Original article
Expression of NMDA receptor subunits in rat prefrontal cortex with CCL4-induced hepatic damage after a treatment with Rosmarinus officinalis L.
Expresión de las subunidades del receptor NMDA en la corteza prefrontal de la rata con daño hepático inducido con CCL4 después del tratamiento con Rosmarinus officinalis L.
C. Soria Fregozoa,
, M.L. Miranda Beltránb, M.E. Flores Sotoc, M.I. Pérez Vegaa, C. Beas Zárated, L. Huacuja Ruize
Corresponding author
a Laboratorio de Psicobiología y Biología Molecular, Departamento de Ciencias de la Tierra y de la Vida, Centro Universitario de los Lagos, Universidad de Guadalajara, Guadalajara, Mexico
b Laboratorio de Fitofarmacología, Departamento de Ciencias de la Tierra y de la Vida, Centro Universitario de los Lagos, Universidad de Guadalajara, Guadalajara, Mexico
c Laboratorio de Investigación y Desarrollo Farmacéutico, Centro Universitario de Ciencias Exactas e Ingenierias, CUCEI, Universidad de Guadalajara, Mexico
d Laboratorio de Neurobiología Celular y Molecular, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Mexico
e Instituto de Enfermedades Crónico-Degenerativas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Mexico
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"apellidos" => "Huacuja Ruiz" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">e</span>" "identificador" => "aff0025" ] ] ] ] "afiliaciones" => array:5 [ 0 => array:3 [ "entidad" => "Laboratorio de Psicobiología y Biología Molecular, Departamento de Ciencias de la Tierra y de la Vida, Centro Universitario de los Lagos, Universidad de Guadalajara, Guadalajara, Mexico" "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Laboratorio de Fitofarmacología, Departamento de Ciencias de la Tierra y de la Vida, Centro Universitario de los Lagos, Universidad de Guadalajara, Guadalajara, Mexico" "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Laboratorio de Investigación y Desarrollo Farmacéutico, Centro Universitario de Ciencias Exactas e Ingenierias, CUCEI, Universidad de Guadalajara, Mexico" "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Laboratorio de Neurobiología Celular y Molecular, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Mexico" "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Instituto de Enfermedades Crónico-Degenerativas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Mexico" "etiqueta" => "<span class="elsevierStyleSup">e</span>" "identificador" => "aff0025" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Expresión de las subunidades del receptor NMDA en la corteza prefrontal de la rata con daño hepático inducido con CCL4 después del tratamiento con <span class="elsevierStyleItalic">Rosmarinus officinalis</span> L." ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 961 "Ancho" => 1520 "Tamanyo" => 59952 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Levels of NR2A mRNA in the prefrontal cortex of the rat. (A) Gel photograph representing the different study groups. Mean<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>SD of 4 duplicate experiments. *<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>.05 CCI4 vs C. **<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>.05 CCI4<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>ROM vs CCI4.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Liver cirrhosis is a pathological state that occurs when chronic hepatic damage causes diffuse scarring of the tissue, thereby preventing blood from circulating freely through the scar tissue.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> The mechanisms leading to cirrhosis are alcohol abuse and chronic liver damage secondary to infection with hepatitis B or C. We also know that tissue damage resulting from oxidative stress is one of the important factors in liver failure.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> The use of experimental models of hepatic damage has suggested some mechanisms that may be active in the development of this disease. Moreover, these models have shown the effect of these mechanisms on other organs, such as the brain, where they may trigger the onset of hepatic encephalopathy (HE).<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> In HE, disorders in brain function are the consequence of a prior failure in normal liver function.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Liver function failure impedes the detoxification process for ammonia and other toxic substances that may reach the brain and modify its function.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Hyperammonaemia is one of the factors that contribute to neurological disorders caused by both acute and chronic liver failure.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The glutamatergic system is the neurotransmission system most commonly involved in liver failure.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> The alterations of this system affect the function of NMDA receptors and some glutamate (Glu) transporters. This in turn is related to motor and cognitive impairment in subjects with HE.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> It has been reported that acute liver failure decreases expression of astrocytic glutamate transporters (GLT-1) and increases the extracellular concentration of Glu in different regions of the brain.<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8,9</span></a> Additionally, different models of chronic hyperammonaemia and chronic liver failure have shown a decrease in NMDA receptor binding sites in the cerebral cortex, hippocampus, striatum and thalamus.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> It has been suggested that this decrease takes place as an adaptive response by these receptors so that they do not become over-activated. We should also point out that hyperammonaemia and acute liver failure do not modify binding by these receptors.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> It has also been reported that in cases of hepatic damage, certain toxic substances may reach the brain and provoke morphological changes affecting only the astrocytes. Nevertheless, we read reports of neuronal death mediated by excitotoxicity mechanisms via activation of NMDA receptors, similar to that occurring in cerebral ischaemia, in models of carbon tetrachloride (CCI4) hepatotoxicity.<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12,13</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Treating cirrhosis is expensive and treatment must be increased as the disease progresses. The incidence of diseases associated with liver failure, such as HE, is high. Such diseases have a considerable impact on the quality of life of a large number of people, and in advanced stages may result in coma or death.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> Moreover, despite the progress that has been made in liver diseases, there is no effective treatment. Therapeutic strategies use a palliative approach that delays the symptoms associated with cirrhosis. They mainly consist of low-fat diets and vitamin supplements.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> At present, the only effective treatment is liver transplantation. Survival rates at 1 year after the surgery are as high as 70%.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> However, it has also been suggested that medicinal plants are a viable alternative that can contribute to resolving health problems. Therefore, studies in both ethnobotany and popular medicine have reported a wide variety of medicinal plants used for gastrointestinal complaints which have a protective effect on the liver due to their high hydroxyphenolic compound content. For instance, silymarin (a compound obtained from <span class="elsevierStyleItalic">Silybum marianum</span> [<span class="elsevierStyleItalic">Asteraceae</span>]) has been shown to protect the liver from multiple types of damage.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> In addition, HD-03, a polyherbal formulation containing 7 plants, is reported to be effective in different models of hepatotoxicity. It is able to regulate ammonia metabolism and reduce pathological neuronal morphological characteristics in the case of CCI4-induced HE.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> Moreover, we know that the extract obtained from <span class="elsevierStyleItalic">Rosmarinus officinalis</span> L. contains flavonoids, phenols, volatile oils, and terpenes, and it has a high antioxidant activity attributed to carnosol and carnosic acid (CA).<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> In fact, earlier laboratory studies have demonstrated that <span class="elsevierStyleItalic">R. officinalis</span> L. extract protects the liver from the onset of liver cirrhosis in a model of sustained CCI4 administration.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> This extract also exerts a protective effect on neuronal morphology and the expression of mRNA by the glutamate transporter GLT-1.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> With all of the above in mind, the purpose of our study is to evaluate the expression of subunits NR1, NR2A, and NR2B in glutamate receptors in the prefrontal cortex of rats with CCI4-induced hepatic damage after treatment with <span class="elsevierStyleItalic">R. officinalis</span> L.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Subject and methods</span><p id="par0020" class="elsevierStylePara elsevierViewall">All experiments were carried out according to the <span class="elsevierStyleItalic">Guide for the Care and Use of Laboratory Animals</span> by the National Institute of Health (NIH Publication No. 8023, 1978). Our study included 24 male rats (Wistar strain) with body weights ranging from 80 to 90<span class="elsevierStyleHsp" style=""></span>g. They lived in standard vivarium conditions, with 12:12 light–dark cycles and free access to food and water. We established three study groups: a control group without treatment (C), a CCI4 group, and a group receiving CCI4 plus extract of <span class="elsevierStyleItalic">R. officinalis</span> L. (CCI4<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>ROM; 1.5<span class="elsevierStyleHsp" style=""></span>g extract/kg body weight administered orally). Treatments were administered 3 times a week during 8 weeks.</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Inducing hepatic damage with CCI<span class="elsevierStyleInf">4</span> and treatment with extract of <span class="elsevierStyleItalic">R. officinalis</span> L.</span><p id="par0025" class="elsevierStylePara elsevierViewall">Hepatic damage was induced by intraperitoneal administration of a blend of 0.2<span class="elsevierStyleHsp" style=""></span>mL CCI4 and mineral oil in a ratio of 1:1 (v/v), 3 times a week during 8 weeks, decreasing the volume of the initial blend of mineral oil and CCI4; first week 1:6, second week 1:5, third week 1:4 and fourth week, 1:3 continuing until the eighth week.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> The plant extract was administered orally prior to hepatic damage (1.5<span class="elsevierStyleHsp" style=""></span>g/kg body weight) one week before beginning administration of CCI4. Treatment resumed on day 8, 1<span class="elsevierStyleHsp" style=""></span>h before administration of CCI4, followed by every third day during 8 weeks (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Preparation of the extract</span><p id="par0030" class="elsevierStylePara elsevierViewall">The plant was harvested in July and August of 2009 in the San Javier communal tract of land located on the Barca Atotonilco road in Guadalajara, Jalisco, Mexico. A specimen was identified (register number IBUG-156 409) and deposited in the herbarium at the Botanical Institute of the University of Guadalajara. The leaves were dried in the shade at 22<span class="elsevierStyleHsp" style=""></span>°C. We then performed a first extraction from 1<span class="elsevierStyleHsp" style=""></span>kg of leaves with 5 L of n-hexane at 60<span class="elsevierStyleHsp" style=""></span>°C during 1<span class="elsevierStyleHsp" style=""></span>h. A second extraction was prepared with 2<span class="elsevierStyleHsp" style=""></span>L of n-hexane. The resulting liquid was extracted with 6<span class="elsevierStyleHsp" style=""></span>L of ethanol (60%) at 60<span class="elsevierStyleHsp" style=""></span>°C during 2<span class="elsevierStyleHsp" style=""></span>h. The extract was filtered and the residue washed with 2<span class="elsevierStyleHsp" style=""></span>L of ethanol (60%) at 60<span class="elsevierStyleHsp" style=""></span>°C. Lastly, the liquid was evaporated using a rotary evaporator (Buchi R152 rotary evaporator) at 40<span class="elsevierStyleHsp" style=""></span>°C and stored at −20<span class="elsevierStyleHsp" style=""></span>°C until the day it was used.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Experiments in molecular biology</span><p id="par0035" class="elsevierStylePara elsevierViewall">At 24<span class="elsevierStyleHsp" style=""></span>h after undergoing treatment, the animals in all 3 groups were killed by decapitation. The brain was extracted under aseptic conditions, and we used previously sterilised material to dissect the prefrontal cortex. The tissue was weighed and stored at −70<span class="elsevierStyleHsp" style=""></span>°C until it was used for extraction of total ribonucleic acid (RNA).</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Obtaining and quantifying total ribonucleic acid</span><p id="par0040" class="elsevierStylePara elsevierViewall">Total RNA was extracted using the guanidinium isothiocyanate–phenol–chloroform method.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> The resulting RNA precipitate was suspended in diethylpyrocarbonate-treated water (1%). The quantity and quality of the extracted RNA were evaluated by determining the 260/280<span class="elsevierStyleHsp" style=""></span>nm absorbance ratio; samples with an absorbance ratio between 1.7 and 2.0 were considered optimal.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Reverse transcriptase and chain reaction of semi-quantitative polymerase</span><p id="par0045" class="elsevierStylePara elsevierViewall">We used Moloney murine leukaemia virus reverse transcriptase to synthesise complementary deoxyribonucleic acid (cDNA). We collected 2<span class="elsevierStyleHsp" style=""></span>μg of RNA from each sample and added sterile water to achieve a total volume of 6<span class="elsevierStyleHsp" style=""></span>μL. Samples were denatured at 70<span class="elsevierStyleHsp" style=""></span>°C for 10<span class="elsevierStyleHsp" style=""></span>min. Afterwards they were immediately incubated in an ice bath with continuous agitation for 5<span class="elsevierStyleHsp" style=""></span>min. We subsequently added a total volume of 14<span class="elsevierStyleHsp" style=""></span>μL of the reverse transcriptase blend, consisting of 5× RT buffer; dNTP (deoxynucleoside triphosphate) 2.5<span class="elsevierStyleHsp" style=""></span>mM; dithiothreitol 1.0<span class="elsevierStyleHsp" style=""></span>mM; random primers 1<span class="elsevierStyleHsp" style=""></span>μg/μL; and RNAse inhibitor (1<span class="elsevierStyleHsp" style=""></span>U/μL). The blend was incubated with the reverse transcriptase (200<span class="elsevierStyleHsp" style=""></span>U/μL) at 37<span class="elsevierStyleHsp" style=""></span>°C for 1<span class="elsevierStyleHsp" style=""></span>h, with a final phase of 95<span class="elsevierStyleHsp" style=""></span>°C for 10<span class="elsevierStyleHsp" style=""></span>min. At the end of that phase, we added 5<span class="elsevierStyleHsp" style=""></span>μL of sterile water.</p><p id="par0050" class="elsevierStylePara elsevierViewall">For the polymerase chain reaction, we used a reaction blend with the following composition: injectable sterile water, primers corresponding to the genes in question (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>) dNTP (2.5<span class="elsevierStyleHsp" style=""></span>mM), 10× PCR buffer, MgCl<span class="elsevierStyleInf">2</span> (50<span class="elsevierStyleHsp" style=""></span>mM), cDNA and Taq DNA polymerase (1<span class="elsevierStyleHsp" style=""></span>U/μL).</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">We added mineral oil to the amplification reactions in order to prevent evaporation. The thermal cycler was set for an initial cycle of 95<span class="elsevierStyleHsp" style=""></span>°C for 5<span class="elsevierStyleHsp" style=""></span>min. The machine automatically completed the number of cycles specified in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. Each cycle was set for 95<span class="elsevierStyleHsp" style=""></span>°C for 1<span class="elsevierStyleHsp" style=""></span>min, 60<span class="elsevierStyleHsp" style=""></span>°C for 1<span class="elsevierStyleHsp" style=""></span>min and 72<span class="elsevierStyleHsp" style=""></span>°C for 1.5<span class="elsevierStyleHsp" style=""></span>min, with a final extension cycle of 72<span class="elsevierStyleHsp" style=""></span>°C for 5<span class="elsevierStyleHsp" style=""></span>min. We also used the expression of the β-actin gene as a PCR control.</p><p id="par0060" class="elsevierStylePara elsevierViewall">We analysed amplified PCR products in a horizontal electrophoresis chamber by using a 100<span class="elsevierStyleHsp" style=""></span>bp molecular weight marker in an agarose gel (1.5%) containing ethidium bromide 0.5<span class="elsevierStyleHsp" style=""></span>mg/mL for 45<span class="elsevierStyleHsp" style=""></span>min at 70<span class="elsevierStyleHsp" style=""></span>V in a 1× TBE (Tris-borate-EDTA) buffer. Band intensity was determined by using a photo-documentation system equipped with analysis software (Molecular Image Gel Doc XR System Quantity One 1-D Analysis Software). Levels of expression of each receptor were calculated and normalised according to the area represented by expression of a constitutive gene (β-actin). Results are expressed as arbitrary units of area by maximum intensity.</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Statistical analysis</span><p id="par0065" class="elsevierStylePara elsevierViewall">We used one-way analysis of variance (ANOVA) to perform statistical evaluation of the data. As a post hoc analysis, we used Tukey's test to compare the different study groups. The accepted level of significance was <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>≤<span class="elsevierStyleHsp" style=""></span>.05.</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Results</span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Brain weight</span><p id="par0070" class="elsevierStylePara elsevierViewall">In animals from the CCI4 group, analysis of brain weights showed a decrease of approximately 10% (180<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>5) compared to animals from the C group (197<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>3) and cirrhotic animals who received treatment with <span class="elsevierStyleItalic">R. officinalis</span> L. extract (200<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>5) (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Expression of the NR1, NR2A and NR2B subunits of the N-methyl-<span class="elsevierStyleSmallCaps">d</span>-aspartate receptor</span><p id="par0075" class="elsevierStylePara elsevierViewall">The mRNA expression of NR1 subunits in the rat prefrontal cortex was significantly higher in animals with induced hepatic damage (85<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>6) than in animals from the C group (10<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>2) and the CCI4<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>ROM group (12<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>6) (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>). At the same time, expression of the NR2A subunit was somewhat higher in the cirrhotic animals (35<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>6) than in animals from the C group (10<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>3) and CCI4<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>ROM (9.5<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>3) (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>). Lastly, the expression of the NR2B subunit of the NMDA receptor in the rat prefrontal cortex showed a statistically significant increase in those animals with induced hepatic damage (90<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>5) compared to animals from the C group (10<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>5) and the CCI4<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>ROM group (9.5<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>5) (<a class="elsevierStyleCrossRef" href="#fig0025">Fig. 5</a>). It should be noted that expression of this subunit is quite pronounced compared to other subunits in both the cirrhotic animals and in those that received the extract.</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><elsevierMultimedia ident="fig0020"></elsevierMultimedia><elsevierMultimedia ident="fig0025"></elsevierMultimedia></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Discussion</span><p id="par0080" class="elsevierStylePara elsevierViewall">An organism's good state of health depends on the proper function of and interaction among its different organs. In particular, the liver and the brain closely interact given that the liver provides the brain with nutrients which the brain itself cannot produce, and eliminates toxic substances from the blood. This includes those substances released by the brain itself (excitotoxins) or by another organ, and which are necessarily released outside of that organ. As a consequence, liver dysfunction may elicit significant cerebral function disorders.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> Results from this study showed that the livers of animals with CCI4-induced hepatic damage show a number of traits typical of hepatic damage.<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20,21</span></a> They present alterations in brain weight and in mRNA expression of the NR1, NR2A and NR2B subunits of the NMDA receptor in the prefrontal cortex.</p><p id="par0085" class="elsevierStylePara elsevierViewall">Due to this close interaction between the liver and brain, the synthesis and delivery of the nutrients necessary for maintaining cerebral function probably decrease following CCI4-induced hepatic damage.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> This may reduce the number of nerve connections that naturally occur in the brain, which is likely to be reflected as a decrease in brain weight in the CCI4 group. It is interesting to note that the extract administered to the cirrhotic animals did not alter their brain weight in comparison with animals in the C group.</p><p id="par0090" class="elsevierStylePara elsevierViewall">The mRNA expression of the NR1, NR2A and NR2B subunits of the NMDA receptor increased significantly in those animals treated with CCI4. It has been reported that hepatic damage induced by different hepatotoxic agents, by hyperammonaemia or by bile duct ligation does not modify binding by NMDA receptors; however, their functions do not remain the same.<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10,24,25</span></a> One might think that some of its subunits, as structural components, could undergo changes, thereby altering receptor function as well. To date, the expression of NMDA receptor subunits in the brain in the presence of hepatic damage has not been reported.</p><p id="par0095" class="elsevierStylePara elsevierViewall">It should be noted that the NMDA receptor, due to its functional tetrameric structure, requires the structural presence of the NR1 and NR2 subunits; the latter performs glutamate recognition. Therefore, the total function of the receptor depends on the variability of the subunits that make it up.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> It has been reported that the presence of the NR2B subunit in the receptor protects the neuron from some harmful stimuli, while the electrophysiological characteristics of NR1 and NR2A make these subunits more susceptible to damage. This is because when this combination of subunits is activated, the channel remains open for a longer amount of time,<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> which promotes neuronal damage. The results for NR1 and NR2B expression were much higher than those for the NR2A subunit, in both cirrhotic animals and those receiving extract of <span class="elsevierStyleItalic">R. officinalis</span> L. This may suggest two things. Firstly, that the CCI4-induced hepatic cirrhosis model may develop a different adaptive mechanism from the one reported for other models of hepatic damage and HE. Secondly, that the increase in NR2B expression, both in cirrhotic animals and after treatment with the extract, may protect the neuron from toxic substances that may trigger neuronal death or damage mechanisms. However, in this CCI4-induced hepatic damage model, we did observe neuronal damage in the prefrontal cortex.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> Changes in the expression of the receptor subunits were very likely not sufficient to exert a protective effect on the neuron. However, we should not rule out the possibility of there being a response mechanism specific to the model employed, or potential participation by other types of receptors. It has been shown that hepatic damage decreases the expression of both GLT-1 protein and its mRNA. It also increases the extracellular concentration of Glu,<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9,11,20</span></a> which may over-activate NMDA receptors, increase calcium influx into the postsynaptic neurons, and cause neuronal damage.</p><p id="par0100" class="elsevierStylePara elsevierViewall">Alterations in the expression of NMDA receptor subunits may be related to the increase in the number of astrocytes, given that we know that ammonium levels in the bloodstream are elevated during hepatic damage.<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> This may be the cause of the increased expression of NR1, NR2A and NR2B subunits of astrocyte NMDA-type receptors.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">We do not completely understand the mechanism of action of <span class="elsevierStyleItalic">R. officinalis</span> L. extract, but the presence of antioxidants and flavonoids may provide an explanation. For instance, it has been reported that one of its components, CA, has neuroprotective effects and is able to penetrate the blood–brain barrier. It has been shown that CA activates the Keap1/Nrf2 pathway and protects neurons from oxidative stress and excitotoxicity.<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> The results of this study suggest that, in addition to the hepatoprotective effect caused by its high polyphenol content and antioxidant activity,<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> the extract could have a neuroprotective effect which would be useful in pathologies involving altered brain function as a result of liver failure. Nevertheless, more research is needed in order to evaluate the activity of certain enzymes involved in glutamate metabolism, and investigate other enzymes with an antioxidant activity that may activate the Keap1/Nrf2 pathway. This would allow us to determine the molecular mechanism of action of <span class="elsevierStyleItalic">R. officinalis</span> L. extract in the brain.</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Funding</span><p id="par0110" class="elsevierStylePara elsevierViewall">Partial funding for this study was provided by <span class="elsevierStyleGrantSponsor">COECYTJAL-UDG</span> as project leaflet PS-209-515.</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflicts of interest</span><p id="par0115" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:2 [ "identificador" => "xres169841" "titulo" => array:5 [ 0 => "Abstract" 1 => "Introduction" 2 => "Methods" 3 => "Results" 4 => "Conclusion" ] ] 1 => array:2 [ "identificador" => "xpalclavsec157915" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres169842" "titulo" => array:5 [ 0 => "Resumen" 1 => "Introducción" 2 => "Métodos" 3 => "Resultados" 4 => "Conclusión" ] ] 3 => array:2 [ "identificador" => "xpalclavsec157916" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Subject and methods" "secciones" => array:6 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Inducing hepatic damage with CCI and treatment with extract of R. officinalis L." ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Preparation of the extract" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Experiments in molecular biology" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Obtaining and quantifying total ribonucleic acid" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Reverse transcriptase and chain reaction of semi-quantitative polymerase" ] 5 => array:2 [ "identificador" => "sec0040" "titulo" => "Statistical analysis" ] ] ] 6 => array:3 [ "identificador" => "sec0045" "titulo" => "Results" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0050" "titulo" => "Brain weight" ] 1 => array:2 [ "identificador" => "sec0055" "titulo" => "Expression of the NR1, NR2A and NR2B subunits of the N-methyl-d-aspartate receptor" ] ] ] 7 => array:2 [ "identificador" => "sec0060" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0065" "titulo" => "Funding" ] 9 => array:2 [ "identificador" => "sec0070" "titulo" => "Conflicts of interest" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2011-10-25" "fechaAceptado" => "2011-10-30" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec157915" "palabras" => array:3 [ 0 => "Hepatic damage" 1 => "NMDA receptor" 2 => "<span class="elsevierStyleItalic">Rosmarinus officinalis</span> L." ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec157916" "palabras" => array:4 [ 0 => "Corteza prefrontal" 1 => "Daño hepático" 2 => "Receptores NMDA" 3 => "<span class="elsevierStyleItalic">Rosmarinus officinalis</span> L." ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span class="elsevierStyleSectionTitle">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">In cirrhosis some toxic substances accumulate in brain and modify the expression of several neuronal receptors. Thus, the use of medicinal plants such as <span class="elsevierStyleItalic">Rosmarinus officinalis</span> L. has been proposed in several pathologies due to its hepatoprotective, antioxidant and neuroprotective activity. In this study we evaluated the expression of the subunits NR1, NR2A and NR2B of the glutamate receptor in rat prefrontal cortex in a model of hepatic damage induced with carbon tetrachloride after a treatment with <span class="elsevierStyleItalic">R. officinalis</span> L.</p> <span class="elsevierStyleSectionTitle">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">We used a total of 24 male Wistar rats weighing 80–90<span class="elsevierStyleHsp" style=""></span>g body weight. We formed three study groups: control group (C) without a treatment, carbon tetrachloride group (CC14), and CC14 group plus <span class="elsevierStyleItalic">R. officinalis</span> L. (CCl4<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>ROM; 1.5<span class="elsevierStyleHsp" style=""></span>g/kg of extract orally).</p> <span class="elsevierStyleSectionTitle">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">The expression of the NR1, NR2A and NR2B subunits in cirrhotic animals increased compared to the control group; however treatment with <span class="elsevierStyleItalic">R. officinalis</span> L. was able to reduce this expression to normal levels compared with CC14 and CCl4<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>ROM groups. These results could be due to an improvement in hepatic function.</p> <span class="elsevierStyleSectionTitle">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Treatment with extract of <span class="elsevierStyleItalic">R. officinalis</span> L. in cirrhotic animals modifies the expression of subunits of the N-methyl-<span class="elsevierStyleSmallCaps">d</span>-aspartate (NMDA) receptor due to an improvement in hepatocellular function in the presence of antioxidant compounds and flavonoids.</p>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span class="elsevierStyleSectionTitle">Introducción</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">En la cirrosis, algunas sustancias tóxicas se acumulan en el cerebro y alteran la expresión de diversos receptores neuronales. En este sentido, se ha propuesto el uso de plantas medicinales como el <span class="elsevierStyleItalic">Rosmarinus officinalis</span> L. en diversas patologías debido su actividad hepatoprotectora, antioxidante y neuroprotectora. En el presente trabajo se evaluó la expresión de las subunidades NR1, NR2A y NR2B del receptor a Glutamato en la corteza prefrontal de la rata en un modelo de daño hepático inducido con tetracloruro de carbono después del tratamiento con <span class="elsevierStyleItalic">Rosmarinus officinalis</span> L.</p> <span class="elsevierStyleSectionTitle">Métodos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Se utilizaron un total de 24 ratas macho Wistar de 80–90<span class="elsevierStyleHsp" style=""></span>g. de peso corporal. Se formaron 3 grupos de trabajo: grupo testigo (T) sin ningún tratamiento, grupo tetracloruro de carbono (CCl4) y grupo CCl4 más <span class="elsevierStyleItalic">Rosmarinus officinalis</span> L. (CCl4<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>ROM; 1.5<span class="elsevierStyleHsp" style=""></span>g/kg del extracto por vía oral).</p> <span class="elsevierStyleSectionTitle">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">La expresión de las subunidades NR1, NR2A y NR2B incrementaron en los animales cirróticos con respecto al grupo T, sin embargo el tratamiento con <span class="elsevierStyleItalic">Rosmarinus officinalis</span> L. fue capaz de disminuir la expresión a niveles normales comparados con los grupos de CCl4 y T. Estos resultados podrían deberse a una mejora en la función hepática.</p> <span class="elsevierStyleSectionTitle">Conclusión</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">El tratamiento con el extracto de <span class="elsevierStyleItalic">Rosmarinus officinalis</span> L. en los animales cirróticos modifica la expresión de las subunidades del receptor NMDA debido a la mejora en la función hepatocelular dada la presencia de compuestos antioxidantes y flavonoides.</p>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara">Please cite this article as: Soria Fregozo C, et al. Expresión de las subunidades del receptor NMDA en la corteza prefrontal de la rata con daño hepático inducido con CCL4 después del tratamiento con <span class="elsevierStyleItalic">Rosmarinus officinalis</span> L. Neurología. 2012;27:261–7.</p>" ] ] "multimedia" => array:6 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1355 "Ancho" => 2105 "Tamanyo" => 115297 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Flow chart showing the model for CCI4-induced hepatic damage and treatment with <span class="elsevierStyleItalic">Rosmarinus officinalis</span> L. extract.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 842 "Ancho" => 1575 "Tamanyo" => 36224 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Brain weight of the animals subjected to different treatments. Mean<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>SD of a total of 8 animals per group. *<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>.05 CCI4 vs C. **<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>.05 CCI4<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>ROM vs CCI4.</p>" ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1057 "Ancho" => 1502 "Tamanyo" => 67104 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Levels of NR1 mRNA in the prefrontal cortex of the rat. (A) Gel photograph representing the different study groups. Mean<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>SD of 4 duplicate experiments. *<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>.05 CCI4 vs C. **<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>.05 CCI4<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>ROM vs CCI4.</p>" ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 961 "Ancho" => 1520 "Tamanyo" => 59952 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Levels of NR2A mRNA in the prefrontal cortex of the rat. (A) Gel photograph representing the different study groups. Mean<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>SD of 4 duplicate experiments. *<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>.05 CCI4 vs C. **<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>.05 CCI4<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>ROM vs CCI4.</p>" ] ] 4 => array:7 [ "identificador" => "fig0025" "etiqueta" => "Figure 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr5.jpeg" "Alto" => 1019 "Ancho" => 1535 "Tamanyo" => 65862 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Levels of NR2B mRNA in the prefrontal cortex of the rat. (A) Gel photograph representing the different study groups. Mean<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>SD of 4 duplicate experiments. *<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>.05 CCI4 vs C. **<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>.05 CCI4<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>ROM vs CCI4.</p>" ] ] 5 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Subunit \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">GenBank \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Sequence \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Product (bp) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Cycles \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NR1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Position 1915–2765 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5′-CTGGACTCATTTATGCAGCCTTTTCAGAGC-3′ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">879 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">28 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleInterRef" href="ncbi-n:NM_017010">NM_017010</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5′-GAGATCGCCTACAAGCGACACAAGGATGCC-3′ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NR2A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Position 1868–2734 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5′-CCTTCTGCTTTCCTCGAACCCTTCAGTGCC-3′ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">906 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleInterRef" href="ncbi-n:NM_012573">NM_012573</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5′-GAGCACCTCTTCTACTGGAAGCTGCGCTTC-3′ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NR2B \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Position 2431–2857 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5′-ATATCCGTAATAACTATGCAGAAATGCATG-3′ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">466 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleInterRef" href="ncbi-n:NM_012574.1">NM_012574.1</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5′-CATCTGTTCTATTGGCAGTTCCCGCATTGC-3′ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">β-Actin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Position 684–1201 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5′-CACCACAGCTGAGAGGGAAATCGTGCGTGA-3′ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">518 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">25 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleInterRef" href="ncbi-n:NM_031144">NM_031144</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5′-ATTTGCGGTGCACGATGGAGGGGCCGGACT-3′ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab264864.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Oligonucleotide sequences used for semi-quantitative PCR.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:29 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Liver cirrhosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:1 [ 0 => "J.M. Crawford" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "LibroEditado" => array:4 [ "titulo" => "Pathology of the liver" "paginaInicial" => "576" "paginaFinal" => "577" "serieFecha" => "2002" ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Oxidative stress markers in the brain of patients with cirrhosis and hepatic encephalopathy" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "B. Görg" 1 => "N. Qvartskhava" 2 => "H.J. Bidmon" 3 => "N. Palomero-Gallagher" 4 => "G. Kircheis" 5 => "K. Zilles" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep.23656" "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "2010" "volumen" => "52" "paginaInicial" => "256" "paginaFinal" => "265" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20583283" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Experimental models of hepatic encephalopathy: ISHEN guidelines" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "R.F. Butterworth" 1 => "M.D. Norenberg" 2 => "V. Felipo" 3 => "P. Ferenci" 4 => "J. Albrecht" 5 => "A.T. Blei" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1478-3231.2009.02034.x" "Revista" => array:6 [ "tituloSerie" => "Liver Int" "fecha" => "2009" "volumen" => "29" "paginaInicial" => "783" "paginaFinal" => "788" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19638106" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mechanisms, diagnosis and management of hepatic encephalopathy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "R. Prakash" 1 => "K.D. Mullen" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/nrgastro.2010.116" "Revista" => array:6 [ "tituloSerie" => "Nat Rev Gastroenterol Hepatol" "fecha" => "2010" "volumen" => "7" "paginaInicial" => "515" "paginaFinal" => "525" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20703237" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cerebral ammonia metabolism in patients with severe liver disease and minimal hepatic encephalopathy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "A.H. Lockwood" 1 => "E.W. Yap" 2 => "W.H. Wong" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/jcbfm.1991.67" "Revista" => array:6 [ "tituloSerie" => "J Cereb Blood Flow Metab" "fecha" => "1991" "volumen" => "11" "paginaInicial" => "337" "paginaFinal" => "3341" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1997506" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0030" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Neurobiology of ammonia" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "V. Felipo" 1 => "R.F. Butterworth" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Prog Neurobiol" "fecha" => "2002" "volumen" => "67" "paginaInicial" => "259" "paginaFinal" => "279" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12207972" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0035" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Evidence for an astrocytic glutamate transporter deficit in hepatic encephalopathy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "H. Chan" 1 => "R.F. Butterworth" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Neurochem Res" "fecha" => "1999" "volumen" => "24" "paginaInicial" => "1397" "paginaFinal" => "1401" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10555780" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0040" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cell-selective effects of ammonia on glutamate transporter and receptor function in the mammalian brain" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "H. Chan" 1 => "R.F. Butterworth" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Neurochem Int" "fecha" => "2003" "volumen" => "43" "paginaInicial" => "525" "paginaFinal" => "532" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12742100" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0045" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Decreased glutamate transporter (GLT-1) expression in frontal cortex of rats with acute liver failure" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "K. Knecht" 1 => "A. Michalak" 2 => "C. Rose" 3 => "J.D. Rothstein" 4 => "R.F. Butterworth" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Neurosci Lett" "fecha" => "1997" "volumen" => "229" "paginaInicial" => "201" "paginaFinal" => "203" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9237493" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0050" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Selective loss of N-methyl-<span class="elsevierStyleSmallCaps">d</span>-aspartatesensitive L-[3H]glutamate binding sites in rat brain following portacaval anastomosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "C. Peterson" 1 => "J.F. Giguere" 2 => "C.W. Cotman" 3 => "R.F. Butterworth" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Neurochem" "fecha" => "1990" "volumen" => "55" "paginaInicial" => "386" "paginaFinal" => "390" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1973453" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0055" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Selective loss of binding sites for the glutamate receptor ligands [3H]kainate and (S)-[3H]5-fluorowillardiine in the brains of rats with acute liver failure" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "A. Michalak" 1 => "R.F. Butterworth" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/hep.510250323" "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "1997" "volumen" => "25" "paginaInicial" => "631" "paginaFinal" => "635" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9049210" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0060" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Glial and neuronal alterations in the corpus striatum of rats with CCl<span class="elsevierStyleInf">4</span> induced liver disease. A quantitative morphological study using an electronic image" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "N.H. Diemer" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Acta Neural Scan" "fecha" => "1997" "volumen" => "55" "paginaInicial" => "16" "paginaFinal" => "32" ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0065" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Brain region-selective mechanisms contribute to the progression of cerebral alterations in acute liver failure in rats" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "O. Cauli" 1 => "P. López-Larrubia" 2 => "R. Rodrigo" 3 => "A. Agusti" 4 => "J. Boix" 5 => "L. Nieto-Charques" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/j.gastro.2010.10.043" "Revista" => array:6 [ "tituloSerie" => "Gastroenterology" "fecha" => "2011" "volumen" => "140" "paginaInicial" => "638" "paginaFinal" => "645" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20977905" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0070" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Estimating the cost of treating patients with liver cirrhosis at the Mexican Social Security Institute" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M.E. Quiroz" 1 => "Y.N. Flores" 2 => "B. Aracena" 3 => "V. Granados-García" 4 => "J. Salmerón" 5 => "R. Pérez" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Salud Publica Mex" "fecha" => "2010" "volumen" => "52" "paginaInicial" => "493" "paginaFinal" => "501" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21271007" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0075" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Therapeutic strategies for hepatic fibrosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "M. Chojkier" 1 => "D.A. Brenner" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "1988" "volumen" => "8" "paginaInicial" => "176" "paginaFinal" => "182" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3276587" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0080" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Silymarin, the antioxidant component and <span class="elsevierStyleItalic">Silybum marianum</span> extracts prevent liver damage" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "E. Shaker" 1 => "H. Mahmoud" 2 => "S. Mnaa" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.fct.2009.12.011" "Revista" => array:6 [ "tituloSerie" => "Food Chem Toxicol" "fecha" => "2010" "volumen" => "48" "paginaInicial" => "803" "paginaFinal" => "806" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20034535" "web" => "Medline" ] ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0085" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The protective effect of HD-03 in CCl4-induced hepatic encephalopathy in rats" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "S.K. Mitra" 1 => "M.V. Venkataranganna" 2 => "S. Gopumadhavan" 3 => "S.D. Anturlikar" 4 => "S.J. Seshadri" 5 => "U. Venkatesha Udupa" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Phytother Res" "fecha" => "2001" "volumen" => "15" "paginaInicial" => "493" "paginaFinal" => "496" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11536377" "web" => "Medline" ] ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0090" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Anti-proliferative and antioxidant properties of rosemary <span class="elsevierStyleItalic">Rosmarinus officinalis</span>" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "S. Cheung" 1 => "J. Tai" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Oncol Rep" "fecha" => "2007" "volumen" => "17" "paginaInicial" => "1525" "paginaFinal" => "1531" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17487414" "web" => "Medline" ] ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0095" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mexican plants used in the treatment of liver diseases" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "M.L. Miranda-Beltrán" 1 => "A.L. López-Velázquez" 2 => "C.A. Panduro" 3 => "M.G. Rosales" 4 => "M.A. López-Alvarado" 5 => "R. Huacuja" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "LibroEditado" => array:4 [ "titulo" => "Book of abstract 7th joint meeting of AFERP, AST, GA, PSE & SIF" "paginaInicial" => "s14" "conferencia" => "Athens, Greece. 3–8 August" "serieFecha" => "2008" ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0100" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Soria Fregozo C, Miranda Beltrán ML, Flores Soto M, Pérez Vega MI, Huacuja Ruiz L, López Velázquez AL, et al. The protective effect of <span class="elsevierStyleItalic">Rosmarinus officinalis</span> L. in rats with hepatic damage induced by CCl4 on the expression of the glutamate transporter (GLT-1) and neuronal damage in the frontal cortex of rat. Neurotoxicology, in press." ] ] ] 20 => array:3 [ "identificador" => "bib0105" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Experimental carbon tetrachloride-induced cirrhosis of the liver" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "T.E. Muñoz" 1 => "J.I. Paz-Bouza" 2 => "M.M. Abad-Hernández" 3 => "M.J. Alonso-Martin" 4 => "B.A. López" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Int J Tissue React" "fecha" => "1988" "volumen" => "10" "paginaInicial" => "245" "paginaFinal" => "251" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3250938" "web" => "Medline" ] ] ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib0110" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Single-step method of RNA isolation by acid guanidinium thiocyanate–phenol–chloroform extraction" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "P. Chomczynski" 1 => "N. Sacchi" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1006/abio.1987.9999" "Revista" => array:6 [ "tituloSerie" => "Anal Biochem" "fecha" => "1987" "volumen" => "162" "paginaInicial" => "156" "paginaFinal" => "159" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2440339" "web" => "Medline" ] ] ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib0115" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hepatic encephalopathy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "R.F. Butterworth" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Alcohol Res Health" "fecha" => "2003" "volumen" => "27" "paginaInicial" => "240" "paginaFinal" => "246" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15535452" "web" => "Medline" ] ] ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib0120" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effects of hyperammonemia and liver failure on glutamatergic neurotransmission" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "P. Monfort" 1 => "M.D. Muñoz" 2 => "A. ElAyadi" 3 => "E. Kosenko" 4 => "V. Felipo" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Metab Brain Dis" "fecha" => "2002" "volumen" => "17" "paginaInicial" => "237" "paginaFinal" => "250" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12602501" "web" => "Medline" ] ] ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib0125" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "NMDA receptors in hyperammonemia and hepatic encephalopathy" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M. Llansola" 1 => "R. Rodrigo" 2 => "P. Monfort" 3 => "C. Montoliu" 4 => "E. Kosenko" 5 => "O. Cauli" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s11011-007-9067-0" "Revista" => array:6 [ "tituloSerie" => "Metab Brain Dis" "fecha" => "2007" "volumen" => "22" "paginaInicial" => "321" "paginaFinal" => "335" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17701332" "web" => "Medline" ] ] ] ] ] ] ] ] 25 => array:3 [ "identificador" => "bib0130" "etiqueta" => "26" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "New advances in NMDA receptor pharmacology" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "K.K. Ogden" 1 => "S.F. Traynelis" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.tips.2011.08.003" "Revista" => array:8 [ "tituloSerie" => "Trends Pharmacol Sci" "fecha" => "2011" "volumen" => "32" "numero" => "12" "paginaInicial" => "726" "paginaFinal" => "733" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21996280" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0959289X01909343" "estado" => "S300" "issn" => "0959289X" ] ] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib0135" "etiqueta" => "27" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Glutamine synthetase in brain: effect of ammonia" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "I. Suarez" 1 => "G. Bodega" 2 => "B. Fernandez" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Neurochem Int" "fecha" => "2002" "volumen" => "41" "paginaInicial" => "123" "paginaFinal" => "142" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12020613" "web" => "Medline" ] ] ] ] ] ] ] ] 27 => array:3 [ "identificador" => "bib0140" "etiqueta" => "28" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Expression of NR1 and NR2A/B subunits of the NMDA receptor in cortical astrocytes" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "F. Conti" 1 => "S. DeBiasi" 2 => "A. Minelli" 3 => "M. Melone" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/(SICI)1098-1136(199607)17:3<254::AID-GLIA7>3.0.CO;2-0" "Revista" => array:6 [ "tituloSerie" => "Glia" "fecha" => "1996" "volumen" => "17" "paginaInicial" => "254" "paginaFinal" => "258" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8840166" "web" => "Medline" ] ] ] ] ] ] ] ] 28 => array:3 [ "identificador" => "bib0145" "etiqueta" => "29" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Carnosic acid, a catechol-type electrophilic compound, protects neurons both in vitro and in vivo through activation of the Keap1/Nrf2 pathway via S-alkylation of targeted cysteines on Keap1" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "T. Satoh" 1 => "K. Kosaka" 2 => "K. Itoh" 3 => "A. Kobayashi" 4 => "M. Yamamoto" 5 => "Y. Shimojo" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1471-4159.2007.05039.x" "Revista" => array:6 [ "tituloSerie" => "J Neurochem" "fecha" => "2008" "volumen" => "104" "paginaInicial" => "1116" "paginaFinal" => "1131" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17995931" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/21735808/0000002700000005/v1_201305151332/S2173580812000727/v1_201305151332/en/main.assets" "Apartado" => array:4 [ "identificador" => "9491" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Original Articles" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/21735808/0000002700000005/v1_201305151332/S2173580812000727/v1_201305151332/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173580812000727?idApp=UINPBA00004N" ]
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| 2024 September | 24 | 6 | 30 |
| 2024 August | 20 | 1 | 21 |
| 2024 July | 23 | 7 | 30 |
| 2024 June | 16 | 6 | 22 |
| 2024 May | 10 | 3 | 13 |
| 2024 April | 11 | 3 | 14 |
| 2024 March | 49 | 9 | 58 |
| 2024 February | 28 | 9 | 37 |
| 2024 January | 16 | 3 | 19 |
| 2023 December | 20 | 8 | 28 |
| 2023 November | 14 | 6 | 20 |
| 2023 October | 13 | 8 | 21 |
| 2023 September | 12 | 4 | 16 |
| 2023 August | 13 | 8 | 21 |
| 2023 July | 17 | 4 | 21 |
| 2023 June | 19 | 10 | 29 |
| 2023 May | 34 | 6 | 40 |
| 2023 April | 34 | 7 | 41 |
| 2023 March | 17 | 4 | 21 |
| 2023 February | 24 | 3 | 27 |
| 2023 January | 19 | 5 | 24 |
| 2022 December | 18 | 6 | 24 |
| 2022 November | 28 | 13 | 41 |
| 2022 October | 18 | 7 | 25 |
| 2022 September | 24 | 12 | 36 |
| 2022 August | 19 | 11 | 30 |
| 2022 July | 13 | 13 | 26 |
| 2022 June | 9 | 11 | 20 |
| 2022 May | 29 | 7 | 36 |
| 2022 April | 19 | 8 | 27 |
| 2022 March | 18 | 11 | 29 |
| 2022 February | 8 | 4 | 12 |
| 2022 January | 8 | 8 | 16 |
| 2021 December | 15 | 11 | 26 |
| 2021 November | 15 | 7 | 22 |
| 2021 October | 15 | 11 | 26 |
| 2021 September | 18 | 13 | 31 |
| 2021 August | 18 | 4 | 22 |
| 2021 July | 40 | 5 | 45 |
| 2021 June | 28 | 17 | 45 |
| 2021 May | 25 | 4 | 29 |
| 2021 April | 27 | 8 | 35 |
| 2021 March | 13 | 14 | 27 |
| 2021 February | 29 | 6 | 35 |
| 2021 January | 28 | 9 | 37 |
| 2020 December | 18 | 7 | 25 |
| 2020 November | 13 | 8 | 21 |
| 2020 October | 18 | 4 | 22 |
| 2020 September | 21 | 10 | 31 |
| 2020 August | 9 | 10 | 19 |
| 2020 July | 20 | 9 | 29 |
| 2020 June | 15 | 4 | 19 |
| 2020 May | 11 | 13 | 24 |
| 2020 April | 16 | 3 | 19 |
| 2020 March | 17 | 0 | 17 |
| 2020 February | 17 | 3 | 20 |
| 2020 January | 17 | 1 | 18 |
| 2019 December | 12 | 6 | 18 |
| 2019 November | 9 | 8 | 17 |
| 2019 October | 13 | 5 | 18 |
| 2019 September | 9 | 3 | 12 |
| 2019 August | 6 | 6 | 12 |
| 2019 July | 13 | 8 | 21 |
| 2019 June | 38 | 11 | 49 |
| 2019 May | 101 | 26 | 127 |
| 2019 April | 32 | 17 | 49 |
| 2019 March | 8 | 3 | 11 |
| 2019 February | 6 | 8 | 14 |
| 2019 January | 15 | 6 | 21 |
| 2018 December | 8 | 7 | 15 |
| 2018 November | 14 | 1 | 15 |
| 2018 October | 15 | 4 | 19 |
| 2018 September | 9 | 0 | 9 |
| 2018 August | 17 | 0 | 17 |
| 2018 July | 13 | 1 | 14 |
| 2018 June | 10 | 0 | 10 |
| 2018 May | 23 | 1 | 24 |
| 2018 April | 25 | 1 | 26 |
| 2018 March | 5 | 0 | 5 |
| 2018 February | 77 | 1 | 78 |
| 2018 January | 58 | 0 | 58 |
| 2017 December | 84 | 2 | 86 |
| 2017 November | 62 | 0 | 62 |
| 2017 October | 10 | 2 | 12 |
| 2017 September | 12 | 1 | 13 |
| 2017 August | 13 | 2 | 15 |
| 2017 July | 5 | 3 | 8 |
| 2017 June | 12 | 1 | 13 |
| 2017 May | 9 | 2 | 11 |
| 2017 April | 1 | 1 | 2 |
| 2017 March | 4 | 2 | 6 |
| 2017 February | 8 | 0 | 8 |
| 2017 January | 16 | 0 | 16 |
| 2016 December | 14 | 10 | 24 |
| 2016 November | 22 | 3 | 25 |
| 2016 October | 21 | 1 | 22 |
| 2016 September | 27 | 8 | 35 |
| 2016 August | 27 | 3 | 30 |
| 2016 July | 12 | 2 | 14 |
| 2016 June | 22 | 1 | 23 |
| 2016 May | 27 | 20 | 47 |
| 2016 April | 24 | 9 | 33 |
| 2016 March | 25 | 15 | 40 |
| 2016 February | 22 | 9 | 31 |
| 2016 January | 11 | 10 | 21 |
| 2015 December | 11 | 5 | 16 |
| 2015 November | 17 | 2 | 19 |
| 2015 October | 21 | 6 | 27 |
| 2015 September | 19 | 4 | 23 |
| 2015 August | 7 | 5 | 12 |
| 2015 July | 10 | 5 | 15 |
| 2015 June | 8 | 3 | 11 |
| 2015 May | 14 | 2 | 16 |
| 2015 April | 23 | 8 | 31 |
| 2015 March | 25 | 5 | 30 |
| 2015 February | 28 | 2 | 30 |
| 2015 January | 44 | 4 | 48 |
| 2014 December | 58 | 8 | 66 |
| 2014 November | 38 | 1 | 39 |
| 2014 October | 48 | 4 | 52 |
| 2014 September | 36 | 4 | 40 |
| 2014 August | 68 | 1 | 69 |
| 2014 July | 58 | 7 | 65 |
| 2014 June | 28 | 2 | 30 |
| 2014 May | 31 | 1 | 32 |
| 2014 April | 22 | 3 | 25 |
| 2014 March | 29 | 3 | 32 |
| 2014 February | 24 | 2 | 26 |
| 2014 January | 28 | 7 | 35 |
| 2013 December | 28 | 3 | 31 |
| 2013 November | 19 | 6 | 25 |
| 2013 October | 64 | 4 | 68 |
| 2013 September | 43 | 5 | 48 |
| 2013 August | 41 | 4 | 45 |
| 2013 July | 21 | 1 | 22 |
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