib61" "etiqueta" => "61" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Levothyroxin restores hypothyroidisminduced impairment of hippocampus-dependent learning and memory: Behavioral, electrophysiological, and molecular studies" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ …4] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1002/hipo.20476" "Revista" => array:6 [ "tituloSerie" => "Hippocampus" "fecha" => "2009" "volumen" => "19" "paginaInicial" => "66" "paginaFinal" => "78" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.1002/hipo.20476" "WWW" => array:1 [ "link" => "10.1002/hipo.20476" ] ] ] ] ] ] 61 => array:3 [ "identificador" => "bib62" "etiqueta" => "62" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "An inhibitor of nitric oxide synthesis prevents memory formation in the chick" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] "host" => array:2 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Neurosci Lett" "fecha" => "1992" "volumen" => "145" "paginaInicial" => "165" "paginaFinal" => "167" ] ] 1 => array:1 [ "WWW" => array:1 [ "link" => "10.1016/0304-3940(92)90012-V" ] ] ] ] ] ] 62 => array:3 [ "identificador" => "bib63" "etiqueta" => "63" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "On the respective roles of nitric oxide and carbon monoxide in long-term potentiation in the hippocampus" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ …4] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Learn Mem" "fecha" => "1998" "volumen" => "5" "paginaInicial" => "467" "paginaFinal" => "480" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 63 => array:3 [ "identificador" => "bib64" "etiqueta" => "64" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "On the respective roles of nitric oxide and carbon monoxide in long-term potentiation in the hippocampus" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ …4] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Learn Mem" "fecha" => "1999" "volumen" => "6" "paginaInicial" => "63" "paginaFinal" => "76" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 64 => array:3 [ "identificador" => "bib65" "etiqueta" => "65" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Nitric oxide and carbon monoxide produce activity-dependent long-term synaptic enhancement in hippocampus" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ …4] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1126/science.8100368" "Revista" => array:6 [ "tituloSerie" => "Science" "fecha" => "1993" "volumen" => "260" "paginaInicial" => "1946" "paginaFinal" => "1950" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.1126/science.8100368" "WWW" => array:1 [ "link" => "10.1126/science.8100368" ] ] ] ] ] ] 65 => array:3 [ "identificador" => "bib66" "etiqueta" => "66" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Inhibition of nitric oxide synthase does not prevent the induction of long-term potentiation in vivo" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1523/JNEUROSCI.14-12-07415.1994" "Revista" => array:6 [ "tituloSerie" => "J Neurosci" "fecha" => "1994" "volumen" => "14" "paginaInicial" => "7415" "paginaFinal" => "7425" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 66 => array:3 [ "identificador" => "bib67" "etiqueta" => "67" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Maternal thyroid hormone: a strong repressor of neuronal nitric oxide synthase in rat embryonic neocortex" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ …6] ] ] ] ] "host" => array:2 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Endocrinology" "fecha" => "2008" "volumen" => "149" "paginaInicial" => "4396" "paginaFinal" => "4401" ] ] 1 => array:1 [ "WWW" => array:1 [ "link" => "10.1210/en.2007-1617" ] ] ] ] ] ] 67 => array:3 [ "identificador" => "bib68" "etiqueta" => "68" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Nitric oxide acts in a positive feedback loop with BDNF to regulate neural progenitor cell proliferation and differentiation in the mammalian brain" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1016/s0012-1606(03)00120-9" "Revista" => array:6 [ "tituloSerie" => "Dev Biol" "fecha" => "2003 15" "volumen" => "258" "paginaInicial" => "319" "paginaFinal" => "333" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.1016/s0012-1606(03)00120-9" "WWW" => array:1 [ "link" => "10.1016/S0012-1606(03)00120-9" ] ] ] ] ] ] 68 => array:3 [ "identificador" => "bib69" "etiqueta" => "69" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Neuronal nitric oxide synthase (NOS-I) knockout increases the survival rate of neural cells in the hippocampus independently of BDNF" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ …6] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1016/j.mcn.2007.02.021" "Revista" => array:6 [ "tituloSerie" => "Mol Cell Neurosci" "fecha" => "2007" "volumen" => "35" "paginaInicial" => "261" "paginaFinal" => "271" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.1016/j.mcn.2007.02.021" "WWW" => array:1 [ "link" => "10.1016/j.mcn.2007.02.021" ] ] ] ] ] ] 69 => array:3 [ "identificador" => "bib70" "etiqueta" => "70" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Distribution of nitric oxide synthase immunoreactive neurons in fetal rat brains at embryonic day 15 and day 19" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1016/0891-0618(96)00141-x" "Revista" => array:6 [ "tituloSerie" => "J Chem Neuroanat" "fecha" => "1996" "volumen" => "10" "paginaInicial" => "273" "paginaFinal" => "278" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.1016/0891-0618(96)00141-x" "WWW" => array:1 [ "link" => "10.1016/0891-0618(96)00141-X" ] ] ] ] ] ] 70 => array:3 [ "identificador" => "bib71" "etiqueta" => "71" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Differential susceptibility to neurotoxicity mediated by neurotrophins and neuronal nitric oxide synthase" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1523/JNEUROSCI.17-12-04633.1997" "Revista" => array:6 [ "tituloSerie" => "J Neurosci" "fecha" => "1997 15" "volumen" => "17" "paginaInicial" => "4633" "paginaFinal" => "4641" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 71 => array:3 [ "identificador" => "bib72" "etiqueta" => "72" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Thyroid hormones affect the level and activity of nitric oxide synthase in rat cerebral cortex during postnatal development" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1007/s11064-007-9480-0" "Revista" => array:6 [ "tituloSerie" => "Neurochem Res" "fecha" => "2008" "volumen" => "33" "paginaInicial" => "569" "paginaFinal" => "578" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.1007/s11064-007-9480-0" "WWW" => array:1 [ "link" => "10.1007/s11064-007-9480-0" ] ] ] ] ] ] 72 => array:3 [ "identificador" => "bib73" "etiqueta" => "73" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Nitric oxide synthase activity in hyperthyroid and hypothyroid rats" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ …6] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1530/eje.0.1470117" "Revista" => array:6 [ "tituloSerie" => "Eur J Endocrinol" "fecha" => "2002" "volumen" => "147" "paginaInicial" => "117" "paginaFinal" => "122" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.1530/eje.0.1470117" "WWW" => array:1 [ "link" => "10.1530/eje.0.1470117" ] ] ] ] ] ] 73 => array:3 [ "identificador" => "bib74" "etiqueta" => "74" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cognitive deficits following blast injury-induced neurotrauma: possible involvement of nitric oxide" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:2 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Brain Inj" "fecha" => "2001" "volumen" => "15" "paginaInicial" => "593" "paginaFinal" => "612" ] ] 1 => array:1 [ "WWW" => array:1 [ "link" => "10.1080/02699050010009559" ] ] ] ] ] ] 74 => array:3 [ "identificador" => "bib75" "etiqueta" => "75" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A novel neuronal messenger molecule in brain: the free radical, nitric oxide" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1002/ana.410320302" "Revista" => array:6 [ "tituloSerie" => "Ann Neurol" "fecha" => "1992" "volumen" => "32" "paginaInicial" => "297" "paginaFinal" => "311" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.1002/ana.410320302" "WWW" => array:1 [ "link" => "10.1002/ana.410320302" ] ] ] ] ] ] 75 => array:3 [ "identificador" => "bib76" "etiqueta" => "76" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Nitric oxide activation of poly(ADP-ribose) synthetase in neurotoxicity" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ …4] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1126/science.8080500" "Revista" => array:6 [ "tituloSerie" => "Science" "fecha" => "1994 Feb 4" "volumen" => "263" "paginaInicial" => "687" "paginaFinal" => "689" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.1126/science.8080500" "WWW" => array:1 [ "link" => "10.1126/science.8080500" ] ] ] ] ] ] 76 => array:3 [ "identificador" => "bib77" "etiqueta" => "77" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Oxidative damage in the central nervous system: protection by melatonin" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ …1] ] ] ] ] "host" => array:2 [ 0 => array:2 [ "doi" => "10.1016/s0301-0082(98)00052-5" "Revista" => array:6 [ "tituloSerie" => "Prog Neurobiol" "fecha" => "1998" "volumen" => "56" "paginaInicial" => "359" "paginaFinal" => "384" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] 1 => array:2 [ "doi" => "10.1016/s0301-0082(98)00052-5" "WWW" => array:1 [ "link" => "10.1016/S0301-0082(98)00052-5" ] ] ] ] ] ] 77 => array:3 [ "identificador" => "bib78" "etiqueta" => "78" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:2 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Proc Natl Acad Sci U S A" "fecha" => "1991" "volumen" => "88" "paginaInicial" => "6368" "paginaFinal" => "6371" ] ] 1 => array:1 [ "WWW" => array:1 [ "link" => "10.1073/pnas.88.14.6368" ] ] ] ] ] ] ] ] ] ] "agradecimientos" => array:1 [ 0 => array:4 [ "identificador" => "xack638839" "titulo" => "ACKNOWLEDGEMENTS" "texto" => "We would like to thank the Vice Chancellor of Research of Mashhad University of Medical Sciences for financial support." "vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/18075932/0000006500000011/v1_202212010805/S1807593222029052/v1_202212010805/en/main.assets" "Apartado" => null "PDF" => "https://static.elsevier.es/multimedia/18075932/0000006500000011/v1_202212010805/S1807593222029052/v1_202212010805/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1807593222029052?idApp=UINPBA00004N"]

Statistics

BASIC RESEARCH

Mahmoud HosseiniI,,II,

Corresponding author

hosseinim@MUMS.ac.ir

Tel.: 0511-8828564-5

, Samaneh Sadat DastghaibI, Houshang RafatpanahIII, Mosa Al-Reza HadjzadehI,,II, Hossein NahrevanianIV, Ismaeil FarrokhiI

I Neuroscience Research Center, Mashhad University of Medical Sciences (MUMS), Mashhad, Iran

II Department of Physiology, School of Medicine, Mashhad University of Medical Sciences (MUMS), Mashhad, Iran

III Immunology Research Center, Buali Institute, Mashhad University of Medical Sciences (MUMS), Mashhad, Iran

IV Department of Parasitology, Pasteur Institute of Iran, Tehran, Iran

Read

940

Times
was read the article

260

Total PDF

680

Total HTML

Share statistics

 array:24 [
  "pii" => "S1807593222029052"
  "issn" => "18075932"
  "doi" => "10.1590/S1807-59322010001100021"
  "estado" => "S300"
  "fechaPublicacion" => "2010-01-01"
  "aid" => "2905"
  "copyright" => "CLINICS"
  "copyrightAnyo" => "2010"
  "documento" => "article"
  "crossmark" => 0
  "licencia" => "https://creativecommons.org/licenses/by-nc/3.0/"
  "subdocumento" => "fla"
  "cita" => "Clinics. 2010;65:1175-81"
  "abierto" => array:3 [
    "ES" => true
    "ES2" => true
    "LATM" => true
  ]
  "gratuito" => true
  "lecturas" => array:1 [
    "total" => 0
  ]
  "itemSiguiente" => array:19 [
    "pii" => "S1807593222029064"
    "issn" => "18075932"
    "doi" => "10.1590/S1807-59322010001100022"
    "estado" => "S300"
    "fechaPublicacion" => "2010-01-01"
    "aid" => "2906"
    "copyright" => "CLINICS"
    "documento" => "article"
    "crossmark" => 0
    "licencia" => "https://creativecommons.org/licenses/by-nc/3.0/"
    "subdocumento" => "fla"
    "cita" => "Clinics. 2010;65:1183-7"
    "abierto" => array:3 [
      "ES" => true
      "ES2" => true
      "LATM" => true
    ]
    "gratuito" => true
    "lecturas" => array:1 [
      "total" => 0
    ]
    "en" => array:12 [
      "idiomaDefecto" => true
      "cabecera" => "<span class="elsevierStyleTextfn">BASIC RESEARCH</span>"
      "titulo" => "The role of central mechanisms in the anti-inflammatory effect of amitriptyline on carrageenan-induced paw edema in rats"
      "tienePdf" => "en"
      "tieneTextoCompleto" => "en"
      "tieneResumen" => "en"
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "1183"
          "paginaFinal" => "1187"
        ]
      ]
      "contieneResumen" => array:1 [
        "en" => true
      ]
      "contieneTextoCompleto" => array:1 [
        "en" => true
      ]
      "contienePdf" => array:1 [
        "en" => true
      ]
      "resumenGrafico" => array:2 [
        "original" => 0
        "multimedia" => array:7 [
          "identificador" => "fig3-cln_65p1183"
          "etiqueta" => "Figure 3"
          "tipo" => "MULTIMEDIAFIGURA"
          "mostrarFloat" => true
          "mostrarDisplay" => false
          "figura" => array:1 [
            0 => array:4 [
              "imagen" => "gr3.jpeg"
              "Alto" => 316
              "Ancho" => 498
              "Tamanyo" => 11702
            ]
          ]
          "descripcion" => array:1 [
            "en" => "<p id="spara30" class="elsevierStyleSimplePara elsevierViewall">Lack of effect of intrathecal injection of amitriptyline on carrageenan-induced paw edema in the rats&#46; Amitriptyline or the vehicle was administrated intrathecally 30 min prior to carrageenan &#40;1&#37;&#41; injection&#44; and the rats were evaluated for paw edema 4 h post-carrageenan&#46; The values represent the mean variation in the paw volume &#177; S&#46;D&#46; &#40;n &#61; 6&#41;&#46;</p>"
          ]
        ]
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "Valiollah Hajhashemi, Hossein Sadeghi, Mohsen Minaiyan, Ahmad Movahedian, Ardeshir Talebi"
          "autores" => array:5 [
            0 => array:2 [
              "nombre" => "Valiollah"
              "apellidos" => "Hajhashemi"
            ]
            1 => array:2 [
              "nombre" => "Hossein"
              "apellidos" => "Sadeghi"
            ]
            2 => array:2 [
              "nombre" => "Mohsen"
              "apellidos" => "Minaiyan"
            ]
            3 => array:2 [
              "nombre" => "Ahmad"
              "apellidos" => "Movahedian"
            ]
            4 => array:2 [
              "nombre" => "Ardeshir"
              "apellidos" => "Talebi"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1807593222029064?idApp=UINPBA00004N"
    "url" => "/18075932/0000006500000011/v1_202212010805/S1807593222029064/v1_202212010805/en/main.assets"
  ]
  "itemAnterior" => array:19 [
    "pii" => "S1807593222029040"
    "issn" => "18075932"
    "doi" => "10.1590/S1807-59322010001100020"
    "estado" => "S300"
    "fechaPublicacion" => "2010-01-01"
    "aid" => "2904"
    "copyright" => "CLINICS"
    "documento" => "article"
    "crossmark" => 0
    "licencia" => "https://creativecommons.org/licenses/by-nc/3.0/"
    "subdocumento" => "fla"
    "cita" => "Clinics. 2010;65:1167-73"
    "abierto" => array:3 [
      "ES" => true
      "ES2" => true
      "LATM" => true
    ]
    "gratuito" => true
    "lecturas" => array:1 [
      "total" => 0
    ]
    "en" => array:12 [
      "idiomaDefecto" => true
      "cabecera" => "<span class="elsevierStyleTextfn">BASIC RESEARCH</span>"
      "titulo" => "Phagocytic responses of peritoneal macrophages and neutrophils are different in rats following prolonged exercise"
      "tienePdf" => "en"
      "tieneTextoCompleto" => "en"
      "tieneResumen" => "en"
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "1167"
          "paginaFinal" => "1173"
        ]
      ]
      "contieneResumen" => array:1 [
        "en" => true
      ]
      "contieneTextoCompleto" => array:1 [
        "en" => true
      ]
      "contienePdf" => array:1 [
        "en" => true
      ]
      "resumenGrafico" => array:2 [
        "original" => 0
        "multimedia" => array:7 [
          "identificador" => "fig2-cln_65p1167"
          "etiqueta" => "Figure 2"
          "tipo" => "MULTIMEDIAFIGURA"
          "mostrarFloat" => true
          "mostrarDisplay" => false
          "figura" => array:1 [
            0 => array:4 [
              "imagen" => "gr2.jpeg"
              "Alto" => 604
              "Ancho" => 662
              "Tamanyo" => 41430
            ]
          ]
          "descripcion" => array:1 [
            "en" => "<p id="spara20" class="elsevierStyleSimplePara elsevierViewall">Total number and phagocytic capacity of peritoneal macrophages and neutrophils&#46; A&#44; macrophage study&#46; B&#44; neutrophil study&#46; The results are expressed as the average number of peritoneal macrophages and neutrophils and the percentage of phagocytosis &#177; standard error of the average&#46; &#8727; p &#8804; 0&#46;05 for exercise groups submitted to low- and moderate-intensity exercise &#40;unadapted low intensity &#61; EXAGL&#59; moderate intensity &#61; EXAGM and corresponding preadapted groups&#44; EXADL and EXADM&#41; as compared to the control group &#40;C&#41;&#59; &#35; p &#8804; 0&#46;05 for comparisons made among the groups&#46;</p>"
          ]
        ]
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "Cl&#237;lton K O Ferreira, Jonato Prestes, Felipe F Donatto, Rozangela Verlengia, James W Navalta, Cl&#225;udia R Cavaglieri"
          "autores" => array:6 [
            0 => array:2 [
              "nombre" => "Cl&#237;lton K O"
              "apellidos" => "Ferreira"
            ]
            1 => array:2 [
              "nombre" => "Jonato"
              "apellidos" => "Prestes"
            ]
            2 => array:2 [
              "nombre" => "Felipe F"
              "apellidos" => "Donatto"
            ]
            3 => array:2 [
              "nombre" => "Rozangela"
              "apellidos" => "Verlengia"
            ]
            4 => array:2 [
              "nombre" => "James W"
              "apellidos" => "Navalta"
            ]
            5 => array:2 [
              "nombre" => "Cl&#225;udia R"
              "apellidos" => "Cavaglieri"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1807593222029040?idApp=UINPBA00004N"
    "url" => "/18075932/0000006500000011/v1_202212010805/S1807593222029040/v1_202212010805/en/main.assets"
  ]
  "en" => array:19 [
    "idiomaDefecto" => true
    "cabecera" => "<span class="elsevierStyleTextfn">BASIC RESEARCH</span>"
    "titulo" => "Nitric oxide contributes to learning and memory deficits observed in hypothyroid rats during neonatal and juvenile growth"
    "tieneTextoCompleto" => true
    "paginas" => array:1 [
      0 => array:2 [
        "paginaInicial" => "1175"
        "paginaFinal" => "1181"
      ]
    ]
    "autores" => array:1 [
      0 => array:4 [
        "autoresLista" => "Mahmoud Hosseini, Samaneh Sadat Dastghaib, Houshang Rafatpanah, Mosa Al-Reza Hadjzadeh, Hossein Nahrevanian, Ismaeil Farrokhi"
        "autores" => array:6 [
          0 => array:4 [
            "nombre" => "Mahmoud"
            "apellidos" => "Hosseini"
            "email" => array:1 [
              0 => "hosseinim@MUMS.ac.ir"
            ]
            "referencia" => array:3 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">I&#44;</span>"
                "identificador" => "af1-cln_65p1175"
              ]
              1 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">II</span>"
                "identificador" => "af2-cln_65p1175"
              ]
              2 => array:2 [
                "etiqueta" => "&#42;"
                "identificador" => "c1-cln_65p1175"
              ]
            ]
          ]
          1 => array:3 [
            "nombre" => "Samaneh Sadat"
            "apellidos" => "Dastghaib"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">I</span>"
                "identificador" => "af1-cln_65p1175"
              ]
            ]
          ]
          2 => array:3 [
            "nombre" => "Houshang"
            "apellidos" => "Rafatpanah"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">III</span>"
                "identificador" => "af3-cln_65p1175"
              ]
            ]
          ]
          3 => array:3 [
            "nombre" => "Mosa Al-Reza"
            "apellidos" => "Hadjzadeh"
            "referencia" => array:2 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">I&#44;</span>"
                "identificador" => "af1-cln_65p1175"
              ]
              1 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">II</span>"
                "identificador" => "af2-cln_65p1175"
              ]
            ]
          ]
          4 => array:3 [
            "nombre" => "Hossein"
            "apellidos" => "Nahrevanian"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">IV</span>"
                "identificador" => "af4-cln_65p1175"
              ]
            ]
          ]
          5 => array:3 [
            "nombre" => "Ismaeil"
            "apellidos" => "Farrokhi"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">I</span>"
                "identificador" => "af1-cln_65p1175"
              ]
            ]
          ]
        ]
        "afiliaciones" => array:4 [
          0 => array:3 [
            "entidad" => "Neuroscience Research Center&#44; Mashhad University of Medical Sciences &#40;MUMS&#41;&#44; Mashhad&#44; Iran"
            "etiqueta" => "I"
            "identificador" => "af1-cln_65p1175"
          ]
          1 => array:3 [
            "entidad" => "Department of Physiology&#44; School of Medicine&#44; Mashhad University of Medical Sciences &#40;MUMS&#41;&#44; Mashhad&#44; Iran"
            "etiqueta" => "II"
            "identificador" => "af2-cln_65p1175"
          ]
          2 => array:3 [
            "entidad" => "Immunology Research Center&#44; Buali Institute&#44; Mashhad University of Medical Sciences &#40;MUMS&#41;&#44; Mashhad&#44; Iran"
            "etiqueta" => "III"
            "identificador" => "af3-cln_65p1175"
          ]
          3 => array:3 [
            "entidad" => "Department of Parasitology&#44; Pasteur Institute of Iran&#44; Tehran&#44; Iran"
            "etiqueta" => "IV"
            "identificador" => "af4-cln_65p1175"
          ]
        ]
        "correspondencia" => array:1 [
          0 => array:3 [
            "identificador" => "c1-cln_65p1175"
            "etiqueta" => "&#42;"
            "correspondencia" => "Tel&#46;&#58; 0511-8828564-5"
          ]
        ]
      ]
    ]
    "resumenGrafico" => array:2 [
      "original" => 0
      "multimedia" => array:7 [
        "identificador" => "fig3-cln_65p1175"
        "etiqueta" => "Figure 3"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr3.jpeg"
            "Alto" => 313
            "Ancho" => 498
            "Tamanyo" => 16353
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara30" class="elsevierStyleSimplePara elsevierViewall">Comparison of the length of the swimming path &#40;cm&#41; between methimazole-treated animals and controls using a repeated measure ANOVA&#46; The length of the swimming path in the offspring of the methimazole group was significantly higher than that of controls &#40;<span class="elsevierStyleItalic">P</span>&#60;0&#46;001&#41;&#46; Data are shown as mean &#177; SEM of seven animals per group&#46;</p>"
        ]
      ]
    ]
    "textoCompleto" => "<span class="elsevierStyleSections"><span id="cesec10" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle60">INTRODUCTION</span><p id="para10" class="elsevierStylePara elsevierViewall">Many studies have shown a significant role for thyroid hormones in the development and maturation of the mammalian central nervous system&#46;<a class="elsevierStyleCrossRefs" href="#bib1">1&#44;2</a> These hormones regulate axonal and dendritic growth and synapse formation&#46;<a class="elsevierStyleCrossRef" href="#bib3">3</a> Growth retardation and severe cognitive impairment are known complications following thyroid hormone deficiency in the prenatal and neonatal periods&#46;<a class="elsevierStyleCrossRef" href="#bib4">4</a> It has been shown that hypothyroidism is associated with changes in gene expression in both the central and peripheral nervous system&#46;<a class="elsevierStyleCrossRef" href="#bib5">5</a> The inability to produce long-term potentiation &#40;LTP&#41; in the rat hippocampus and impaired learning and memory in both rats and humans are among the functional consequences of hypothyroidism&#46;<a class="elsevierStyleCrossRef" href="#bib6">6</a> Other studies have suggested that hypothyroidism affects behavioral conditions and is accompanied by emotional symptoms&#44; including lethargy and dysphoria&#46;<a class="elsevierStyleCrossRefs" href="#bib7">7-11</a> The results of other studies have shown that several cognitive deficits&#44; including attention and memory processing deficits&#44; general intelligence and visual-spatial skills&#44; are induced by hypothyroidism&#46;<a class="elsevierStyleCrossRefs" href="#bib9">9&#44;10</a> Hypothyroidism has a lesser effect on auditory attention&#44; motor skills&#44; language and set-shifting&#46;<a class="elsevierStyleCrossRefs" href="#bib7">7&#44;10&#44;12</a> In addition&#44; there is evidence indicating that even subclinical hypothyroidism is associated with depressive symptoms and cognitive impairment&#46;<a class="elsevierStyleCrossRef" href="#bib13">13</a></p><p id="para20" class="elsevierStylePara elsevierViewall">Nitric oxide &#40;NO&#41;&#44; a free radical gas&#44; is known to play critical roles in biologic systems&#59;<a class="elsevierStyleCrossRef" href="#bib14">14</a> It acts like a diffusible intercellular signaling molecule in the brain and spinal cord&#46;<a class="elsevierStyleCrossRef" href="#bib15">15</a> NO synthase &#40;NOS&#41; is the enzyme that produces NO from l-arginine&#46; NO can act as an important mediator in synaptic plasticity&#44; LTP and the consolidation of LTP&#46;<a class="elsevierStyleCrossRefs" href="#bib16">16-18</a> In addition&#44; there are reports that suggest a relationship between NMDA &#40;N-methyl-D-aspartate&#41;receptors and the NO system in learning and memory&#46;<a class="elsevierStyleCrossRefs" href="#bib19">19&#44;20</a> Several studies have shown that NOS inhibitors impair the consolidation of memory<a class="elsevierStyleCrossRefs" href="#bib21">21&#44;22</a> and block the induction of LTP&#46;<a class="elsevierStyleCrossRefs" href="#bib21">21-24</a> There is&#44; however&#44; some evidence showing that l-arginine&#44; an NO precursor&#44; improves memory formation and reverses the effect of NOS inhibition&#46;<a class="elsevierStyleCrossRef" href="#bib25">25</a> There are also reports indicating that NO donors activate both LTP and long-term depression&#46;<a class="elsevierStyleCrossRefs" href="#bib23">23&#44;26</a> These results suggest the involvement of NO in learning and memory processes&#46;</p><p id="para30" class="elsevierStylePara elsevierViewall">The relationship between thyroid hormones and the NO system has been well documented&#46;<a class="elsevierStyleCrossRefs" href="#bib23">23&#44;26-28</a> There is evidence that thyroid hormones are involved in regulating NO synthase gene expression in the brain&#46; Considering the aforementioned findings&#44; this study aimed to investigate the effect of hypothyroidism induced during the neonatal and juvenile periods on learning and memory of offspring and on NO metabolite concentrations in the hippocampus&#46;</p></span><span id="cesec20" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle70">MATERIALS AND METHODS</span><span id="cesec30" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle80">Animals and treatments</span><p id="para40" class="elsevierStylePara elsevierViewall">Twenty pregnant female Wistar rats &#40;8 weeks old and weighing 200 &#177; 20 g&#41; were kept in separate cages at 22 &#177; 2 &#176;C in a room with a 12 h light&#47;dark cycle &#40;light on at 7&#58;00 am&#41;&#46; Offspring were randomly divided into two groups and treated according to the experimental protocol from the first day after birth through the first two months of life&#46; Rats in the control group received normal drinking water&#44; whereas the second group received the same drinking water supplemented with 0&#46;03&#37; methimazole &#40;Sigma&#44; USA&#41; to induce hypothyroidism&#46;<a class="elsevierStyleCrossRef" href="#bib29">29</a> After 60 days&#44; seven male offspring of each group were randomly selected and tested in the Morris water maze &#40;MWM&#41;&#46;</p><p id="para50" class="elsevierStylePara elsevierViewall">In the methimazole group&#44; hypothyroidism was confirmed by testing serum thyroxine concentration levels using the radioimmunoassay method &#40;Daisource&#44; T4- RIA - CT&#41;&#46;</p><p id="para60" class="elsevierStylePara elsevierViewall">Animal handling and all related procedures were carried out in accordance with the rules set by the Mashhad University of Medical Sciences Ethical Committee&#46;</p></span><span id="cesec40" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle90">Morris water maze apparatus and procedures</span><p id="para70" class="elsevierStylePara elsevierViewall">A circular black pool &#40;136 cm diameter&#44; 60 cm high&#44; 30 cm deep&#41; was filled with water &#40;20&#8211;24 &#176;C&#41;&#46; A circular platform &#40;10 cm diameter&#44; 28 cm high&#41; was placed within the pool and was submerged approximately 2 cm below the surface of the water in the center of the southwest quadrant&#46; Outside the maze&#44; fixed visual cues were present at various locations around the room &#40;i&#46;e&#46;&#44; a computer&#44; hardware and posters&#41;&#46; An infrared camera was mounted above the center of the maze and an infrared LED was attached to each rat for motion tracking&#46; Before each experiment&#44; each rat was handled daily for 3 days and habituated to the water maze for 30 sec without a platform&#46; The animals performed four trials on each of the eight consecutive days&#44; and each trial began with the rat being placed in the pool and released facing the side wall at one of four positions &#40;the boundaries of the four quadrants&#44; labeled North &#40;N&#41;&#44; East &#40;E&#41;&#44; South &#40;S&#41; and West &#40;W&#41;&#46; Release positions were randomly predetermined&#46; For each trial&#44; the rat was allowed to swim until it found and remained on the platform for 15 seconds&#46; If 60 seconds had passed and the animal had not found the platform&#44; it was guided to the platform by the experimenter and allowed to stay on the platform for 15 sec&#46; The rat was then removed from the pool&#44; dried and placed in its holding bin for 5 min&#46; The time latency to reach the platform and the length of the swimming path were recorded by a video tracking system&#46;<a class="elsevierStyleCrossRefs" href="#bib29">29&#44;32-34</a> On the ninth day&#44; the platform was removed&#44; and the animals were allowed to swim for 60 s&#46; The time spent in the target quadrant &#40;Q1&#41; and the traveled path were compared between groups&#46; All measurements were performed during the first half of the light cycle&#46;</p></span><span id="cesec50" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle100">Biochemical assessment</span><p id="para80" class="elsevierStylePara elsevierViewall">After the last session of the MWM test&#44; blood samples were taken from all rats to determine hypothyroidism status and to measure the NO metabolites NO<span class="elsevierStyleInf">2</span> and NO<span class="elsevierStyleInf">3</span> &#40;Griess reagent method&#41;&#46; The animals were then sacrificed&#44; and hippocampi were removed and submitted to NO metabolite measurements in the tissue&#46; The Griess reaction was adapted to assay nitrates as previously described&#46;<a class="elsevierStyleCrossRef" href="#bib35">35</a> Briefly&#44; standard curves for nitrates &#40;Sigma&#44; St&#46; Louis&#44; Missouri&#44; USA&#41; were prepared&#44; and samples &#40;50 &#181;l plasma and 100 &#181;l tissue suspension&#41; were added to the Griess reagent&#46; The proteins were subsequently precipitated by the addition of 50 &#181;l of 10&#37; trichloroacetic acid &#40;Sigma&#41;&#46; The contents were then vortex-mixed and centrifuged&#44; and the supernatants were transferred to a 96-well flat-bottomed microplate&#46; Absorbance was read at 520 nm using a microplate reader&#44; and final values were calculated from standard calibration plots&#46;<a class="elsevierStyleCrossRef" href="#bib36">36</a></p></span><span id="cesec60" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle110">Statistical analysis</span><p id="para90" class="elsevierStylePara elsevierViewall">All data are expressed as mean &#177; SEM&#46; Swim time latency and the length of the traveled path over the eight training days were analyzed by repeated measures analysis of variance ANOVA&#46; The time spent in the target quadrant &#40;Q1&#41; and the length of the swimming path in this quadrant was compared using unpaired t-tests&#46; Comparison of serum thyroxin levels and plasma levels of NO metabolites was carried out using unpaired t-tests&#46; The criterion for statistical significance was <span class="elsevierStyleItalic">P</span>&#60;0&#46;05&#46;</p></span></span><span id="cesec70" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle120">RESULTS</span><p id="para100" class="elsevierStylePara elsevierViewall">The serum thyroxine concentration in methimazole-treated animals was significantly lower compared to that of control animals &#40;<span class="elsevierStyleItalic">P</span>&#60;0&#46;01&#59; <a class="elsevierStyleCrossRef" href="#fig1-cln_65p1175">Fig&#46; 1</a>&#41;&#46; In addition&#44; the time latency and the length of the swimming path over the eight training days were significantly higher in offspring of the methimazole group &#40;<span class="elsevierStyleItalic">P</span>&#60;0&#46;001&#59; <a class="elsevierStyleCrossRefs" href="#fig2-cln_65p1175">Figs&#46; 2 and 3</a>&#44; respectively&#41;&#46; In the probe trial&#44; the time spent in the target quadrant &#40;Q1&#41; by the offspring of the methimazole group was significantly lower compared to controls &#40;<span class="elsevierStyleItalic">P</span>&#60;0&#46;001&#59; <a class="elsevierStyleCrossRef" href="#fig4-cln_65p1175">Fig&#46; 4A</a>&#41;&#46; Furthermore&#44; the length of the traveled path in Q1 by animals in the methimazole group was shorter than for those in the control group &#40;<span class="elsevierStyleItalic">P</span>&#60;0&#46;001&#59; <a class="elsevierStyleCrossRef" href="#fig4-cln_65p1175">Fig&#46; 4B</a>&#41;&#46; There were no significant differences in the time spent or the length of the swim path in the other quadrants between the two groups&#46; In addition&#44; there were no significant differences between the plasma concentrations of NO<span class="elsevierStyleInf">2</span> or NO<span class="elsevierStyleInf">3</span>&#59; however&#44; the concentration of NO metabolites in the hippocampi of the methimazole group offspring was higher than that of the control animals &#40;<span class="elsevierStyleItalic">P</span>&#60;0&#46;05&#59; <a class="elsevierStyleCrossRef" href="#fig5-cln_65p1175">Figs&#46; 5A and 5B</a>&#44; respectively&#41;&#46;</p><elsevierMultimedia ident="fig1-cln_65p1175"></elsevierMultimedia><elsevierMultimedia ident="fig2-cln_65p1175"></elsevierMultimedia><elsevierMultimedia ident="fig3-cln_65p1175"></elsevierMultimedia><elsevierMultimedia ident="fig4-cln_65p1175"></elsevierMultimedia><elsevierMultimedia ident="fig5-cln_65p1175"></elsevierMultimedia></span><span id="cesec80" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle130">DISCUSSION</span><p id="para110" class="elsevierStylePara elsevierViewall">Neonatal hypothyroidism has been clearly shown to be related to cognitive dysfunction&#46;<a class="elsevierStyleCrossRefs" href="#bib9">9-11&#44;37&#44;38</a> For example&#44; studies in humans have shown that a temporal deficiency in thyroid hormones during developmental periods impairs cognitive functions such as attention&#44; learning and memory&#46;<a class="elsevierStyleCrossRef" href="#bib39">39</a> Experimental hypothyroidism in developing rats has also been shown to result in impaired learning and memory&#46;<a class="elsevierStyleCrossRefs" href="#bib40">40&#44;41</a> In this study we induced hypothyroidism in rats&#44; resulting in impaired learning and memory during the neonatal and juvenile periods&#46;</p><p id="para120" class="elsevierStylePara elsevierViewall">Hypothyroidism impairs hippocampal-dependent learning and short- and long-term memory&#46;<a class="elsevierStyleCrossRefs" href="#bib42">42&#44;43</a> In addition&#44; hypothyroidism impairs early and late phases of LTP&#46;<a class="elsevierStyleCrossRef" href="#bib44">44</a> The exact mechanisms underlying the induced deficits in memory and LTP have not been elucidated&#46; Many studies have demonstrated that cognitive dysfunction in hypothyroidism is likely due to abnormal brain development&#44; diminished inter-neuronal connectivity and&#44; in particular&#44; impaired synaptic plasticity in the hippocampus&#46;<a class="elsevierStyleCrossRef" href="#bib45">45</a> It has been shown that maturation and function of the hippocampus are dependent on thyroid hormones&#46;<a class="elsevierStyleCrossRef" href="#bib43">43</a> Transient hypothyroidism has even been shown to impair synaptic transmission and plasticity in the adult hippocampus&#46;<a class="elsevierStyleCrossRefs" href="#bib46">46&#44;47</a> It has also been reported that impairment of LTP and memory due to hypothyroidism correlates with changes in c-jun and c-fos protein expression and extracellular signal regulated kinases &#40;ERKs&#41; levels in the hippocampus during crucial periods of brain development&#46;<a class="elsevierStyleCrossRefs" href="#bib48">48&#44;49</a> Changes in the expression of other proteins such as synapsin I&#44; synaptotagmin I&#44; and syntaxin may also be involved in hypothyroidism-induced memory deficits&#46;<a class="elsevierStyleCrossRef" href="#bib50">50</a> It has also been suggested that thyroid hormone deficiency results in changes in brain regions such as the dorsal hippocampal-mPFC pathway and changes in the glutamate release&#44; which can lead to cognitive disturbances&#46;<a class="elsevierStyleCrossRefs" href="#bib51">51-53</a> Moreover&#44; hypothyroidism has been shown to induce oxidative stress in the hippocampus&#46;<a class="elsevierStyleCrossRef" href="#bib54">54</a></p><p id="para130" class="elsevierStylePara elsevierViewall">The relationship between oxidative stress&#44; neuronal damage and cognitive dysfunction has been well documented&#46;<a class="elsevierStyleCrossRefs" href="#bib55">55-58</a> In addition&#44; it is well known that neonatal hypothyroidism is accompanied by a delay in myelinogenesis and a decrease in the number of myelinated axons&#46;<a class="elsevierStyleCrossRefs" href="#bib59">59&#44;60</a> In the present study&#44; we have shown that a deficiency of thyroid hormones during lactation and in the neonatal period could impair learning of offspring in the MWM test&#46; The animals in the hypothyroid group had significantly higher time latency to find the platform during every day of training &#40;<a class="elsevierStyleCrossRef" href="#fig2-cln_65p1175">Fig&#46; 2</a>&#41;&#44; indicating a deleterious effect of the lack of thyroid hormones on spatial learning processes&#46; The results presented here also confirm that methimazole-induced hypothyroidism during the neonatal and juvenile periods impairs spatial memory given that the animals in the hypothyroid group spent less time in the target quadrant compared to the control group when tested on the ninth day &#40;probe trial&#59; <a class="elsevierStyleCrossRef" href="#fig4-cln_65p1175">Fig&#46; 4</a>&#41;&#46; The results of the present study are consistent with findings from our previous study&#44; in which we found an impairment in the MWM in adult rats with methimazole-induced hypothyroidism over a 180-day period&#46;<a class="elsevierStyleCrossRef" href="#bib29">29</a> It has also been reported that treatment of thyroidectomized adult rats with thyroxine improved radial arm water maze tasks and LTP in the CA1 area of the hippocampus&#46;<a class="elsevierStyleCrossRef" href="#bib61">61</a> These researchers showed that cyclic-AMP response element binding protein &#40;CREB&#41; and mitogen-activated protein kinases &#40;MAPKs&#41; may contribute to the impairment of hippocampal-dependent learning and memory&#59; however&#44; the authors suggested that calcium-calmodulin-dependent NOS and brain-derived neurotrophic factor &#40;BDNF&#41; may not have roles in this process&#46;<a class="elsevierStyleCrossRef" href="#bib61">61</a></p><p id="para140" class="elsevierStylePara elsevierViewall">The free radical gas NO has been associated with different forms of learning and memory and in several forms of synaptic plasticity thought to be involved in memory formation&#46; This association has been widely confirmed via pharmacological studies&#44; which have utilized a variety of substances and methods to inhibit NO synthase&#46; Results from knockout studies in mice have revealed that mice deficient in eNOS and nNOS expression exhibit impaired LTP&#46;<a class="elsevierStyleCrossRefs" href="#bib20">20&#44;61-65</a> It has also been reported that nitrergic neurons&#44; the neurons that produce NO&#44; increase in number after spatial learning in rats&#44; which can be interpreted as upregulation induced by behavioral training&#46;<a class="elsevierStyleCrossRef" href="#bib63">63</a> This evidence implies that NO participates in the memory process&#46;<a class="elsevierStyleCrossRef" href="#bib63">63</a> In contrast to these results&#44; which indicate a positive role for NO in learning and memory&#44; it has been shown that inhibition of NOS does not prevent the induction of LTP or impair spatial memory&#46; Thus&#44; these findings suggest that NO does not play an important role in memory and learning&#46;<a class="elsevierStyleCrossRef" href="#bib66">66</a> Here&#44; we have examined the relationship between NO and hypothyroidism&#46; We found that both hypothyroidism and impaired MWM performance were present in the methimazole group&#46;</p><p id="para150" class="elsevierStylePara elsevierViewall">We also found a significant increase in hippocampal NO metabolites in the methimazole-treated group&#46; The association between hypothyroidism and increased NO levels in the brain has been previously investigated&#46; One study indicated that maternal thyroid hormone deficiency during the early gestational period resulted in a significant elevation in neuronal nitric oxide synthase &#40;nNOS&#41; expression with associated neuronal death in the embryonic rat neocortex&#46;<a class="elsevierStyleCrossRef" href="#bib67">67</a> It has also been shown that nNOS acts as a negative regulator of neurogenesis&#46;<a class="elsevierStyleCrossRefs" href="#bib67">67-69</a> The inhibitory effect of NO on neurogenesis may be due to a reduction in the proliferative potential of neural precursor cells<a class="elsevierStyleCrossRef" href="#bib70">70</a> or a defect in the survival of newly generated neurons after differentiation&#46;<a class="elsevierStyleCrossRef" href="#bib71">71</a> There is evidence showing that thyroid hormone deficiency increases cell death&#46;<a class="elsevierStyleCrossRef" href="#bib67">67</a> The relationship between nNOS and poor survival of neurons and thyroid hormone deprivation has also been suggested&#46;<a class="elsevierStyleCrossRef" href="#bib67">67</a> It has been shown that even a moderate and transient decrease in maternal thyroxine significantly increases nNOS expression&#44; which is reversible by hormone replacement&#46;<a class="elsevierStyleCrossRefs" href="#bib67">67&#44;72</a> In contrast&#44; another report showed that propylthiouracil &#40;PTU&#41;-treated animals exhibited reduced NOS activity that could be rescued by T4 administration&#46;<a class="elsevierStyleCrossRef" href="#bib72">72</a></p><p id="para160" class="elsevierStylePara elsevierViewall">It has also been shown that hypothyroidism changes the pattern of NOS activity in a tissue-dependent manner&#46; NOS activity was significantly increased in both the right and left ventricles&#44; but it was significantly reduced in the aorta&#44; whereas in the vena cava&#44; renal cortex and medulla&#44; the enzyme activity was non-significantly higher compared to controls&#46;<a class="elsevierStyleCrossRef" href="#bib73">73</a> The results of the present study also showed no difference in NO metabolites between the hypothyroid group and controls in peripheral blood samples&#46; It might be suggested that an increase in NO in the hippocampus is due to stimulatory effects of thyroid hormone deprivation on nNOS activity&#46; Although some studies have suggested NO to be a neurotransmitter that plays an important role in enhancing memory&#44; others have claimed that its excess in the hippocampus may result in memory deficits&#46;<a class="elsevierStyleCrossRef" href="#bib74">74</a> NO has been shown to have bidirectional effects&#46; Under normal physiological conditions&#44; it acts as an important neuronal messenger&#59; however&#44; when NO increases to high concentrations&#44; it has a toxic effect that can lead to neuronal death&#46;<a class="elsevierStyleCrossRefs" href="#bib75">75-77</a> A common example of the toxic effect of NO in the CNS is due to glutamate neurotransmission and the activation N-methyl-D-aspartate &#40;NMDA&#41; receptors&#44; which leads to significant increases in intracellular calcium&#44; followed by stimulation of neuronal NOS&#46;<a class="elsevierStyleCrossRefs" href="#bib77">77&#44;78</a></p><p id="para170" class="elsevierStylePara elsevierViewall">Finally&#44; other findings have suggested selective enhancement of reactive oxygen species &#40;ROS&#41; and lipid peroxidation in the amygdala and hippocampus of rats after three weeks of treatment with methimazole&#46; These authors showed a significant increase in NOS activity&#44;<a class="elsevierStyleCrossRef" href="#bib54">54</a> suggesting a correlation between increased NOS activity and elevated oxidative stress&#46; It may therefore be suggested that increased NO production in the hippocampus during hypothyroidism acts as an oxidative stressor&#44; which may explain the deficits in learning and memory observed here&#46;</p></span><span id="cesec90" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle140">CONCLUSIONS</span><p id="para180" class="elsevierStylePara elsevierViewall">In this study&#44; we found that hypothyroidism induced during the neonatal and juvenile periods resulted in impaired learning and memory of rats tested in the Morris water maze&#46; In addition&#44; we found an increase in NO metabolites in the hippocampus&#44; suggesting that the impairment of memory in hypothyroidism may be due to increases in NOS and NO&#46;</p></span></span>"
    "textoCompletoSecciones" => array:1 [
      "secciones" => array:8 [
        0 => array:2 [
          "identificador" => "xpalclavsec1581421"
          "titulo" => "KEYWORDS"
        ]
        1 => array:2 [
          "identificador" => "cesec10"
          "titulo" => "INTRODUCTION"
        ]
        2 => array:3 [
          "identificador" => "cesec20"
          "titulo" => "MATERIALS AND METHODS"
          "secciones" => array:4 [
            0 => array:2 [
              "identificador" => "cesec30"
              "titulo" => "Animals and treatments"
            ]
            1 => array:2 [
              "identificador" => "cesec40"
              "titulo" => "Morris water maze apparatus and procedures"
            ]
            2 => array:2 [
              "identificador" => "cesec50"
              "titulo" => "Biochemical assessment"
            ]
            3 => array:2 [
              "identificador" => "cesec60"
              "titulo" => "Statistical analysis"
            ]
          ]
        ]
        3 => array:2 [
          "identificador" => "cesec70"
          "titulo" => "RESULTS"
        ]
        4 => array:2 [
          "identificador" => "cesec80"
          "titulo" => "DISCUSSION"
        ]
        5 => array:2 [
          "identificador" => "cesec90"
          "titulo" => "CONCLUSIONS"
        ]
        6 => array:2 [
          "identificador" => "xack638839"
          "titulo" => "ACKNOWLEDGEMENTS"
        ]
        7 => array:1 [
          "titulo" => "REFERENCES"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2010-05-02"
    "fechaAceptado" => "2010-08-23"
    "PalabrasClave" => array:1 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "KEYWORDS"
          "identificador" => "xpalclavsec1581421"
          "palabras" => array:5 [
            0 => "Hypothyroidism"
            1 => "Learning"
            2 => "Memory"
            3 => "Nitric Oxide"
            4 => "Offspring"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:1 [
      "en" => array:2 [
        "resumen" => "<span id="ceabs10" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle10">INTRODUCTION&#58;</span><p id="spara60" class="elsevierStyleSimplePara elsevierViewall">Severe cognitive impairment follows thyroid hormone deficiency during the neonatal period&#46; The role of nitric oxide &#40;NO&#41; in learning and memory has been widely investigated&#46;</p></span> <span id="ceabs20" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle20">METHODS&#58;</span><p id="spara70" class="elsevierStyleSimplePara elsevierViewall">This study aimed to investigate the effect of hypothyroidism during neonatal and juvenile periods on NO metabolites in the hippocampi of rats and on learning and memory&#46; Animals were divided into two groups and treated for 60 days from the first day of lactation&#46; The control group received regular water&#44; whereas animals in a separate group were given water supplemented with 0&#46;03&#37; methimazole to induce hypothyroidism&#46; Male offspring were selected and tested in the Morris water maze&#46; Samples of blood were collected to measure the metabolites of NO&#44; NO<span class="elsevierStyleInf">2</span>&#44; NO<span class="elsevierStyleInf">3</span> and thyroxine&#46; The animals were then sacrificed&#44; and their hippocampi were removed to measure the tissue concentrations of NO<span class="elsevierStyleInf">2</span> and NO<span class="elsevierStyleInf">3</span>&#46;</p></span> <span id="ceabs30" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle30">DISCUSSION&#58;</span><p id="spara80" class="elsevierStyleSimplePara elsevierViewall">Compared to the control group&#39;s offspring&#44; serum thyroxine levels in the methimazole group&#39;s offspring were significantly lower &#40;<span class="elsevierStyleItalic">P</span>&#60;0&#46;01&#41;&#46; In addition&#44; the swim distance and time latency were significantly higher in the methimazole group &#40;<span class="elsevierStyleItalic">P</span>&#60;0&#46;001&#41;&#44; and the time spent by this group in the target quadrant &#40;Q1&#41; during the probe trial was significantly lower &#40;<span class="elsevierStyleItalic">P</span>&#60;0&#46;001&#41;&#46; There was no significant difference in the plasma levels of NO metabolites between the two groups&#59; however&#44; significantly higher NO metabolite levels in the hippocampi of the methimazole group were observed compared to controls &#40;<span class="elsevierStyleItalic">P</span>&#60;0&#46;05&#41;&#46;</p></span> <span id="ceabs40" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle40">CONCLUSION&#58;</span><p id="spara90" class="elsevierStyleSimplePara elsevierViewall">These results suggest that the increased NO level in the hippocampus may play a role in the learning and memory deficits observed in childhood hypothyroidism&#59; however&#44; the precise underlying mechanism&#40;s&#41; remains to be elucidated&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "ceabs10"
            "titulo" => "INTRODUCTION&#58;"
          ]
          1 => array:2 [
            "identificador" => "ceabs20"
            "titulo" => "METHODS&#58;"
          ]
          2 => array:2 [
            "identificador" => "ceabs30"
            "titulo" => "DISCUSSION&#58;"
          ]
          3 => array:2 [
            "identificador" => "ceabs40"
            "titulo" => "CONCLUSION&#58;"
          ]
        ]
      ]
    ]
    "multimedia" => array:5 [
      0 => array:7 [
        "identificador" => "fig1-cln_65p1175"
        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 221
            "Ancho" => 478
            "Tamanyo" => 13979
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara10" class="elsevierStyleSimplePara elsevierViewall">Serum thyroxine concentrations &#40;&#181;g&#47;dl&#41; in offspring of methimazole and control groups&#46; The animals in the control group received regular drinking water&#44; whereas the methimazole group received the water supplemented with 0&#46;03&#37; methimazole&#46; Data are shown as mean &#177; SEM &#40;n &#61; 7 in each group&#41;&#46; &#8727;&#8727;<span class="elsevierStyleItalic">P</span>&#60;0&#46;01 compared to controls&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "fig2-cln_65p1175"
        "etiqueta" => "Figure 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
            "Alto" => 366
            "Ancho" => 531
            "Tamanyo" => 16872
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara20" class="elsevierStyleSimplePara elsevierViewall">Comparison of swim time latency &#40;sec&#41; to find the platform between offspring of the methimazole and control groups&#46; The latency was significantly higher in offspring of rats in the methimazole group compared to controls &#40;<span class="elsevierStyleItalic">P</span>&#60;0&#46;001&#41;&#46; Data are shown as mean &#177; SEM of seven animals per group&#46;</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "fig3-cln_65p1175"
        "etiqueta" => "Figure 3"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr3.jpeg"
            "Alto" => 313
            "Ancho" => 498
            "Tamanyo" => 16353
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara30" class="elsevierStyleSimplePara elsevierViewall">Comparison of the length of the swimming path &#40;cm&#41; between methimazole-treated animals and controls using a repeated measure ANOVA&#46; The length of the swimming path in the offspring of the methimazole group was significantly higher than that of controls &#40;<span class="elsevierStyleItalic">P</span>&#60;0&#46;001&#41;&#46; Data are shown as mean &#177; SEM of seven animals per group&#46;</p>"
        ]
      ]
      3 => array:7 [
        "identificador" => "fig4-cln_65p1175"
        "etiqueta" => "Figure 4"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr4.jpeg"
            "Alto" => 618
            "Ancho" => 441
            "Tamanyo" => 41725
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara40" class="elsevierStyleSimplePara elsevierViewall">The results of the time &#40;sec&#41; spent &#40;<span class="elsevierStyleBold">4A</span>&#41; and the length of the swimming path &#40;cm&#41; &#40;<span class="elsevierStyleBold">4B</span>&#41; in each quadrant during the probe trial on day 9 &#40;24 h after the last secession of learning&#41;&#46; Data are shown as mean &#177; SEM of seven animals per group&#46; The platform was removed&#44; and the time spent and the length of the swim path in the target quadrant &#40;Q1&#41; was compared between the groups&#46; The time spent and the length of the swim path in Q1 by the offspring of the methimazole group was significantly lower compared to controls&#46; &#8727;&#8727;&#8727;<span class="elsevierStyleItalic">P</span>&#60;0&#46;001 compared to controls&#46;</p>"
        ]
      ]
      4 => array:7 [
        "identificador" => "fig5-cln_65p1175"
        "etiqueta" => "Figure 5"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr5.jpeg"
            "Alto" => 475
            "Ancho" => 431
            "Tamanyo" => 34881
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara50" class="elsevierStyleSimplePara elsevierViewall">Comparison of plasma NO metabolite levels &#40;<span class="elsevierStyleBold">A</span>&#41; and the concentrations of these metabolites in hippocampal tissue &#40;<span class="elsevierStyleBold">B</span>&#41; between offspring of the methimazole and control groups&#46; Data are shown as mean &#177; SEM of seven animals per group&#46; There were no significant differences between the plasma concentrations of NO<span class="elsevierStyleInf">2</span> or NO<span class="elsevierStyleInf">3</span>&#59; however&#44; the concentration of NO metabolites in the hippocampi of the methimazole group offspring was higher than that of the control animals&#46; &#8727;<span class="elsevierStyleItalic">P</span>&#60;0&#46;05 compared to controls&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "REFERENCES"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "cebibsec10"
          "bibliografiaReferencia" => array:78 [
            0 => array:3 [
              "identificador" => "bib1"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Thyroid hormones and nervous system development"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => """
                              PS Timiras \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              EU Nzekwe \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1159/000242941"
                      "Revista" => array:6 [
                        "tituloSerie" => "Biol Neonate"
                        "fecha" => "1989"
                        "volumen" => "55"
                        "paginaInicial" => "376"
                        "paginaFinal" => "385"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2663092"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1159/000242941"
                      "WWW" => array:1 [
                        "link" => "10&#46;1159&#47;000242941"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib2"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "T3 administration in adult hypothyroid mice modulates expression of proteins involved in striatal synaptic plasticity and improves motor behavior"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => """
                              J Vallortigara \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              S Alfos \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              J Micheau \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              P Higueret \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              V Enderlin \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1016/j.nbd.2008.05.015"
                      "Revista" => array:6 [
                        "tituloSerie" => "Neurobiol Dis"
                        "fecha" => "2008"
                        "volumen" => "31"
                        "paginaInicial" => "378"
                        "paginaFinal" => "385"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18585460"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1016/j.nbd.2008.05.015"
                      "WWW" => array:1 [
                        "link" => "10&#46;1016&#47;j&#46;nbd&#46;2008&#46;05&#46;015"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib3"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Thyroid hormone enhances the formation of synapses between cultured neurons of rat cerebral cortex"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => """
                              R Hosoda \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              K Nakayama \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              M Kato-Negishi \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              M Kawahara \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              K Muramoto \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              Y Kuroda \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Cell Mol Neurobiol"
                        "fecha" => "2003"
                        "volumen" => "23"
                        "paginaInicial" => "895"
                        "paginaFinal" => "906"
                      ]
                    ]
                    1 => array:1 [
                      "WWW" => array:1 [
                        "link" => "10&#46;1023&#47;B&#58;CEMN&#46;0000005318&#46;53810&#46;de"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib4"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The role of thyroid hormones in prenatal and neonatal neurological development&#8211;current perspectives"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => """
                              SP Porterfield \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              CE Hendrich \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1210/edrv-14-1-94"
                      "Revista" => array:6 [
                        "tituloSerie" => "Endocr Rev"
                        "fecha" => "1993"
                        "volumen" => "14"
                        "paginaInicial" => "94"
                        "paginaFinal" => "106"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8491157"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib5"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effects of hypothyroidism induced by perinatal exposure to PTU on rat behavior and synaptic gene expression"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              K Kobayashi \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              R Tsuji \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              T Yoshioka \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              M Kushida \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              S Yabushita \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              M Sasaki \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1016/j.tox.2005.04.012"
                      "Revista" => array:6 [
                        "tituloSerie" => "Toxicology"
                        "fecha" => "2005"
                        "volumen" => "212"
                        "paginaInicial" => "135"
                        "paginaFinal" => "147"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15941614"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1016/j.tox.2005.04.012"
                      "WWW" => array:1 [
                        "link" => "10&#46;1016&#47;j&#46;tox&#46;2005&#46;04&#46;012"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib6"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Thyroid hormone regulation of N-methyl-D-aspartic acid receptor subunit mRNA expression in adult brain"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => """
                              PR Lee \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              D Brady \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              JI Koenig \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1046/j.1365-2826.2003.00959.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Neuroendocrinol"
                        "fecha" => "2003"
                        "volumen" => "15"
                        "paginaInicial" => "87"
                        "paginaFinal" => "92"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12535174"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1046/j.1365-2826.2003.00959.x"
                      "WWW" => array:1 [
                        "link" => "10&#46;1046&#47;j&#46;1365-2826&#46;2003&#46;00959&#46;x"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib7"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hypothyroidism and cognition&#58; preliminary evidence for a specific defect in memory"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => """
                              LA Burmeister \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              M Ganguli \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              HH Dodge \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              T Toczek \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              ST DeKosky \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              RD Nebes \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1089/10507250152741037"
                      "Revista" => array:6 [
                        "tituloSerie" => "Thyroid"
                        "fecha" => "2001"
                        "volumen" => "11"
                        "paginaInicial" => "1177"
                        "paginaFinal" => "1185"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12186506"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1089/10507250152741037"
                      "WWW" => array:1 [
                        "link" => "10&#46;1089&#47;10507250152741037"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib8"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "&#91;Is cognitive change related to hypothyroidism reversible with replacement therapy&#63;&#93;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              C Capet \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              A Jego \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              P Denis \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              D Noel \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              I Clerc \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              AC Cornier \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1016/s0248-8663(00)80022-3"
                      "Revista" => array:6 [
                        "tituloSerie" => "Rev Med Interne"
                        "fecha" => "2000"
                        "volumen" => "21"
                        "paginaInicial" => "672"
                        "paginaFinal" => "678"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10989492"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1016/s0248-8663(00)80022-3"
                      "WWW" => array:1 [
                        "link" => "10&#46;1016&#47;S0248-8663&#40;00&#41;80022-3"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib9"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Thyroid hormones&#44; brain function and cognition&#58; a brief review"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => """
                              JW Smith \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              AT Evans \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              B Costall \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              JW Smythe \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1016/s0149-7634(01)00037-9"
                      "Revista" => array:6 [
                        "tituloSerie" => "Neurosci Biobehav Rev"
                        "fecha" => "2002"
                        "volumen" => "26"
                        "paginaInicial" => "45"
                        "paginaFinal" => "60"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11835983"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1016/s0149-7634(01)00037-9"
                      "WWW" => array:1 [
                        "link" => "10&#46;1016&#47;S0149-7634&#40;01&#41;00037-9"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib10"
              "etiqueta" => "10"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Neurocognitive aspects of hypothyroidism"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => """
                              AT Dugbartey \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1001/archinte.158.13.1413"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arch Intern Med"
                        "fecha" => "1998"
                        "volumen" => "158"
                        "paginaInicial" => "1413"
                        "paginaFinal" => "1418"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9665349"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1001/archinte.158.13.1413"
                      "WWW" => array:1 [
                        "link" => "10&#46;1001&#47;archinte&#46;158&#46;13&#46;1413"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib11"
              "etiqueta" => "11"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Subclinical hypothyroidism&#58; a review of neuropsychiatric aspects"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              JJ Haggerty Jr \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              JC Garbutt \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              DL Evans \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              RN Golden \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              C Pedersen \n
                              \t\t\t\t\t\t\t\t
                              """
                            5 => """
                              JS Simon \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.2190/ADLY-1UU0-1A8L-HPXY"
                      "Revista" => array:6 [
                        "tituloSerie" => "Int J Psychiatry Med"
                        "fecha" => "1990"
                        "volumen" => "20"
                        "paginaInicial" => "193"
                        "paginaFinal" => "208"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2203696"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.2190/ADLY-1UU0-1A8L-HPXY"
                      "WWW" => array:1 [
                        "link" => "10&#46;2190&#47;ADLY-1UU0-1A8L-HPXY"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib12"
              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Verbal memory retrieval deficits associated with untreated hypothyroidism"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => """
                              KJ Miller \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              TD Parsons \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              PC Whybrow \n
                              \t\t\t\t\t\t\t\t
                              """
                             …3
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1176/jnp.2007.19.2.132"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Neuropsychiatry Clin Neurosci"
                        "fecha" => "2007"
                        "volumen" => "19"
                        "paginaInicial" => "132"
                        "paginaFinal" => "136"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib13"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Subclinical hypothyroidism is mild thyroid failure and should be treated"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1210/jcem.86.10.7959"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Endocrinol Metab"
                        "fecha" => "2001"
                        "volumen" => "86"
                        "paginaInicial" => "4585"
                        "paginaFinal" => "4590"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1210/jcem.86.10.7959"
                      "WWW" => array:1 [
                        "link" => "10&#46;1210&#47;jc&#46;86&#46;10&#46;4585"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib14"
              "etiqueta" => "14"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "7-Nitroindazole&#44; a neuronal nitric oxide synthase inhibitor&#44; impairs passive-avoidance and elevated plus-maze memory performance in rats"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1016/j.pbb.2007.05.019"
                      "Revista" => array:6 [
                        "tituloSerie" => "Pharmacol Biochem Behav"
                        "fecha" => "2007"
                        "volumen" => "87"
                        "paginaInicial" => "434"
                        "paginaFinal" => "443"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1016/j.pbb.2007.05.019"
                      "WWW" => array:1 [
                        "link" => "10&#46;1016&#47;j&#46;pbb&#46;2007&#46;05&#46;019"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib15"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Nitric oxide and memory"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [ …4]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1177/1073858403261226"
                      "Revista" => array:6 [
                        "tituloSerie" => "Neuroscientist"
                        "fecha" => "2004"
                        "volumen" => "10"
                        "paginaInicial" => "153"
                        "paginaFinal" => "162"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1177/1073858403261226"
                      "WWW" => array:1 [
                        "link" => "10&#46;1177&#47;1073858403261226"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib16"
              "etiqueta" => "16"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The pharmacodynamics of L-arginine"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [ …1]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/jn/137.6.1650S"
                      "Revista" => array:7 [
                        "tituloSerie" => "J Nutr"
                        "fecha" => "2007"
                        "volumen" => "137"
                        "numero" => "6 Suppl 2"
                        "paginaInicial" => "1650S"
                        "paginaFinal" => "1655S"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib17"
              "etiqueta" => "17"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Changes in NMDA receptor&#47;nitric oxide signaling pathway in the brain with aging"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1002/(SICI)1097-0029(19981001)43:1<68::AID-JEMT10>3.0.CO;2-W"
                      "Revista" => array:6 [
                        "tituloSerie" => "Microsc Res Tech"
                        "fecha" => "1998"
                        "volumen" => "43"
                        "paginaInicial" => "68"
                        "paginaFinal" => "74"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1002/(SICI)1097-0029(19981001)43:1<68::AID-JEMT10>3.0.CO;2-W"
                      "WWW" => array:1 [
                        "link" => "10&#46;1002&#47;&#40;SICI&#41;1097-0029&#40;19981001&#41;43&#58;1&#60;68&#58;&#58;AID-JEMT10&#62;3&#46;0&#46;CO&#59;2-W"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib18"
              "etiqueta" => "18"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Long-term deprivation of oestrogens by ovariectomy potentiates beta-amyloid-induced working memory deficits in rats"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Br J Pharmacol"
                        "fecha" => "1999"
                        "volumen" => "128"
                        "paginaInicial" => "419"
                        "paginaFinal" => "427"
                      ]
                    ]
                    1 => array:1 [
                      "WWW" => array:1 [
                        "link" => "10&#46;1038&#47;sj&#46;bjp&#46;0702811"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            18 => array:3 [
              "identificador" => "bib19"
              "etiqueta" => "19"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Glutamate&#44; nitric oxide and cell-cell signalling in the nervous system"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [ …1]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1016/0166-2236(91)90022-m"
                      "Revista" => array:6 [
                        "tituloSerie" => "Trends Neurosci"
                        "fecha" => "1991"
                        "volumen" => "14"
                        "paginaInicial" => "60"
                        "paginaFinal" => "67"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1016/0166-2236(91)90022-m"
                      "WWW" => array:1 [
                        "link" => "10&#46;1016&#47;0166-2236&#40;91&#41;90022-M"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            19 => array:3 [
              "identificador" => "bib20"
              "etiqueta" => "20"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Nitric oxide as modulator of neuronal function"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1016/s0301-0082(00)00044-7"
                      "Revista" => array:6 [
                        "tituloSerie" => "Prog Neurobiol"
                        "fecha" => "2001"
                        "volumen" => "64"
                        "paginaInicial" => "51"
                        "paginaFinal" => "68"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1016/s0301-0082(00)00044-7"
                      "WWW" => array:1 [
                        "link" => "10&#46;1016&#47;S0301-0082&#40;00&#41;00044-7"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            20 => array:3 [
              "identificador" => "bib21"
              "etiqueta" => "21"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "NO synthesis inhibition decreases cortical ACh release and impairs retention of a conditioned response"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1016/s0006-8993(00)03148-6"
                      "Revista" => array:6 [
                        "tituloSerie" => "Brain Res"
                        "fecha" => "2001"
                        "volumen" => "894"
                        "paginaInicial" => "141"
                        "paginaFinal" => "144"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1016/s0006-8993(00)03148-6"
                      "WWW" => array:1 [
                        "link" => "10&#46;1016&#47;S0006-8993&#40;00&#41;03148-6"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            21 => array:3 [
              "identificador" => "bib22"
              "etiqueta" => "22"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effects of nitric oxide on passive avoidance learning in rats"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Int J Neurosci"
                        "fecha" => "2004"
                        "volumen" => "114"
                        "paginaInicial" => "597"
                        "paginaFinal" => "606"
                      ]
                    ]
                    1 => array:1 [
                      "WWW" => array:1 [
                        "link" => "10&#46;1080&#47;00207450490430471"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            22 => array:3 [
              "identificador" => "bib23"
              "etiqueta" => "23"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Possible involvement of nitric oxide in long-term potentiation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1016/0014-2999(91)90505-k"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur J Pharmacol"
                        "fecha" => "1991"
                        "volumen" => "199"
                        "paginaInicial" => "379"
                        "paginaFinal" => "381"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1016/0014-2999(91)90505-k"
                      "WWW" => array:1 [
                        "link" => "10&#46;1016&#47;0014-2999&#40;91&#41;90505-K"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            23 => array:3 [
              "identificador" => "bib24"
              "etiqueta" => "24"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "On the role of nitric oxide in hippocampal long-term potentiation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1523/JNEUROSCI.23-05-01941.2003"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Neurosci"
                        "fecha" => "2003"
                        "volumen" => "23"
                        "paginaInicial" => "1941"
                        "paginaFinal" => "1948"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            24 => array:3 [
              "identificador" => "bib25"
              "etiqueta" => "25"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Involvement of hippocampal nitric oxide in spatial learning in the rat"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [ …4]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1016/j.nlm.2008.04.010"
                      "Revista" => array:6 [
                        "tituloSerie" => "Neurobiol Learn Mem"
                        "fecha" => "2008"
                        "volumen" => "90"
                        "paginaInicial" => "413"
                        "paginaFinal" => "419"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1016/j.nlm.2008.04.010"
                      "WWW" => array:1 [
                        "link" => "10&#46;1016&#47;j&#46;nlm&#46;2008&#46;04&#46;010"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            25 => array:3 [
              "identificador" => "bib26"
              "etiqueta" => "26"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Endogenous nitric oxide release required for long-term synaptic depression in the cerebellum"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1038/349326a0"
                      "Revista" => array:6 [
                        "tituloSerie" => "Nature"
                        "fecha" => "1991"
                        "volumen" => "349"
                        "paginaInicial" => "326"
                        "paginaFinal" => "328"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1038/349326a0"
                      "WWW" => array:1 [
                        "link" => "10&#46;1038&#47;349326a0"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            26 => array:3 [
              "identificador" => "bib27"
              "etiqueta" => "27"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Plasma concentration of asymmetric dimethylarginine&#44; an endogenous inhibitor of nitric oxide synthase&#44; is elevated in hyperthyroid patients"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "J Clin Endocrinol Metab"
                        "fecha" => "2002"
                        "volumen" => "87"
                        "paginaInicial" => "5636"
                        "paginaFinal" => "5640"
                      ]
                    ]
                    1 => array:1 [
                      "WWW" => array:1 [
                        "link" => "10&#46;1210&#47;jc&#46;2002-020905"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            27 => array:3 [
              "identificador" => "bib28"
              "etiqueta" => "28"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hypothalamic nitric oxide synthase gene expression is regulated by thyroid hormones"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [ …4]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1210/endo.136.10.7545100"
                      "Revista" => array:6 [
                        "tituloSerie" => "Endocrinology"
                        "fecha" => "1995"
                        "volumen" => "136"
                        "paginaInicial" => "4182"
                        "paginaFinal" => "4187"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1210/endo.136.10.7545100"
                      "WWW" => array:1 [
                        "link" => "10&#46;1210&#47;en&#46;136&#46;10&#46;4182"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            28 => array:3 [
              "identificador" => "bib29"
              "etiqueta" => "29"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The beneficial effects of olibanum on memory deficit induced by hypothyroidism in adult rats tested in Morris water maze"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Arch Pharm Res"
                        "fecha" => "2010"
                        "volumen" => "33"
                        "paginaInicial" => "463"
                        "paginaFinal" => "468"
                      ]
                    ]
                    1 => array:1 [
                      "WWW" => array:1 [
                        "link" => "10&#46;1007&#47;s12272-010-0317-z"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            29 => array:3 [
              "identificador" => "bib30"
              "etiqueta" => "30"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effect of hypothyroidism on beta-adrenoceptor-mediated relaxation in the rat thoracic aortae&#46; A time-dependent study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1016/s1537-1891(02)00166-0"
                      "Revista" => array:6 [
                        "tituloSerie" => "Vascul Pharmacol"
                        "fecha" => "2002"
                        "volumen" => "38"
                        "paginaInicial" => "149"
                        "paginaFinal" => "155"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1016/s1537-1891(02)00166-0"
                      "WWW" => array:1 [
                        "link" => "10&#46;1016&#47;S1537-1891&#40;02&#41;00166-0"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            30 => array:3 [
              "identificador" => "bib31"
              "etiqueta" => "31"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hypothyroidism and hyperthyroidism modulates Ras-MAPK intracellular pathway in rat thyroids"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Endocrine"
                        "fecha" => "2007"
                        "volumen" => "31"
                        "paginaInicial" => "174"
                        "paginaFinal" => "178"
                      ]
                    ]
                    1 => array:1 [
                      "WWW" => array:1 [
                        "link" => "10&#46;1007&#47;s12020-007-0029-4"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            31 => array:3 [
              "identificador" => "bib32"
              "etiqueta" => "32"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Vitamins E and C pretreatment prevents ovariectomy-induced memory deficits in water maze"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1016/j.nlm.2005.08.002"
                      "Revista" => array:6 [
                        "tituloSerie" => "Neurobiol Learn Mem"
                        "fecha" => "2005"
                        "volumen" => "84"
                        "paginaInicial" => "192"
                        "paginaFinal" => "199"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1016/j.nlm.2005.08.002"
                      "WWW" => array:1 [
                        "link" => "10&#46;1016&#47;j&#46;nlm&#46;2005&#46;08&#46;002"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            32 => array:3 [
              "identificador" => "bib33"
              "etiqueta" => "33"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The effect of L-Arginin on Morris water maze tasks of ovariectomized rats"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1556/APhysiol.97.2010.2.8"
                      "Revista" => array:6 [
                        "tituloSerie" => "Acta Physiol Hung"
                        "fecha" => "2010"
                        "volumen" => "97"
                        "paginaInicial" => "216"
                        "paginaFinal" => "223"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1556/APhysiol.97.2010.2.8"
                      "WWW" => array:1 [
                        "link" => "10&#46;1556&#47;APhysiol&#46;97&#46;2010&#46;2&#46;8"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            33 => array:3 [
              "identificador" => "bib34"
              "etiqueta" => "34"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effects of treadmill running on mid-term memory and swim speed in the rat with Morris water maze test"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jbmt.2007.05.004"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Bodyw Mov Ther"
                        "fecha" => "2008"
                        "volumen" => "12"
                        "paginaInicial" => "72"
                        "paginaFinal" => "75"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1016/j.jbmt.2007.05.004"
                      "WWW" => array:1 [
                        "link" => "10&#46;1016&#47;j&#46;jbmt&#46;2007&#46;05&#46;004"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            34 => array:3 [
              "identificador" => "bib35"
              "etiqueta" => "35"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Nitric oxide and reactive nitrogen intermediates during lethal and nonlethal strains of murine malaria"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1046/j.1365-3024.2001.00406.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Parasite Immunol"
                        "fecha" => "2001"
                        "volumen" => "23"
                        "paginaInicial" => "491"
                        "paginaFinal" => "501"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1046/j.1365-3024.2001.00406.x"
                      "WWW" => array:1 [
                        "link" => "10&#46;1046&#47;j&#46;1365-3024&#46;2001&#46;00406&#46;x"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            35 => array:3 [
              "identificador" => "bib36"
              "etiqueta" => "36"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Antileishmanial effects of trinitroglycerin in BALB&#47;C mice infected with Leishmania major via nitric oxide pathway"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.3347/kjp.2009.47.2.109"
                      "Revista" => array:6 [
                        "tituloSerie" => "Korean J Parasitol"
                        "fecha" => "2009"
                        "volumen" => "47"
                        "paginaInicial" => "109"
                        "paginaFinal" => "115"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.3347/kjp.2009.47.2.109"
                      "WWW" => array:1 [
                        "link" => "10&#46;3347&#47;kjp&#46;2009&#46;47&#46;2&#46;109"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            36 => array:3 [
              "identificador" => "bib37"
              "etiqueta" => "37"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Motor and cognitive development in children with congenital hypothyroidism&#58; a long-term evaluation of the effects of neonatal treatment"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1016/s0022-3476(05)83178-6"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Pediatr"
                        "fecha" => "1994"
                        "volumen" => "124"
                        "paginaInicial" => "903"
                        "paginaFinal" => "909"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1016/s0022-3476(05)83178-6"
                      "WWW" => array:1 [
                        "link" => "10&#46;1016&#47;S0022-3476&#40;05&#41;83178-6"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            37 => array:3 [
              "identificador" => "bib38"
              "etiqueta" => "38"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Age-dependent alterations of long-term synaptic plasticity in thyroid-deficient rats"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Hippocampus"
                        "fecha" => "2003"
                        "volumen" => "13"
                        "paginaInicial" => "816"
                        "paginaFinal" => "825"
                      ]
                    ]
                    1 => array:1 [
                      "WWW" => array:1 [
                        "link" => "10&#46;1002&#47;hipo&#46;10132"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            38 => array:3 [
              "identificador" => "bib39"
              "etiqueta" => "39"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Syndrome of resistance to thyroid hormone&#58; insights into thyroid hormone action"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3181/00379727-211-43951"
                      "Revista" => array:6 [
                        "tituloSerie" => "Proc Soc Exp Biol Med"
                        "fecha" => "1996"
                        "volumen" => "211"
                        "paginaInicial" => "49"
                        "paginaFinal" => "61"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            39 => array:3 [
              "identificador" => "bib40"
              "etiqueta" => "40"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hyperactivity and spatial maze learning impairment of adult rats with temporary neonatal hypothyroidism"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [ …4]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1016/0892-0362(91)90077-a"
                      "Revista" => array:6 [
                        "tituloSerie" => "Neurotoxicol Teratol"
                        "fecha" => "1991"
                        "volumen" => "13"
                        "paginaInicial" => "317"
                        "paginaFinal" => "322"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1016/0892-0362(91)90077-a"
                      "WWW" => array:1 [
                        "link" => "10&#46;1016&#47;0892-0362&#40;91&#41;90077-A"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            40 => array:3 [
              "identificador" => "bib41"
              "etiqueta" => "41"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "An unliganded thyroid hormone receptor causes severe neurological dysfunction"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1073/pnas.051454698"
                      "Revista" => array:6 [
                        "tituloSerie" => "Proc Natl Acad Sci U S A"
                        "fecha" => "2001"
                        "volumen" => "98"
                        "paginaInicial" => "3998"
                        "paginaFinal" => "4003"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1073/pnas.051454698"
                      "WWW" => array:1 [
                        "link" => "10&#46;1073&#47;pnas&#46;051454698"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            41 => array:3 [
              "identificador" => "bib42"
              "etiqueta" => "42"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Adverse effect of the combination of hypothyroidism and chronic psychosocial stress on hippocampus-dependent memory in rats"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1016/j.bbr.2004.04.003"
                      "Revista" => array:6 [
                        "tituloSerie" => "Behav Brain Res"
                        "fecha" => "2004"
                        "volumen" => "155"
                        "paginaInicial" => "77"
                        "paginaFinal" => "84"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1016/j.bbr.2004.04.003"
                      "WWW" => array:1 [
                        "link" => "10&#46;1016&#47;j&#46;bbr&#46;2004&#46;04&#46;003"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            42 => array:3 [
              "identificador" => "bib43"
              "etiqueta" => "43"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hypothyroidism impairs late LTP in CA1 region but not in dentate gyrus of the intact rat hippocampus&#58; MAPK involvement"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Hippocampus"
                        "fecha" => "2004"
                        "volumen" => "14"
                        "paginaInicial" => "40"
                        "paginaFinal" => "45"
                      ]
                    ]
                    1 => array:1 [
                      "WWW" => array:1 [
                        "link" => "10&#46;1002&#47;hipo&#46;10165"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            43 => array:3 [
              "identificador" => "bib44"
              "etiqueta" => "44"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Nicotine reverses adult-onset hypothyroidism-induced impairment of learning and memory&#58; Behavioral and electrophysiological studies"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [ …4]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1002/jnr.21014"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Neurosci Res"
                        "fecha" => "2006"
                        "volumen" => "84"
                        "paginaInicial" => "944"
                        "paginaFinal" => "953"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1002/jnr.21014"
                      "WWW" => array:1 [
                        "link" => "10&#46;1002&#47;jnr&#46;21014"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            44 => array:3 [
              "identificador" => "bib45"
              "etiqueta" => "45"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Thyroid hormone and development of the rat hippocampus&#58; cell acquisition in the dentate gyrus"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1016/0306-4522(86)90134-x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Neuroscience"
                        "fecha" => "1986"
                        "volumen" => "19"
                        "paginaInicial" => "1207"
                        "paginaFinal" => "1216"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1016/0306-4522(86)90134-x"
                      "WWW" => array:1 [
                        "link" => "10&#46;1016&#47;0306-4522&#40;86&#41;90134-X"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            45 => array:3 [
              "identificador" => "bib46"
              "etiqueta" => "46"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Alterations in synaptic transmission and plasticity in area CA1 of adult hippocampus following developmental hypothyroidism"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [ …1]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1016/j.devbrainres.2003.09.018"
                      "Revista" => array:6 [
                        "tituloSerie" => "Brain Res Dev Brain Res"
                        "fecha" => "2004"
                        "volumen" => "148"
                        "paginaInicial" => "11"
                        "paginaFinal" => "18"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1016/j.devbrainres.2003.09.018"
                      "WWW" => array:1 [
                        "link" => "10&#46;1016&#47;j&#46;devbrainres&#46;2003&#46;09&#46;018"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            46 => array:3 [
              "identificador" => "bib47"
              "etiqueta" => "47"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Propylthiouracil &#40;PTU&#41;-induced hypothyroidism in the developing rat impairs synaptic transmission and plasticity in the dentate gyrus of the adult hippocampus"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1016/s0165-3806(03)00191-3"
                      "Revista" => array:6 [
                        "tituloSerie" => "Brain Res Dev Brain Res"
                        "fecha" => "2003"
                        "volumen" => "145"
                        "paginaInicial" => "19"
                        "paginaFinal" => "29"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1016/s0165-3806(03)00191-3"
                      "WWW" => array:1 [
                        "link" => "10&#46;1016&#47;S0165-3806&#40;03&#41;00191-3"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            47 => array:3 [
              "identificador" => "bib48"
              "etiqueta" => "48"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Congenital iodine deficiency and hypothyroidism impair LTP and decrease C-fos and C-jun expression in rat hippocampus"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1016/j.neuro.2005.03.003"
                      "Revista" => array:6 [
                        "tituloSerie" => "Neurotoxicology"
                        "fecha" => "2005"
                        "volumen" => "26"
                        "paginaInicial" => "417"
                        "paginaFinal" => "426"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1016/j.neuro.2005.03.003"
                      "WWW" => array:1 [
                        "link" => "10&#46;1016&#47;j&#46;neuro&#46;2005&#46;03&#46;003"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            48 => array:3 [
              "identificador" => "bib49"
              "etiqueta" => "49"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Impairment in short-term but enhanced long-term synaptic potentiation and ERK activation in adult hippocampal area CA1 following developmental thyroid hormone insufficiency"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1093/toxsci/kfi095"
                      "Revista" => array:6 [
                        "tituloSerie" => "Toxicol Sci"
                        "fecha" => "2005"
                        "volumen" => "85"
                        "paginaInicial" => "647"
                        "paginaFinal" => "656"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1093/toxsci/kfi095"
                      "WWW" => array:1 [
                        "link" => "10&#46;1093&#47;toxsci&#47;kfi095"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            49 => array:3 [
              "identificador" => "bib50"
              "etiqueta" => "50"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Thyroid hormone regulates neurotransmitter release in neonatal rat hippocampus"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [ …4]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1016/s0306-4522(01)00541-3"
                      "Revista" => array:6 [
                        "tituloSerie" => "Neuroscience"
                        "fecha" => "2002"
                        "volumen" => "110"
                        "paginaInicial" => "19"
                        "paginaFinal" => "28"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1016/s0306-4522(01)00541-3"
                      "WWW" => array:1 [
                        "link" => "10&#46;1016&#47;S0306-4522&#40;01&#41;00541-3"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            50 => array:3 [
              "identificador" => "bib51"
              "etiqueta" => "51"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Decreased glutamate release during hypothyroidism may contribute to protection in cerebral ischemia"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1006/exnr.1994.1135"
                      "Revista" => array:6 [
                        "tituloSerie" => "Exp Neurol"
                        "fecha" => "1994"
                        "volumen" => "128"
                        "paginaInicial" => "260"
                        "paginaFinal" => "265"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1006/exnr.1994.1135"
                      "WWW" => array:1 [
                        "link" => "10&#46;1006&#47;exnr&#46;1994&#46;1135"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            51 => array:3 [
              "identificador" => "bib52"
              "etiqueta" => "52"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Adult-onset hypothyroidism impairs paired-pulse facilitation and longterm potentiation of the rat dorsal hippocampo-medial prefrontal cortex pathway in vivo"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1016/j.brainres.2006.04.042"
                      "Revista" => array:6 [
                        "tituloSerie" => "Brain Res"
                        "fecha" => "2006 22"
                        "volumen" => "1096"
                        "paginaInicial" => "53"
                        "paginaFinal" => "60"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1016/j.brainres.2006.04.042"
                      "WWW" => array:1 [
                        "link" => "10&#46;1016&#47;j&#46;brainres&#46;2006&#46;04&#46;042"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            52 => array:3 [
              "identificador" => "bib53"
              "etiqueta" => "53"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Expression of vesicular glutamate transporter-2 in gonadotropin-releasing hormone neurons of the adult male rat"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [ …4]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1210/en.2004-0589"
                      "Revista" => array:6 [
                        "tituloSerie" => "Endocrinology"
                        "fecha" => "2004"
                        "volumen" => "145"
                        "paginaInicial" => "4018"
                        "paginaFinal" => "4021"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1210/en.2004-0589"
                      "WWW" => array:1 [
                        "link" => "10&#46;1210&#47;en&#46;2004-0589"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            53 => array:3 [
              "identificador" => "bib54"
              "etiqueta" => "54"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hypothyroidism induces selective oxidative stress in amygdala and hippocampus of rat"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1007/s11011-008-9099-0"
                      "Revista" => array:6 [
                        "tituloSerie" => "Metab Brain Dis"
                        "fecha" => "2008"
                        "volumen" => "23"
                        "paginaInicial" => "275"
                        "paginaFinal" => "287"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1007/s11011-008-9099-0"
                      "WWW" => array:1 [
                        "link" => "10&#46;1007&#47;s11011-008-9099-0"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            54 => array:3 [
              "identificador" => "bib55"
              "etiqueta" => "55"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Biomarkers in Alzheimer&#39;s disease&#58; past&#44; present and future"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.2217/bmm.09.86"
                      "Revista" => array:6 [
                        "tituloSerie" => "Biomark Med"
                        "fecha" => "2010"
                        "volumen" => "4"
                        "paginaInicial" => "15"
                        "paginaFinal" => "26"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.2217/bmm.09.86"
                      "WWW" => array:1 [
                        "link" => "10&#46;2217&#47;bmm&#46;09&#46;86"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            55 => array:3 [
              "identificador" => "bib56"
              "etiqueta" => "56"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Oxidative damage and cognitive dysfunction&#58; antioxidant treatments to promote healthy brain aging"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [ …1]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1007/s11064-008-9808-4"
                      "Revista" => array:6 [
                        "tituloSerie" => "Neurochem Res"
                        "fecha" => "2009"
                        "volumen" => "34"
                        "paginaInicial" => "670"
                        "paginaFinal" => "678"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1007/s11064-008-9808-4"
                      "WWW" => array:1 [
                        "link" => "10&#46;1007&#47;s11064-008-9808-4"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            56 => array:3 [
              "identificador" => "bib57"
              "etiqueta" => "57"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pathophysiology of neuronal energy crisis in Alzheimer&#39;s disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [ …1]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1159/000113681"
                      "Revista" => array:6 [
                        "tituloSerie" => "Neurodegener Dis"
                        "fecha" => "2008"
                        "volumen" => "5"
                        "paginaInicial" => "126"
                        "paginaFinal" => "132"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1159/000113681"
                      "WWW" => array:1 [
                        "link" => "10&#46;1159&#47;000113681"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            57 => array:3 [
              "identificador" => "bib58"
              "etiqueta" => "58"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Recent advances in our understanding of neurodegeneration"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [ …1]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1007/s00702-009-0240-y"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Neural Transm"
                        "fecha" => "2009"
                        "volumen" => "116"
                        "paginaInicial" => "1111"
                        "paginaFinal" => "1162"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1007/s00702-009-0240-y"
                      "WWW" => array:1 [
                        "link" => "10&#46;1007&#47;s00702-009-0240-y"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            58 => array:3 [
              "identificador" => "bib59"
              "etiqueta" => "59"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "2&#8242;3&#8242;Cyclic nucleotide 3&#8242;phosphodiesterase immunohistochemistry shows an impairment on myelin compaction in hypothyroid rats"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1016/s0736-5748(00)00028-9"
                      "Revista" => array:6 [
                        "tituloSerie" => "Int J Dev Neurosci"
                        "fecha" => "2000"
                        "volumen" => "18"
                        "paginaInicial" => "887"
                        "paginaFinal" => "892"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1016/s0736-5748(00)00028-9"
                      "WWW" => array:1 [
                        "link" => "10&#46;1016&#47;S0736-5748&#40;00&#41;00028-9"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            59 => array:3 [
              "identificador" => "bib60"
              "etiqueta" => "60"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The development of the anterior commissure in normal and hypothyroid rats"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Brain Res Dev Brain Res"
                        "fecha" => "1994"
                        "volumen" => "81"
                        "paginaInicial" => "293"
                        "paginaFinal" => "308"
                      ]
                    ]
                    1 => array:1 [
                      "WWW" => array:1 [
                        "link" => "10&#46;1016&#47;0165-3806&#40;94&#41;90315-8"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            60 => array:3 [
              "identificador" => "bib61"
              "etiqueta" => "61"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Levothyroxin restores hypothyroidisminduced impairment of hippocampus-dependent learning and memory&#58; Behavioral&#44; electrophysiological&#44; and molecular studies"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [ …4]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1002/hipo.20476"
                      "Revista" => array:6 [
                        "tituloSerie" => "Hippocampus"
                        "fecha" => "2009"
                        "volumen" => "19"
                        "paginaInicial" => "66"
                        "paginaFinal" => "78"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1002/hipo.20476"
                      "WWW" => array:1 [
                        "link" => "10&#46;1002&#47;hipo&#46;20476"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            61 => array:3 [
              "identificador" => "bib62"
              "etiqueta" => "62"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "An inhibitor of nitric oxide synthesis prevents memory formation in the chick"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Neurosci Lett"
                        "fecha" => "1992"
                        "volumen" => "145"
                        "paginaInicial" => "165"
                        "paginaFinal" => "167"
                      ]
                    ]
                    1 => array:1 [
                      "WWW" => array:1 [
                        "link" => "10&#46;1016&#47;0304-3940&#40;92&#41;90012-V"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            62 => array:3 [
              "identificador" => "bib63"
              "etiqueta" => "63"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "On the respective roles of nitric oxide and carbon monoxide in long-term potentiation in the hippocampus"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [ …4]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Learn Mem"
                        "fecha" => "1998"
                        "volumen" => "5"
                        "paginaInicial" => "467"
                        "paginaFinal" => "480"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            63 => array:3 [
              "identificador" => "bib64"
              "etiqueta" => "64"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "On the respective roles of nitric oxide and carbon monoxide in long-term potentiation in the hippocampus"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [ …4]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Learn Mem"
                        "fecha" => "1999"
                        "volumen" => "6"
                        "paginaInicial" => "63"
                        "paginaFinal" => "76"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            64 => array:3 [
              "identificador" => "bib65"
              "etiqueta" => "65"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Nitric oxide and carbon monoxide produce activity-dependent long-term synaptic enhancement in hippocampus"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [ …4]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1126/science.8100368"
                      "Revista" => array:6 [
                        "tituloSerie" => "Science"
                        "fecha" => "1993"
                        "volumen" => "260"
                        "paginaInicial" => "1946"
                        "paginaFinal" => "1950"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1126/science.8100368"
                      "WWW" => array:1 [
                        "link" => "10&#46;1126&#47;science&#46;8100368"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            65 => array:3 [
              "identificador" => "bib66"
              "etiqueta" => "66"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Inhibition of nitric oxide synthase does not prevent the induction of long-term potentiation in vivo"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1523/JNEUROSCI.14-12-07415.1994"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Neurosci"
                        "fecha" => "1994"
                        "volumen" => "14"
                        "paginaInicial" => "7415"
                        "paginaFinal" => "7425"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            66 => array:3 [
              "identificador" => "bib67"
              "etiqueta" => "67"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Maternal thyroid hormone&#58; a strong repressor of neuronal nitric oxide synthase in rat embryonic neocortex"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Endocrinology"
                        "fecha" => "2008"
                        "volumen" => "149"
                        "paginaInicial" => "4396"
                        "paginaFinal" => "4401"
                      ]
                    ]
                    1 => array:1 [
                      "WWW" => array:1 [
                        "link" => "10&#46;1210&#47;en&#46;2007-1617"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            67 => array:3 [
              "identificador" => "bib68"
              "etiqueta" => "68"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Nitric oxide acts in a positive feedback loop with BDNF to regulate neural progenitor cell proliferation and differentiation in the mammalian brain"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1016/s0012-1606(03)00120-9"
                      "Revista" => array:6 [
                        "tituloSerie" => "Dev Biol"
                        "fecha" => "2003 15"
                        "volumen" => "258"
                        "paginaInicial" => "319"
                        "paginaFinal" => "333"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1016/s0012-1606(03)00120-9"
                      "WWW" => array:1 [
                        "link" => "10&#46;1016&#47;S0012-1606&#40;03&#41;00120-9"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            68 => array:3 [
              "identificador" => "bib69"
              "etiqueta" => "69"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Neuronal nitric oxide synthase &#40;NOS-I&#41; knockout increases the survival rate of neural cells in the hippocampus independently of BDNF"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1016/j.mcn.2007.02.021"
                      "Revista" => array:6 [
                        "tituloSerie" => "Mol Cell Neurosci"
                        "fecha" => "2007"
                        "volumen" => "35"
                        "paginaInicial" => "261"
                        "paginaFinal" => "271"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1016/j.mcn.2007.02.021"
                      "WWW" => array:1 [
                        "link" => "10&#46;1016&#47;j&#46;mcn&#46;2007&#46;02&#46;021"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            69 => array:3 [
              "identificador" => "bib70"
              "etiqueta" => "70"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Distribution of nitric oxide synthase immunoreactive neurons in fetal rat brains at embryonic day 15 and day 19"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1016/0891-0618(96)00141-x"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Chem Neuroanat"
                        "fecha" => "1996"
                        "volumen" => "10"
                        "paginaInicial" => "273"
                        "paginaFinal" => "278"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1016/0891-0618(96)00141-x"
                      "WWW" => array:1 [
                        "link" => "10&#46;1016&#47;0891-0618&#40;96&#41;00141-X"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            70 => array:3 [
              "identificador" => "bib71"
              "etiqueta" => "71"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Differential susceptibility to neurotoxicity mediated by neurotrophins and neuronal nitric oxide synthase"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1523/JNEUROSCI.17-12-04633.1997"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Neurosci"
                        "fecha" => "1997 15"
                        "volumen" => "17"
                        "paginaInicial" => "4633"
                        "paginaFinal" => "4641"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            71 => array:3 [
              "identificador" => "bib72"
              "etiqueta" => "72"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Thyroid hormones affect the level and activity of nitric oxide synthase in rat cerebral cortex during postnatal development"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1007/s11064-007-9480-0"
                      "Revista" => array:6 [
                        "tituloSerie" => "Neurochem Res"
                        "fecha" => "2008"
                        "volumen" => "33"
                        "paginaInicial" => "569"
                        "paginaFinal" => "578"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1007/s11064-007-9480-0"
                      "WWW" => array:1 [
                        "link" => "10&#46;1007&#47;s11064-007-9480-0"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            72 => array:3 [
              "identificador" => "bib73"
              "etiqueta" => "73"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Nitric oxide synthase activity in hyperthyroid and hypothyroid rats"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1530/eje.0.1470117"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur J Endocrinol"
                        "fecha" => "2002"
                        "volumen" => "147"
                        "paginaInicial" => "117"
                        "paginaFinal" => "122"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1530/eje.0.1470117"
                      "WWW" => array:1 [
                        "link" => "10&#46;1530&#47;eje&#46;0&#46;1470117"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            73 => array:3 [
              "identificador" => "bib74"
              "etiqueta" => "74"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cognitive deficits following blast injury-induced neurotrauma&#58; possible involvement of nitric oxide"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Brain Inj"
                        "fecha" => "2001"
                        "volumen" => "15"
                        "paginaInicial" => "593"
                        "paginaFinal" => "612"
                      ]
                    ]
                    1 => array:1 [
                      "WWW" => array:1 [
                        "link" => "10&#46;1080&#47;02699050010009559"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            74 => array:3 [
              "identificador" => "bib75"
              "etiqueta" => "75"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A novel neuronal messenger molecule in brain&#58; the free radical&#44; nitric oxide"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1002/ana.410320302"
                      "Revista" => array:6 [
                        "tituloSerie" => "Ann Neurol"
                        "fecha" => "1992"
                        "volumen" => "32"
                        "paginaInicial" => "297"
                        "paginaFinal" => "311"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1002/ana.410320302"
                      "WWW" => array:1 [
                        "link" => "10&#46;1002&#47;ana&#46;410320302"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            75 => array:3 [
              "identificador" => "bib76"
              "etiqueta" => "76"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Nitric oxide activation of poly&#40;ADP-ribose&#41; synthetase in neurotoxicity"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [ …4]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1126/science.8080500"
                      "Revista" => array:6 [
                        "tituloSerie" => "Science"
                        "fecha" => "1994 Feb 4"
                        "volumen" => "263"
                        "paginaInicial" => "687"
                        "paginaFinal" => "689"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1126/science.8080500"
                      "WWW" => array:1 [
                        "link" => "10&#46;1126&#47;science&#46;8080500"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            76 => array:3 [
              "identificador" => "bib77"
              "etiqueta" => "77"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Oxidative damage in the central nervous system&#58; protection by melatonin"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [ …1]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:2 [
                      "doi" => "10.1016/s0301-0082(98)00052-5"
                      "Revista" => array:6 [
                        "tituloSerie" => "Prog Neurobiol"
                        "fecha" => "1998"
                        "volumen" => "56"
                        "paginaInicial" => "359"
                        "paginaFinal" => "384"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                    1 => array:2 [
                      "doi" => "10.1016/s0301-0082(98)00052-5"
                      "WWW" => array:1 [
                        "link" => "10&#46;1016&#47;S0301-0082&#40;98&#41;00052-5"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            77 => array:3 [
              "identificador" => "bib78"
              "etiqueta" => "78"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:2 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Proc Natl Acad Sci U S A"
                        "fecha" => "1991"
                        "volumen" => "88"
                        "paginaInicial" => "6368"
                        "paginaFinal" => "6371"
                      ]
                    ]
                    1 => array:1 [
                      "WWW" => array:1 [
                        "link" => "10&#46;1073&#47;pnas&#46;88&#46;14&#46;6368"
                      ]
                    ]
                  ]
                ]
              ]
            ]
          ]
        ]
      ]
    ]
    "agradecimientos" => array:1 [
      0 => array:4 [
        "identificador" => "xack638839"
        "titulo" => "ACKNOWLEDGEMENTS"
        "texto" => "<p id="para190" class="elsevierStylePara elsevierViewall">We would like to thank the Vice Chancellor of Research of Mashhad University of Medical Sciences for financial support&#46;</p>"
        "vista" => "all"
      ]
    ]
  ]
  "idiomaDefecto" => "en"
  "url" => "/18075932/0000006500000011/v1_202212010805/S1807593222029052/v1_202212010805/en/main.assets"
  "Apartado" => null
  "PDF" => "https://static.elsevier.es/multimedia/18075932/0000006500000011/v1_202212010805/S1807593222029052/v1_202212010805/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/"
  "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1807593222029052?idApp=UINPBA00004N"
]

Article information

ISSN: 18075932
Original language: English

DOI:10.1590/S1807-59322010001100021

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	2	0	2
2024 October	39	29	68
2024 September	40	17	57
2024 August	41	24	65
2024 July	44	16	60
2024 June	41	17	58
2024 May	41	9	50
2024 April	32	8	40
2024 March	40	12	52
2024 February	39	14	53
2024 January	39	6	45
2023 December	20	21	41
2023 November	22	18	40
2023 October	30	17	47
2023 September	28	18	46
2023 August	14	5	19
2023 July	6	12	18
2023 June	13	10	23
2023 May	23	1	24
2023 April	29	0	29
2023 March	30	2	32
2023 February	41	1	42
2023 January	18	2	20
2022 December	8	1	9

Show all

Indexed in:

Follow us:

Statistics

Indexed in:

Follow us:

Statistics

Subscribe to our newsletter