Human recombinant erythropoietin reduces sensorimotor dysfunction and cognitive impairment in rat models of chronic kidney disease

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A) Prueba de campo abierto. Se muestran los tiempos de latencia y exploración en cada una de las sesiones. B) Prueba de laberinto acuático de Morris. Se muestran el tiempo de nado hacia la plataforma en cada una de las sesiones y el recorrido representativo de los animales hacia la plataforma. Los datos son presentados como medias ± error estándar (N = 24). Los valores de p representan los resultados del análisis de varianza ANOVA cuando p < 0,05 se consideró una diferencia significativa *ERC vs. control y **ERC + rHuEPO vs. ERC." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "E.E. Reza-Zaldívar, S. Sandoval-Avila, Y.K. Gutiérrez-Mercado, E. Vázquez-Méndez, A.A. Canales-Aguirre, H. Esquivel-Solís, U. Gómez-Pinedo, A.L. Márquez-Aguirre" "autores" => array:8 [ 0 => array:2 [ "nombre" => "E.E." "apellidos" => "Reza-Zaldívar" ] 1 => array:2 [ "nombre" => "S." "apellidos" => "Sandoval-Avila" ] 2 => array:2 [ "nombre" => "Y.K." 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The central line shows the mean difference, whereas the top and bottom lines indicate the 95% confidence interval. The plot indicates good agreement between techniques but reveals the influence of a measurement bias: POC-INR testing underestimates the INR when values are high." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "D. Guisado-Alonso, F. Fayos-Vidal, J. Martí-Fàbregas, L. Prats-Sánchez, R. Marín-Bueno, A. Martínez-Domeño, R. Delgado-Mederos, P. Camps-Renom" "autores" => array:8 [ 0 => array:2 [ "nombre" => "D." "apellidos" => "Guisado-Alonso" ] 1 => array:2 [ "nombre" => "F." "apellidos" => "Fayos-Vidal" ] 2 => array:2 [ "nombre" => "J." "apellidos" => "Martí-Fàbregas" ] 3 => array:2 [ "nombre" => "L." "apellidos" => "Prats-Sánchez" ] 4 => array:2 [ "nombre" => "R." "apellidos" => "Marín-Bueno" ] 5 => array:2 [ "nombre" => "A." "apellidos" => "Martínez-Domeño" ] 6 => array:2 [ "nombre" => "R." "apellidos" => "Delgado-Mederos" ] 7 => array:2 [ "nombre" => "P." "apellidos" => "Camps-Renom" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0213485317302773" "doi" => "10.1016/j.nrl.2017.07.017" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0213485317302773?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173580820300493?idApp=UINPBA00004N" "url" => "/21735808/0000003500000003/v1_202005131017/S2173580820300493/v1_202005131017/en/main.assets" ] "en" => array:20 [ "idiomaDefecto" => true "cabecera" => "Original article" "titulo" => "Human recombinant erythropoietin reduces sensorimotor dysfunction and cognitive impairment in rat models of chronic kidney disease" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "147" "paginaFinal" => "154" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "E.E. Reza-Zaldívar, S. Sandoval-Avila, Y.K. Gutiérrez-Mercado, E. Vázquez-Méndez, A.A. Canales-Aguirre, H. Esquivel-Solís, U. Gómez-Pinedo, A.L. Márquez-Aguirre" "autores" => array:8 [ 0 => array:3 [ "nombre" => "E.E." "apellidos" => "Reza-Zaldívar" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 1 => array:3 [ "nombre" => "S." "apellidos" => "Sandoval-Avila" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "Y.K." "apellidos" => "Gutiérrez-Mercado" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "E." "apellidos" => "Vázquez-Méndez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 4 => array:3 [ "nombre" => "A.A." 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"apellidos" => "Márquez-Aguirre" "email" => array:1 [ 0 => "amarquez@ciatej.mx" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Biotecnología Médica y Farmacéutica, Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco, Guadalajara, Jalisco, Mexico" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Unidad de Evaluación Preclínica, Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco, Guadalajara, Jalisco, Mexico" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Departamento de Neurología, Laboratorio de Neurociencias, IdISSC, Hospital Clínico San Carlos, Universidad Complutense, Madrid, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "La eritropoyetina humana recombinante reduce la disfunción sensoriomotora y el deterioro cognitivo en ratas con enfermedad renal crónica" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1856 "Ancho" => 3379 "Tamanyo" => 362630 ] ] "descripcion" => array:1 [ "en" => "Behavioural tests. (A) Open field test. The graphs show latency and exploration times for each session. (B) Morris water maze test. The graph shows swimming time to platform for each session, and a representative illustration of paths taken to the platform. Data are expressed as means (error bars denote standard deviation). Statistical significance was set at P<.05 (one-way ANOVA). *Significant difference between CKD and control rats. **Significant difference between CKD+rHuEPO and CKD+sham rats. ANOVA: analysis of variance; CKD: chronic kidney disease; rHuEPO: recombinant human erythropoietin." ] ] ] "textoCompleto" => "IntroductionCognitive impairment is a frequent complication of chronic kidney disease (CKD), causing such alterations as attention deficits and difficulties with verbal communication, learning, and memory.<a class="elsevierStyleCrossRef" href="#bib0265">1</a> According to epidemiological data, over 60% of patients with CKD are highly likely to develop cerebrovascular diseases, which promote cognitive impairment and dementia.<a class="elsevierStyleCrossRefs" href="#bib0270">2–4</a>The main pathogenic factors involved in neurological complications of CKD are high concentrations of circulating uraemic toxins,<a class="elsevierStyleCrossRef" href="#bib0285">5</a> proinflammatory cytokines, and reactive oxygen species,<a class="elsevierStyleCrossRef" href="#bib0270">2</a> which cause alterations in serotonergic and cholinergic neurotransmission, and endothelial inflammation and dysfunction.<a class="elsevierStyleCrossRef" href="#bib0290">6</a> These factors can affect all levels of the nervous system, promoting such neurological alterations as uraemic encephalopathy, cognitive problems, and such neuromuscular disorders as mononeuropathy, polyneuropathy, and myopathy.<a class="elsevierStyleCrossRef" href="#bib0295">7</a>At advanced stages, patients with kidney disease may present severe anaemia, known as renal anaemia, caused by a deficiency in renal erythropoietin production.<a class="elsevierStyleCrossRefs" href="#bib0300">8–10</a> Numerous studies have reported that anaemia negatively affects cognitive function<a class="elsevierStyleCrossRefs" href="#bib0315">11,12</a> due to insufficient cerebral oxygen supply caused by a decrease in the oxygen transport capacity.<a class="elsevierStyleCrossRef" href="#bib0325">13</a> Chronic hypoxia causes toxicity secondary to oxidative stress; combined with the accumulation of uraemic toxins,<a class="elsevierStyleCrossRefs" href="#bib0295">7,14</a> this accelerates neuronal degeneration.<a class="elsevierStyleCrossRefs" href="#bib0320">12,15</a> In patients with CKD, anaemia is treated with erythropoiesis-stimulating agents, such as recombinant human erythropoietin (rHuEPO).<a class="elsevierStyleCrossRef" href="#bib0310">10</a>While erythropoietin plays an essential role in erythropoiesis, it has been reported to have other functions, such as anti-inflammatory<a class="elsevierStyleCrossRef" href="#bib0340">16</a> and anti-apoptotic activities,<a class="elsevierStyleCrossRef" href="#bib0345">17</a> stimulating neurogenesis and neuronal differentiation in early developmental stages,<a class="elsevierStyleCrossRef" href="#bib0350">18</a> and tissue protection in the kidneys<a class="elsevierStyleCrossRef" href="#bib0355">19</a> and brain.<a class="elsevierStyleCrossRefs" href="#bib0360">20,21</a>Both in vitro<a class="elsevierStyleCrossRefs" href="#bib0345">17,22</a> and in vivo models have demonstrated the neuroprotective effects of this growth factor; in animal models, rHuEPO has promoted angiogenesis, neurogenesis, and the migration of neural precursor cells to the lesion site, and inhibited apoptosis by suppressing glutamate secretion and modulating intracellular calcium.<a class="elsevierStyleCrossRefs" href="#bib0375">23–28</a> Strikingly, clinical trials have reported that administration of rHuEPO reduces cognitive impairment, with a positive impact on memory and learning problems.<a class="elsevierStyleCrossRefs" href="#bib0405">29–31</a>In addition to learning and memory impairment, motor problems are reported in some animal models of CKD.<a class="elsevierStyleCrossRefs" href="#bib0420">32,33</a> However, there is little evidence on the neuroprotective effects of erythropoietin in CKD. This study aims to evaluate the effect of rHuEPO on sensorimotor activity, memory, and learning when the agent is administered simultaneously with the induction of kidney damage in a model of CKD.MethodsSubjectsWe used 24 male Wistar rats (Envigo RMS) weighing 250 to 300g at the beginning of the study. Rats were housed in translucent polycarbonate cages in a vivarium with a temperature of 25±2°C and a 12:12hour light-dark cycle; rats had free access to food and water. Rats were handled according to the international ethical standards established in the Guide for care and use of laboratory animals and official Mexican guidelines established in regulation NOM-062-ZOO-1999. The institutional ethical approval code for the study is CICUAL-2016-019.Experimental groups and treatmentsThe animals were randomly assigned to the following study groups: (1) control+sham (n=5); (2) control+rHuEPO (n=5); (3) CKD+sham (n=7); and (4) CKD+rHuEPO (n=7). CKD was induced with adenine, administered orogastrically at 100mg/kg/day for 28 days.<a class="elsevierStyleCrossRefs" href="#bib0430">34,35</a> Groups 1 and 3 received a sham treatment (saline solution) and groups 2 and 4 were treated with rHuEPO administered at 1050IU/kg via dorsal subcutaneous injection once weekly for 4 weeks. All behavioural tests were performed simultaneously with CKD induction and treatment.Sample collection and determination of biochemical and haematological parametersAt the end of the treatment and behavioural testing period, animals were placed for 24hours in metabolic cages for urine collection. They were subsequently euthanised with an overdose of sodium pentobarbital (40-60mg/kg, intraperitoneal administration), and we collected total blood with ethylenediaminetetraacetic acid and serum. Finally, kidneys were dissected, measured, and weighed. Creatinine and urea levels were determined by dry chemistry using a Vitros 250 system (Ortho Clinical Diagnostics); haemoglobin, haematocrit, erythrocyte, and reticulocyte levels were measured with a KX-21N haematology analyser (Sysmex Corporation).Open field testThe open field test enables general assessment of animals’ locomotor activity and anxiety.<a class="elsevierStyleCrossRef" href="#bib0440">36</a> The test was performed in a white open-field arena measuring 50cm×50cm×50cm. Rats were placed in the centre of the arena and allowed to explore freely for 3minutes. Video footage was recorded for subsequent analysis. The entire arena was cleaned with 70% ethanol after each rat completed the test. The behavioural parameters evaluated were: (1) exploration time, (2) latency time, (3) number of escape attempts, and (4) instances of grooming.Adhesive removal testThis test assesses somatosensory and motor function. Adhesive tape strips are placed on the rat's fore or hind paws and the animal's performance is assessed by measuring the time taken for it to feel and remove the tape.<a class="elsevierStyleCrossRefs" href="#bib0445">37,38</a> The test was performed 3 times per day for 3 days. Two adhesive tape strips of equal size were placed on the hind paws. Tactile response was determined by measuring the time between initial contact with the tape and removal of the tape. Rats that did not complete the task within 60seconds were considered unable to remove the tape.Morris water maze testThe water maze test was performed with a circular pool (110cm diameter by 60cm depth) filled with water (mean temperature [SD], 23°C [2°C]), as specified by Tóthová et al.,<a class="elsevierStyleCrossRef" href="#bib0455">39</a> with the modifications described below. The maze was divided virtually into 4 quadrants and a geometric shape was placed on the wall in each quadrant to act as an external clue for orientation. A 10cm×10cm polycarbonate platform was placed in the centre of one quadrant. In an initial training phase (4 sessions daily for 3 days), rats were allowed to swim freely for one minute (beginning in a different quadrant each time), enabling them to see the platform, 1cm above the surface of the water; in the final test, the platform was submerged 1cm below the water level. Animals that were unable to reach the platform within 60seconds were guided and placed on top of the platform for 20seconds to enable spatial orientation. Video footage was recorded for subsequent analysis; the parameters evaluated were time taken to reach the platform and distance swum.Statistical analysisData on kidney function and anaemia were analysed using one-way ANOVA; data from the open-field, adhesive removal, and water maze tests were analysed using two-way repeated measures ANOVA with treatment and training days as factors. Statistical significance was set at P<.05, and the Tukey post hoc test was applied. Results are expressed as mean (standard deviation).ResultsTreatment with recombinant human erythropoietin reduces kidney damage and corrects renal anaemia in rats with chronic kidney diseaseStatistical analysis found that animals with CKD had significantly lower body weight (data not shown), reduced urine creatinine levels (P<.05), and increased serum creatinine and urea levels (P<.05). These rats also had increased urine volume (P<.05) and increased kidney size and weight (39% and 152% greater, respectively) compared to control rats. This represents a 66% reduction in glomerular filtration rate (GFR), demonstrating a loss of kidney function in these animals (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). Haematological findings indicated significant reductions in haemoglobin concentration (21%), haematocrit (25%), erythrocytes (21%), and reticulocytes (65%) in CKD rats vs. controls (P<.05) (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Treatment with rHuEPO significantly reduced the increase in serum creatinine and urea levels in CKD rats (P<.05). The treatment also prevented kidney hypertrophy: kidney weight and size were 1.5 times and 1.2 times smaller than in CKD rats not receiving rHuEPO (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). In addition, animals receiving rHuEPO presented decreased urine volume and GFR (9.4% and 33% less, respectively), although these differences were not statistically significant (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). Treatment with rHuEPO in rats with CKD also corrected renal anaemia, with haemoglobin levels, reticulocyte and erythrocyte counts, and haematocrit returning to the levels observed in the control group (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).Treatment with recombinant human erythropoietin reduces sensorimotor dysfunction in rats with chronic kidney diseaseAnimals with CKD showed increased latency times in the open field and adhesive removal tests, with increased periods of inactivity compared to control animals (P<.05) (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>). They also showed significant reductions in exploration time, escape attempts, and instances of grooming in the open-field test (P<.05); similarly, they took longer to remove adhesive strips, demonstrating reduced tactile response compared to control rats (P<.05) (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>Treatment with rHuEPO was associated with significant increases in the number of escape attempts and instances of grooming in the open field test (P<.05) and reduced time taken to remove adhesive tape strips, compared to animals receiving the sham treatment (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>). Interestingly, rHuEPO treatment was associated with decreased latency times in both tests and increased exploration time in CKD rats (P<.05) (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>A).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Treatment with recombinant human erythropoietin reduces swimming time to platform in rats with chronic kidney diseaseIn the water maze test, all groups showed significant reductions in the time taken to swim to the platform between training sessions 1 and 4 (P<.05). While all animals showed a significant reduction in swimming time in tests 5 to 7, a consistent reduction was observed from session 3 in CKD rats treated with rHuEPO (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>B).DiscussionThis study aimed to evaluate the effects of treatment with rHuEPO on sensorimotor and cognitive function in a model of CKD. CKD is characterised by abnormalities in kidney structure and function.<a class="elsevierStyleCrossRef" href="#bib0460">40</a> Our findings show that administration of adenine (used to induce CKD) increased serum creatinine and urea concentrations, reduced GFR, and caused renal anaemia; these observations are consistent with those of previous studies of this model.<a class="elsevierStyleCrossRefs" href="#bib0420">32,41</a> In rats with CKD, rHuEPO corrected anaemia and decreased kidney damage. Coldewey et al.<a class="elsevierStyleCrossRef" href="#bib0470">42</a> report similar findings, with erythropoietin administration attenuating acute kidney dysfunction in a murine model of sepsis.By performing behavioural tests in parallel with the induction of kidney damage, we were able to observe progressive sensorimotor dysfunction. Rats with CKD showed a gradual increase in latency times in these tests, as well as decreased ability to remove the adhesive tape and reductions in exploration times and the number of escape attempts and instances of grooming. Mazumder et al.<a class="elsevierStyleCrossRef" href="#bib0475">43</a> and Karthick et al.<a class="elsevierStyleCrossRef" href="#bib0425">33</a> make similar observations, reporting that inactivity times are 2-3 times greater in animals with kidney damage. Behavioural changes in rats with CKD may be attributed to increased plasma urea concentration and reduced GFR, which would cause neurotoxicity due to the accumulation of uraemic toxins, promoting neurodegeneration.<a class="elsevierStyleCrossRefs" href="#bib0270">2,44</a> They may also be related to anaemia, which contributes to reduced cerebral oxygen supply and consequently greater distribution of uraemic toxins, with an impact on brain metabolism.<a class="elsevierStyleCrossRefs" href="#bib0320">12,45</a>While some studies do not report that treatment with erythropoietin has any effect on cognitive function,<a class="elsevierStyleCrossRefs" href="#bib0490">46,47</a> several studies do observe beneficial effects on motor function, learning, and memory.<a class="elsevierStyleCrossRefs" href="#bib0385">25,27,33,48</a>Our results demonstrate that rHuEPO treatment reduces latency time and tape removal time and increases exploration time; this reflects an improvement in the sensorimotor impairment observed in rats with CKD. Similarly, other studies report that preventive treatment with a single dose of erythropoietin improves animals’ motor performance in models of traumatic brain injury<a class="elsevierStyleCrossRefs" href="#bib0400">28,46</a> and ischaemia.<a class="elsevierStyleCrossRef" href="#bib0505">49</a> One study of an adenine-induced CKD model found that simultaneous and subsequent treatment with erythropoietin improved the behavioural alterations.<a class="elsevierStyleCrossRef" href="#bib0425">33</a>Finally, it should be noted that slight alterations were observed in memory and learning during the induction of CKD. As explained by Tóthová et al.,<a class="elsevierStyleCrossRef" href="#bib0455">39</a> the duration of the study period is an important factor in observing cognitive alterations in rats with kidney damage. Other studies report increases in memory and learning alterations several weeks after kidney failure is established.<a class="elsevierStyleCrossRefs" href="#bib0510">50,51</a> This is explained by the association between cognitive impairment and CKD severity due to uraemia and anaemia, which lead to a state of chronic hypoxia of the brain.<a class="elsevierStyleCrossRef" href="#bib0520">52</a>In conclusion, despite the slight changes in cognitive function at 4 weeks, adenine-induced kidney damage was associated with progressive sensorimotor alterations. Simultaneous treatment with rHuEPO corrected anaemia and reduced uraemia and kidney damage, which may be associated with reductions in sensorimotor dysfunction in animals with CKD.FundingThis project was supported by the Sectoral Fund for Research in Education (Ciencia Básica SEP-CONACyT; project code 243118); the technical supervisor is Dr Ana Laura Márquez.Conflicts of interestThe authors have no conflicts of interest to declare." "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres1335522" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1230052" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1335523" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1230051" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Methods" "secciones" => array:7 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Subjects" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Experimental groups and treatments" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Sample collection and determination of biochemical and haematological parameters" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Open field test" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Adhesive removal test" ] 5 => array:2 [ "identificador" => "sec0040" "titulo" => "Morris water maze test" ] 6 => array:2 [ "identificador" => "sec0045" "titulo" => "Statistical analysis" ] ] ] 6 => array:3 [ "identificador" => "sec0050" "titulo" => "Results" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0055" "titulo" => "Treatment with recombinant human erythropoietin reduces kidney damage and corrects renal anaemia in rats with chronic kidney disease" ] 1 => array:2 [ "identificador" => "sec0060" "titulo" => "Treatment with recombinant human erythropoietin reduces sensorimotor dysfunction in rats with chronic kidney disease" ] 2 => array:2 [ "identificador" => "sec0065" "titulo" => "Treatment with recombinant human erythropoietin reduces swimming time to platform in rats with chronic kidney disease" ] ] ] 7 => array:2 [ "identificador" => "sec0070" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0075" "titulo" => "Funding" ] 9 => array:2 [ "identificador" => "sec0080" "titulo" => "Conflicts of interest" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2017-07-07" "fechaAceptado" => "2017-07-18" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1230052" "palabras" => array:4 [ 0 => "Chronic kidney disease" 1 => "Sensorimotor function" 2 => "Cognitive impairment" 3 => "Erythropoietin" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1230051" "palabras" => array:4 [ 0 => "Enfermedad renal crónica" 1 => "Función sensoriomotora" 2 => "Deterioro cognitivo" 3 => "Eritropoyetina" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "IntroductionChronic kidney disease (CKD) can cause anaemia and neurological disorders. Recombinant human erythropoietin (rHuEPO) is used to manage anaemia in CKD. However, there is little evidence on the effects of rHuEPO on behaviour and cognitive function in CKD. This study aimed to evaluate the impact of rHuEPO in sensorimotor and cognitive functions in a CKD model. MethodsMale Wistar rats were randomly assigned to 4 groups: control and CKD, with and without rHuEPO treatment (1050IU per kg body weight, once weekly for 4 weeks). The Morris water maze, open field, and adhesive removal tests were performed simultaneously to kidney damage induction and treatment. Markers of anaemia and renal function were measured at the end of the study. ResultsTreatment with rHuEPO reduced kidney damage and corrected anaemia in rats with CKD. We observed reduced sensorimotor dysfunction in animals with CKD and treated with rHuEPO. These rats also completed the water maze test in a shorter time than the control groups. ConclusionsrHuEPO reduces kidney damage, corrects anaemia, and reduces sensorimotor and cognitive dysfunction in animals with CKD." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "IntroducciónLa enfermedad renal crónica (ERC) puede provocar anemia e inducir afectaciones neurológicas. La eritropoyetina humana recombinante (rHuEPO) se utiliza en el tratamiento de la anemia en la ERC. Sin embargo, existe poca evidencia de los efectos de la rHuEPO sobre la conducta y las funciones cognitivas en la ERC. El objetivo de este estudio fue evaluar el efecto del tratamiento con rHuEPO sobre las funciones sensoriomotoras y cognitivas en un modelo de ERC. MétodosRatas macho de la cepa Wistar fueron asignadas a 4 grupos: control y ERC, con y sin tratamiento con rHuEPO (1.050 UI/kg de peso, una vez por semana durante 4 semanas). Las pruebas conductuales de laberinto acuático de Morris, campo abierto y cinta adhesiva se realizaron de manera simultánea a la inducción del daño renal y el tratamiento. Mientras que la determinación de marcadores de función renal y anemia se realizaron al término del estudio. ResultadosEl tratamiento con rHuEPO redujo el daño en el riñón y corrigió la anemia en las ratas con ERC. En las pruebas conductuales, el tratamiento con rHuEPO redujo la disfunción sensoriomotora observada en los animales con ERC. Por otra parte, en los animales con ERC y tratamiento con rHuEPO resolvieron el laberinto en menor tiempo en comparación a los grupos control. ConclusionesEl tratamiento con rHuEPO reduce el daño en el riñón, corrige la anemia y reduce la disfunción sensoriomotora y cognitiva en los animales con ERC." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Reza-Zaldívar EE, Sandoval-Avila S, Gutiérrez-Mercado YK, Vázquez-Méndez E, Canales-Aguirre AA, Esquivel-Solís H, et al. La eritropoyetina humana recombinante reduce la disfunción sensoriomotora y el deterioro cognitivo en ratas con enfermedad renal crónica. Neurología. 2020;35:147–154." ] ] "multimedia" => array:4 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1856 "Ancho" => 3379 "Tamanyo" => 362630 ] ] "descripcion" => array:1 [ "en" => "Behavioural tests. (A) Open field test. The graphs show latency and exploration times for each session. (B) Morris water maze test. The graph shows swimming time to platform for each session, and a representative illustration of paths taken to the platform. Data are expressed as means (error bars denote standard deviation). Statistical significance was set at P<.05 (one-way ANOVA). *Significant difference between CKD and control rats. **Significant difference between CKD+rHuEPO and CKD+sham rats. ANOVA: analysis of variance; CKD: chronic kidney disease; rHuEPO: recombinant human erythropoietin." ] ] 1 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "Data are expressed as mean (standard deviation).Statistical significance was set at P<.05 (one-way ANOVA)." "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"><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Parameter \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="4" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Group</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Control</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CKD</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Sham \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">rHuEPO \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Sham \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">rHuEPO \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mean kidney weight (g) \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">1.14 (0.05) \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">1.09 (0.05) \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">2.8 (0.2)<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \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">1.8 (0.11)<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mean kidney size (cm) \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">1.7 (0.09) \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">1.6 (0.02) \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">2.3 (0.08)<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \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">1.9 (0.04)<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Urine volume (mL) \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">16.7 (1.9) \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">13.4 (1.7) \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">66 (7.0)<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \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">59.8 (2.8)<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Urea (mg/dL) \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">43.5 (1.5) \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">38.2 (2.5) \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">196.6 (33.4)<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \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">78.2 (5.3)<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Serum creatinine (mg/dL) \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">0.62 (0.04) \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">0.63 (0.04) \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">2.19 (0.42)<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \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">0.93 (0.09)<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Urine creatinine (mg/dL) \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">46.75 (8.4) \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">48.9 (3.7) \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">19 (1.4)<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \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">19.3 (2.2)<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">GFR (mL/min/g) \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">0.73 (0.05) \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">0.67 (0.04) \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">0.24 (0.08)<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \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">0.47 (0.08) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2289771.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "CKD vs. control." ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "CKD+rHuEPO vs. CKD. ANOVA: analysis of variance; CKD: chronic kidney disease; GFR: glomerular filtration rate; rHuEPO: recombinant human erythropoietin." ] ] ] "descripcion" => array:1 [ "en" => "Kidney function markers." ] ] 2 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "Data are expressed as mean (standard deviation).Statistical significance was set at P<.05 (one-way ANOVA)." "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"><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Parameter \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="4" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Group</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Control</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CKD</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Sham \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">rHuEPO \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Sham \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">rHuEPO \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Haemoglobin (g/dL) \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">16.3 (0.14) \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">17.5 (0.37) \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">13.3 (0.42)<a class="elsevierStyleCrossRef" href="#tblfn0015">a</a> \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">17.8 (0.89)<a class="elsevierStyleCrossRef" href="#tblfn0020">b</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Reticulocytes (%) \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">3.2 (0.4) \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">3.6 (0.5) \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">1.2 (0.2)<a class="elsevierStyleCrossRef" href="#tblfn0015">a</a> \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">4 (0.3)<a class="elsevierStyleCrossRef" href="#tblfn0020">b</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Erythrocytes (×106μL−1) \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">8.5 (0.4) \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">8.4 (0.2) \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">6.7 (0.1)<a class="elsevierStyleCrossRef" href="#tblfn0015">a</a> \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">8.8 (0.5)<a class="elsevierStyleCrossRef" href="#tblfn0020">b</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Haematocrit (%) \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">52.8 (0.3) \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">57.3 (1.6) \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">41.3 (1.3)<a class="elsevierStyleCrossRef" href="#tblfn0015">a</a> \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">58.2 (3.4)<a class="elsevierStyleCrossRef" href="#tblfn0020">b</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2289770.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "a" "nota" => "CKD vs. control." ] 1 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "b" "nota" => "CKD+rHuEPO vs. CKD. ANOVA: analysis of variance; CKD: chronic kidney disease; rHuEPO: recombinant human erythropoietin." ] ] ] "descripcion" => array:1 [ "en" => "Haematological data." ] ] 3 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "Data are expressed as mean (standard deviation) for the final test session. Statistical significance was set at P<.05 (two-way ANOVA)." "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"><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Test \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col">Parameter \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="4" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Group</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Control</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CKD</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Sham \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">rHuEPO \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Sham \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">rHuEPO \t\t\t\t\t\t\n \t\t\t\t\t\t</th></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 " rowspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Open-field test</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">Latency time (s) \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">47.0 (3.0) \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">89.8 (7.4) \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">129.8 (6.0)<a class="elsevierStyleCrossRef" href="#tblfn0025">a</a> \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">97.4 (3.2)<a class="elsevierStyleCrossRef" href="#tblfn0030">b</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Exploration time (s) \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">133.0 (3.0) \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">90.2 (7.4) \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">44.2 (1.4)<a class="elsevierStyleCrossRef" href="#tblfn0025">a</a> \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">82.6 (3.2)<a class="elsevierStyleCrossRef" href="#tblfn0030">b</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Escape attempts \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">14.7 (0.8) \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">10.5 (1.7) \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">5.8 (0.9)<a class="elsevierStyleCrossRef" href="#tblfn0025">a</a> \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">10.8 (0.7)<a class="elsevierStyleCrossRef" href="#tblfn0030">b</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Grooming (instances) \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">2.3 (0.2) \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">2.0 (0.3) \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">0.75 (0.2)<a class="elsevierStyleCrossRef" href="#tblfn0025">a</a> \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">2.3 (0.1)<a class="elsevierStyleCrossRef" href="#tblfn0030">b</a> \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 " colspan="6" align="left" valign="\n \t\t\t\t\ttop\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 " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Adhesive removal test</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">Latency time (s) \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">0.75 (0.4) \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">0 \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">1.9 (0.6)<a class="elsevierStyleCrossRef" href="#tblfn0025">a</a> \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">0 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Removal time (s) \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">9.0 (0.8) \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">9.0 (1.1) \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">22.2 (2.2)<a class="elsevierStyleCrossRef" href="#tblfn0025">a</a> \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">14.1 (1.6)<a class="elsevierStyleCrossRef" href="#tblfn0030">b</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2289772.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0025" "etiqueta" => "a" "nota" => "CKD vs. control." ] 1 => array:3 [ "identificador" => "tblfn0030" "etiqueta" => "b" "nota" => "CKD+rHuEPO vs. CKD. ANOVA: analysis of variance; CKD: chronic kidney disease; rHuEPO: recombinant human erythropoietin." ] ] ] "descripcion" => array:1 [ "en" => "Tests of sensorimotor function." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:52 [ 0 => array:3 [ "identificador" => "bib0265" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of improvement in anemia on electroneurophysiological markers (P300) of cognitive dysfunction in chronic kidney disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "N.P. Singh" 1 => "V. Sahni" 2 => "A. Wadhwa" 3 => "S. Garg" 4 => "S.K. Bajaj" 5 => "R. 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La eritropoyetina humana recombinante reduce la disfunción sensoriomotora y el deterioro cognitivo en ratas con enfermedad renal crónica

E.E. Reza-Zaldívara, S. Sandoval-Avilaa, Y.K. Gutiérrez-Mercadoa, E. Vázquez-Méndeza, A.A. Canales-Aguirrea,b, H. Esquivel-Solísa,b, U. Gómez-Pinedoc, A.L. Márquez-Aguirrea,b,

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amarquez@ciatej.mx

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a Biotecnología Médica y Farmacéutica, Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco, Guadalajara, Jalisco, Mexico

b Unidad de Evaluación Preclínica, Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco, Guadalajara, Jalisco, Mexico

c Departamento de Neurología, Laboratorio de Neurociencias, IdISSC, Hospital Clínico San Carlos, Universidad Complutense, Madrid, Spain

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and reactive oxygen species&#44;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">2</span></a> which cause alterations in serotonergic and cholinergic neurotransmission&#44; and endothelial inflammation and dysfunction&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">6</span></a> These factors can affect all levels of the nervous system&#44; promoting such neurological alterations as uraemic encephalopathy&#44; cognitive problems&#44; and such neuromuscular disorders as mononeuropathy&#44; polyneuropathy&#44; and myopathy&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">7</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">At advanced stages&#44; patients with kidney disease may present severe anaemia&#44; known as renal anaemia&#44; caused by a deficiency in renal erythropoietin production&#46;<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">8&#8211;10</span></a> Numerous studies have reported that anaemia negatively affects cognitive function<a class="elsevierStyleCrossRefs" href="#bib0315"><span class="elsevierStyleSup">11&#44;12</span></a> due to insufficient cerebral oxygen supply caused by a decrease in the oxygen transport capacity&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">13</span></a> Chronic hypoxia causes toxicity secondary to oxidative stress&#59; combined with the accumulation of uraemic toxins&#44;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">7&#44;14</span></a> this accelerates neuronal degeneration&#46;<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">12&#44;15</span></a> In patients with CKD&#44; anaemia is treated with erythropoiesis-stimulating agents&#44; such as recombinant human erythropoietin &#40;rHuEPO&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">10</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">While erythropoietin plays an essential role in erythropoiesis&#44; it has been reported to have other functions&#44; such as anti-inflammatory<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">16</span></a> and anti-apoptotic activities&#44;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">17</span></a> stimulating neurogenesis and neuronal differentiation in early developmental stages&#44;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">18</span></a> and tissue protection in the kidneys<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">19</span></a> and brain&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">20&#44;21</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Both in vitro<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">17&#44;22</span></a> and in vivo models have demonstrated the neuroprotective effects of this growth factor&#59; in animal models&#44; rHuEPO has promoted angiogenesis&#44; neurogenesis&#44; and the migration of neural precursor cells to the lesion site&#44; and inhibited apoptosis by suppressing glutamate secretion and modulating intracellular calcium&#46;<a class="elsevierStyleCrossRefs" href="#bib0375"><span class="elsevierStyleSup">23&#8211;28</span></a> Strikingly&#44; clinical trials have reported that administration of rHuEPO reduces cognitive impairment&#44; with a positive impact on memory and learning problems&#46;<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">29&#8211;31</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">In addition to learning and memory impairment&#44; motor problems are reported in some animal models of CKD&#46;<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">32&#44;33</span></a> However&#44; there is little evidence on the neuroprotective effects of erythropoietin in CKD&#46; This study aims to evaluate the effect of rHuEPO on sensorimotor activity&#44; memory&#44; and learning when the agent is administered simultaneously with the induction of kidney damage in a model of CKD&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Subjects</span><p id="par0035" class="elsevierStylePara elsevierViewall">We used 24 male Wistar rats &#40;Envigo RMS&#41; weighing 250 to 300<span class="elsevierStyleHsp" style=""></span>g at the beginning of the study&#46; Rats were housed in translucent polycarbonate cages in a vivarium with a temperature of 25<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>&#176;C and a 12&#58;12<span class="elsevierStyleHsp" style=""></span>hour light-dark cycle&#59; rats had free access to food and water&#46; Rats were handled according to the international ethical standards established in the <span class="elsevierStyleItalic">Guide for care and use of laboratory animals</span> and official Mexican guidelines established in regulation NOM-062-ZOO-1999&#46; The institutional ethical approval code for the study is CICUAL-2016-019&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Experimental groups and treatments</span><p id="par0040" class="elsevierStylePara elsevierViewall">The animals were randomly assigned to the following study groups&#58; &#40;1&#41; control<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>sham &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5&#41;&#59; &#40;2&#41; control<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>rHuEPO &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5&#41;&#59; &#40;3&#41; CKD<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>sham &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>7&#41;&#59; and &#40;4&#41; CKD<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>rHuEPO &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>7&#41;&#46; CKD was induced with adenine&#44; administered orogastrically at 100<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day for 28 days&#46;<a class="elsevierStyleCrossRefs" href="#bib0430"><span class="elsevierStyleSup">34&#44;35</span></a> Groups 1 and 3 received a sham treatment &#40;saline solution&#41; and groups 2 and 4 were treated with rHuEPO administered at 1050<span class="elsevierStyleHsp" style=""></span>IU&#47;kg via dorsal subcutaneous injection once weekly for 4 weeks&#46; All behavioural tests were performed simultaneously with CKD induction and treatment&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Sample collection and determination of biochemical and haematological parameters</span><p id="par0045" class="elsevierStylePara elsevierViewall">At the end of the treatment and behavioural testing period&#44; animals were placed for 24<span class="elsevierStyleHsp" style=""></span>hours in metabolic cages for urine collection&#46; They were subsequently euthanised with an overdose of sodium pentobarbital &#40;40-60<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#44; intraperitoneal administration&#41;&#44; and we collected total blood with ethylenediaminetetraacetic acid and serum&#46; Finally&#44; kidneys were dissected&#44; measured&#44; and weighed&#46; Creatinine and urea levels were determined by dry chemistry using a Vitros 250 system &#40;Ortho Clinical Diagnostics&#41;&#59; haemoglobin&#44; haematocrit&#44; erythrocyte&#44; and reticulocyte levels were measured with a KX-21N haematology analyser &#40;Sysmex Corporation&#41;&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Open field test</span><p id="par0050" class="elsevierStylePara elsevierViewall">The open field test enables general assessment of animals&#8217; locomotor activity and anxiety&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">36</span></a> The test was performed in a white open-field arena measuring 50<span class="elsevierStyleHsp" style=""></span>cm<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>50<span class="elsevierStyleHsp" style=""></span>cm<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>50<span class="elsevierStyleHsp" style=""></span>cm&#46; Rats were placed in the centre of the arena and allowed to explore freely for 3<span class="elsevierStyleHsp" style=""></span>minutes&#46; Video footage was recorded for subsequent analysis&#46; The entire arena was cleaned with 70&#37; ethanol after each rat completed the test&#46; The behavioural parameters evaluated were&#58; &#40;1&#41; exploration time&#44; &#40;2&#41; latency time&#44; &#40;3&#41; number of escape attempts&#44; and &#40;4&#41; instances of grooming&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Adhesive removal test</span><p id="par0055" class="elsevierStylePara elsevierViewall">This test assesses somatosensory and motor function&#46; Adhesive tape strips are placed on the rat&#39;s fore or hind paws and the animal&#39;s performance is assessed by measuring the time taken for it to feel and remove the tape&#46;<a class="elsevierStyleCrossRefs" href="#bib0445"><span class="elsevierStyleSup">37&#44;38</span></a> The test was performed 3 times per day for 3 days&#46; Two adhesive tape strips of equal size were placed on the hind paws&#46; Tactile response was determined by measuring the time between initial contact with the tape and removal of the tape&#46; Rats that did not complete the task within 60<span class="elsevierStyleHsp" style=""></span>seconds were considered unable to remove the tape&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Morris water maze test</span><p id="par0060" class="elsevierStylePara elsevierViewall">The water maze test was performed with a circular pool &#40;110<span class="elsevierStyleHsp" style=""></span>cm diameter by 60<span class="elsevierStyleHsp" style=""></span>cm depth&#41; filled with water &#40;mean temperature &#91;SD&#93;&#44; 23<span class="elsevierStyleHsp" style=""></span>&#176;C &#91;2<span class="elsevierStyleHsp" style=""></span>&#176;C&#93;&#41;&#44; as specified by T&#243;thov&#225; et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">39</span></a> with the modifications described below&#46; The maze was divided virtually into 4 quadrants and a geometric shape was placed on the wall in each quadrant to act as an external clue for orientation&#46; A 10<span class="elsevierStyleHsp" style=""></span>cm<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleHsp" style=""></span>cm polycarbonate platform was placed in the centre of one quadrant&#46; In an initial training phase &#40;4 sessions daily for 3 days&#41;&#44; rats were allowed to swim freely for one minute &#40;beginning in a different quadrant each time&#41;&#44; enabling them to see the platform&#44; 1<span class="elsevierStyleHsp" style=""></span>cm above the surface of the water&#59; in the final test&#44; the platform was submerged 1<span class="elsevierStyleHsp" style=""></span>cm below the water level&#46; Animals that were unable to reach the platform within 60<span class="elsevierStyleHsp" style=""></span>seconds were guided and placed on top of the platform for 20<span class="elsevierStyleHsp" style=""></span>seconds to enable spatial orientation&#46; Video footage was recorded for subsequent analysis&#59; the parameters evaluated were time taken to reach the platform and distance swum&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Statistical analysis</span><p id="par0065" class="elsevierStylePara elsevierViewall">Data on kidney function and anaemia were analysed using one-way ANOVA&#59; data from the open-field&#44; adhesive removal&#44; and water maze tests were analysed using two-way repeated measures ANOVA with treatment and training days as factors&#46; Statistical significance was set at <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;05&#44; and the Tukey post hoc test was applied&#46; Results are expressed as mean &#40;standard deviation&#41;&#46;</p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Results</span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Treatment with recombinant human erythropoietin reduces kidney damage and corrects renal anaemia in rats with chronic kidney disease</span><p id="par0070" class="elsevierStylePara elsevierViewall">Statistical analysis found that animals with CKD had significantly lower body weight &#40;data not shown&#41;&#44; reduced urine creatinine levels &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;05&#41;&#44; and increased serum creatinine and urea levels &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;05&#41;&#46; These rats also had increased urine volume &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;05&#41; and increased kidney size and weight &#40;39&#37; and 152&#37; greater&#44; respectively&#41; compared to control rats&#46; This represents a 66&#37; reduction in glomerular filtration rate &#40;GFR&#41;&#44; demonstrating a loss of kidney function in these animals &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Haematological findings indicated significant reductions in haemoglobin concentration &#40;21&#37;&#41;&#44; haematocrit &#40;25&#37;&#41;&#44; erythrocytes &#40;21&#37;&#41;&#44; and reticulocytes &#40;65&#37;&#41; in CKD rats vs&#46; controls &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;05&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">Treatment with rHuEPO significantly reduced the increase in serum creatinine and urea levels in CKD rats &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;05&#41;&#46; The treatment also prevented kidney hypertrophy&#58; kidney weight and size were 1&#46;5 times and 1&#46;2 times smaller than in CKD rats not receiving rHuEPO &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; In addition&#44; animals receiving rHuEPO presented decreased urine volume and GFR &#40;9&#46;4&#37; and 33&#37; less&#44; respectively&#41;&#44; although these differences were not statistically significant &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Treatment with rHuEPO in rats with CKD also corrected renal anaemia&#44; with haemoglobin levels&#44; reticulocyte and erythrocyte counts&#44; and haematocrit returning to the levels observed in the control group &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Treatment with recombinant human erythropoietin reduces sensorimotor dysfunction in rats with chronic kidney disease</span><p id="par0080" class="elsevierStylePara elsevierViewall">Animals with CKD showed increased latency times in the open field and adhesive removal tests&#44; with increased periods of inactivity compared to control animals &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;05&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; They also showed significant reductions in exploration time&#44; escape attempts&#44; and instances of grooming in the open-field test &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;05&#41;&#59; similarly&#44; they took longer to remove adhesive strips&#44; demonstrating reduced tactile response compared to control rats &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;05&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0085" class="elsevierStylePara elsevierViewall">Treatment with rHuEPO was associated with significant increases in the number of escape attempts and instances of grooming in the open field test &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;05&#41; and reduced time taken to remove adhesive tape strips&#44; compared to animals receiving the sham treatment &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; Interestingly&#44; rHuEPO treatment was associated with decreased latency times in both tests and increased exploration time in CKD rats &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;05&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>A&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Treatment with recombinant human erythropoietin reduces swimming time to platform in rats with chronic kidney disease</span><p id="par0090" class="elsevierStylePara elsevierViewall">In the water maze test&#44; all groups showed significant reductions in the time taken to swim to the platform between training sessions 1 and 4 &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;05&#41;&#46; While all animals showed a significant reduction in swimming time in tests 5 to 7&#44; a consistent reduction was observed from session 3 in CKD rats treated with rHuEPO &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>B&#41;&#46;</p></span></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Discussion</span><p id="par0095" class="elsevierStylePara elsevierViewall">This study aimed to evaluate the effects of treatment with rHuEPO on sensorimotor and cognitive function in a model of CKD&#46; CKD is characterised by abnormalities in kidney structure and function&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">40</span></a> Our findings show that administration of adenine &#40;used to induce CKD&#41; increased serum creatinine and urea concentrations&#44; reduced GFR&#44; and caused renal anaemia&#59; these observations are consistent with those of previous studies of this model&#46;<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">32&#44;41</span></a> In rats with CKD&#44; rHuEPO corrected anaemia and decreased kidney damage&#46; Coldewey et al&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">42</span></a> report similar findings&#44; with erythropoietin administration attenuating acute kidney dysfunction in a murine model of sepsis&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">By performing behavioural tests in parallel with the induction of kidney damage&#44; we were able to observe progressive sensorimotor dysfunction&#46; Rats with CKD showed a gradual increase in latency times in these tests&#44; as well as decreased ability to remove the adhesive tape and reductions in exploration times and the number of escape attempts and instances of grooming&#46; Mazumder et al&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">43</span></a> and Karthick et al&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">33</span></a> make similar observations&#44; reporting that inactivity times are 2-3 times greater in animals with kidney damage&#46; Behavioural changes in rats with CKD may be attributed to increased plasma urea concentration and reduced GFR&#44; which would cause neurotoxicity due to the accumulation of uraemic toxins&#44; promoting neurodegeneration&#46;<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">2&#44;44</span></a> They may also be related to anaemia&#44; which contributes to reduced cerebral oxygen supply and consequently greater distribution of uraemic toxins&#44; with an impact on brain metabolism&#46;<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">12&#44;45</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">While some studies do not report that treatment with erythropoietin has any effect on cognitive function&#44;<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">46&#44;47</span></a> several studies do observe beneficial effects on motor function&#44; learning&#44; and memory&#46;<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">25&#44;27&#44;33&#44;48</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">Our results demonstrate that rHuEPO treatment reduces latency time and tape removal time and increases exploration time&#59; this reflects an improvement in the sensorimotor impairment observed in rats with CKD&#46; Similarly&#44; other studies report that preventive treatment with a single dose of erythropoietin improves animals&#8217; motor performance in models of traumatic brain injury<a class="elsevierStyleCrossRefs" href="#bib0400"><span class="elsevierStyleSup">28&#44;46</span></a> and ischaemia&#46;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">49</span></a> One study of an adenine-induced CKD model found that simultaneous and subsequent treatment with erythropoietin improved the behavioural alterations&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">33</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Finally&#44; it should be noted that slight alterations were observed in memory and learning during the induction of CKD&#46; As explained by T&#243;thov&#225; et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">39</span></a> the duration of the study period is an important factor in observing cognitive alterations in rats with kidney damage&#46; Other studies report increases in memory and learning alterations several weeks after kidney failure is established&#46;<a class="elsevierStyleCrossRefs" href="#bib0510"><span class="elsevierStyleSup">50&#44;51</span></a> This is explained by the association between cognitive impairment and CKD severity due to uraemia and anaemia&#44; which lead to a state of chronic hypoxia of the brain&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">52</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">In conclusion&#44; despite the slight changes in cognitive function at 4 weeks&#44; adenine-induced kidney damage was associated with progressive sensorimotor alterations&#46; Simultaneous treatment with rHuEPO corrected anaemia and reduced uraemia and kidney damage&#44; which may be associated with reductions in sensorimotor dysfunction in animals with CKD&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Funding</span><p id="par0125" class="elsevierStylePara elsevierViewall">This project was supported by the Sectoral Fund for Research in Education &#40;Ciencia B&#225;sica SEP-CONACyT&#59; project code 243118&#41;&#59; the technical supervisor is Dr Ana Laura M&#225;rquez&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Conflicts of interest</span><p id="par0130" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Chronic kidney disease &#40;CKD&#41; can cause anaemia and neurological disorders&#46; Recombinant human erythropoietin &#40;rHuEPO&#41; is used to manage anaemia in CKD&#46; However&#44; there is little evidence on the effects of rHuEPO on behaviour and cognitive function in CKD&#46; This study aimed to evaluate the impact of rHuEPO in sensorimotor and cognitive functions in a CKD model&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Male Wistar rats were randomly assigned to 4 groups&#58; control and CKD&#44; with and without rHuEPO treatment &#40;1050<span class="elsevierStyleHsp" style=""></span>IU per kg body weight&#44; once weekly for 4 weeks&#41;&#46; The Morris water maze&#44; open field&#44; and adhesive removal tests were performed simultaneously to kidney damage induction and treatment&#46; Markers of anaemia and renal function were measured at the end of the study&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Treatment with rHuEPO reduced kidney damage and corrected anaemia in rats with CKD&#46; We observed reduced sensorimotor dysfunction in animals with CKD and treated with rHuEPO&#46; These rats also completed the water maze test in a shorter time than the control groups&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">rHuEPO reduces kidney damage&#44; corrects anaemia&#44; and reduces sensorimotor and cognitive dysfunction in animals with CKD&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Introduction"
          ]
          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Methods"
          ]
          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Results"
          ]
          3 => array:2 [
            "identificador" => "abst0020"
            "titulo" => "Conclusions"
          ]
        ]
      ]
      "es" => array:3 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducci&#243;n</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">La enfermedad renal cr&#243;nica &#40;ERC&#41; puede provocar anemia e inducir afectaciones neurol&#243;gicas&#46; La eritropoyetina humana recombinante &#40;rHuEPO&#41; se utiliza en el tratamiento de la anemia en la ERC&#46; Sin embargo&#44; existe poca evidencia de los efectos de la rHuEPO sobre la conducta y las funciones cognitivas en la ERC&#46; El objetivo de este estudio fue evaluar el efecto del tratamiento con rHuEPO sobre las funciones sensoriomotoras y cognitivas en un modelo de ERC&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Ratas macho de la cepa Wistar fueron asignadas a 4 grupos&#58; control y ERC&#44; con y sin tratamiento con rHuEPO &#40;1&#46;050 UI&#47;kg de peso&#44; una vez por semana durante 4 semanas&#41;&#46; Las pruebas conductuales de laberinto acu&#225;tico de Morris&#44; campo abierto y cinta adhesiva se realizaron de manera simult&#225;nea a la inducci&#243;n del da&#241;o renal y el tratamiento&#46; Mientras que la determinaci&#243;n de marcadores de funci&#243;n renal y anemia se realizaron al t&#233;rmino del estudio&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">El tratamiento con rHuEPO redujo el da&#241;o en el ri&#241;&#243;n y corrigi&#243; la anemia en las ratas con ERC&#46; En las pruebas conductuales&#44; el tratamiento con rHuEPO redujo la disfunci&#243;n sensoriomotora observada en los animales con ERC&#46; Por otra parte&#44; en los animales con ERC y tratamiento con rHuEPO resolvieron el laberinto en menor tiempo en comparaci&#243;n a los grupos control&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">El tratamiento con rHuEPO reduce el da&#241;o en el ri&#241;&#243;n&#44; corrige la anemia y reduce la disfunci&#243;n sensoriomotora y cognitiva en los animales con ERC&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0025"
            "titulo" => "Introducci&#243;n"
          ]
          1 => array:2 [
            "identificador" => "abst0030"
            "titulo" => "M&#233;todos"
          ]
          2 => array:2 [
            "identificador" => "abst0035"
            "titulo" => "Resultados"
          ]
          3 => array:2 [
            "identificador" => "abst0040"
            "titulo" => "Conclusiones"
          ]
        ]
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0050">Please cite this article as&#58; Reza-Zald&#237;var EE&#44; Sandoval-Avila S&#44; Guti&#233;rrez-Mercado YK&#44; V&#225;zquez-M&#233;ndez E&#44; Canales-Aguirre AA&#44; Esquivel-Sol&#237;s H&#44; et al&#46; La eritropoyetina humana recombinante reduce la disfunci&#243;n sensoriomotora y el deterioro cognitivo en ratas con enfermedad renal cr&#243;nica&#46; Neurolog&#237;a&#46; 2020&#59;35&#58;147&#8211;154&#46;</p>"
      ]
    ]
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      0 => array:7 [
        "identificador" => "fig0005"
        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Behavioural tests&#46; &#40;A&#41; Open field test&#46; The graphs show latency and exploration times for each session&#46; &#40;B&#41; Morris water maze test&#46; The graph shows swimming time to platform for each session&#44; and a representative illustration of paths taken to the platform&#46;</p> <p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Data are expressed as means &#40;error bars denote standard deviation&#41;&#46; Statistical significance was set at <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;05 &#40;one-way ANOVA&#41;&#46; &#42;Significant difference between CKD and control rats&#46; &#42;&#42;Significant difference between CKD<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>rHuEPO and CKD<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>sham rats&#46;</p> <p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">ANOVA&#58; analysis of variance&#59; CKD&#58; chronic kidney disease&#59; rHuEPO&#58; recombinant human erythropoietin&#46;</p>"
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        "tipo" => "MULTIMEDIATABLA"
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        "detalles" => array:1 [
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          "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Data are expressed as mean &#40;standard deviation&#41;&#46;</p><p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Statistical significance was set at <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;05 &#40;one-way ANOVA&#41;&#46;</p>"
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Sham&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1&#46;8 &#40;0&#46;11&#41;<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1&#46;9 &#40;0&#46;04&#41;<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">66 &#40;7&#46;0&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">59&#46;8 &#40;2&#46;8&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Urea &#40;mg&#47;dL&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">196&#46;6 &#40;33&#46;4&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Serum creatinine &#40;mg&#47;dL&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;63 &#40;0&#46;04&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">2&#46;19 &#40;0&#46;42&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;93 &#40;0&#46;09&#41;<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Urine creatinine &#40;mg&#47;dL&#41;&nbsp;\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
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                  \t\t\t\t">46&#46;75 &#40;8&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">48&#46;9 &#40;3&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">19 &#40;1&#46;4&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">19&#46;3 &#40;2&#46;2&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">GFR &#40;mL&#47;min&#47;g&#41;&nbsp;\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">0&#46;73 &#40;0&#46;05&#41;&nbsp;\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">0&#46;67 &#40;0&#46;04&#41;&nbsp;\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">0&#46;24 &#40;0&#46;08&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\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">0&#46;47 &#40;0&#46;08&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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              "identificador" => "tblfn0010"
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">CKD<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>rHuEPO vs&#46; CKD&#46;</p> <p class="elsevierStyleNotepara" id="npar0015">ANOVA&#58; analysis of variance&#59; CKD&#58; chronic kidney disease&#59; GFR&#58; glomerular filtration rate&#59; rHuEPO&#58; recombinant human erythropoietin&#46;</p>"
            ]
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          "leyenda" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Data are expressed as mean &#40;standard deviation&#41;&#46;</p><p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">Statistical significance was set at <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;05 &#40;one-way ANOVA&#41;&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Parameter&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="4" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Group</th></tr><tr title="table-row"><th class="td" title="\n
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                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Control</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CKD</th></tr><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Sham&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">rHuEPO&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Sham&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">rHuEPO&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Haemoglobin &#40;g&#47;dL&#41;&nbsp;\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">16&#46;3 &#40;0&#46;14&#41;&nbsp;\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">17&#46;5 &#40;0&#46;37&#41;&nbsp;\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">13&#46;3 &#40;0&#46;42&#41;<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">a</span></a>&nbsp;\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">17&#46;8 &#40;0&#46;89&#41;<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Reticulocytes &#40;&#37;&#41;&nbsp;\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">3&#46;2 &#40;0&#46;4&#41;&nbsp;\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">3&#46;6 &#40;0&#46;5&#41;&nbsp;\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">1&#46;2 &#40;0&#46;2&#41;<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">a</span></a>&nbsp;\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">4 &#40;0&#46;3&#41;<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Erythrocytes &#40;&#215;10<span class="elsevierStyleSup">6</span>&#956;L<span class="elsevierStyleSup">&#8722;1</span>&#41;&nbsp;\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">8&#46;5 &#40;0&#46;4&#41;&nbsp;\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">8&#46;4 &#40;0&#46;2&#41;&nbsp;\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">6&#46;7 &#40;0&#46;1&#41;<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">a</span></a>&nbsp;\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">8&#46;8 &#40;0&#46;5&#41;<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Haematocrit &#40;&#37;&#41;&nbsp;\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">52&#46;8 &#40;0&#46;3&#41;&nbsp;\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">57&#46;3 &#40;1&#46;6&#41;&nbsp;\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">41&#46;3 &#40;1&#46;3&#41;<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">a</span></a>&nbsp;\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">58&#46;2 &#40;3&#46;4&#41;<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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            1 => array:3 [
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            ]
          ]
        ]
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        "tabla" => array:3 [
          "leyenda" => "<p id="spar0105" class="elsevierStyleSimplePara elsevierViewall">Data are expressed as mean &#40;standard deviation&#41; for the final test session&#46; Statistical significance was set at <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;05 &#40;two-way ANOVA&#41;&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col">Parameter&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="4" align="center" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Control</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CKD</th></tr><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Sham&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">rHuEPO&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Sham&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">rHuEPO&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></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  " rowspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Open-field test</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">Latency time &#40;s&#41;&nbsp;\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">47&#46;0 &#40;3&#46;0&#41;&nbsp;\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">89&#46;8 &#40;7&#46;4&#41;&nbsp;\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">129&#46;8 &#40;6&#46;0&#41;<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">a</span></a>&nbsp;\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
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                  \t\t\t\t">97&#46;4 &#40;3&#46;2&#41;<a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">44&#46;2 &#40;1&#46;4&#41;<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">82&#46;6 &#40;3&#46;2&#41;<a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">10&#46;8 &#40;0&#46;7&#41;<a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
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Article information

ISSN: 21735808
Original language: English

DOI:10.1016/j.nrleng.2017.07.006

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	12	0	12
2024 October	20	4	24
2024 September	27	4	31
2024 August	38	6	44
2024 July	24	4	28
2024 June	24	1	25
2024 May	19	4	23
2024 April	19	8	27
2024 March	38	8	46
2024 February	16	1	17
2024 January	40	14	54
2023 December	30	9	39
2023 November	29	8	37
2023 October	32	8	40
2023 September	15	7	22
2023 August	31	6	37
2023 July	24	6	30
2023 June	42	4	46
2023 May	87	6	93
2023 April	61	0	61
2023 March	29	2	31
2023 February	19	4	23
2023 January	18	1	19
2022 December	26	3	29
2022 November	20	13	33
2022 October	23	18	41
2022 September	18	13	31
2022 August	17	15	32
2022 July	17	8	25
2022 June	13	2	15
2022 May	21	6	27
2022 April	23	9	32
2022 March	27	7	34
2022 February	15	9	24
2022 January	11	13	24
2021 December	18	10	28
2021 November	20	8	28
2021 October	41	17	58
2021 September	19	12	31
2021 August	24	7	31
2021 July	25	11	36
2021 June	19	12	31
2021 May	25	13	38
2021 April	46	52	98
2021 March	26	8	34
2021 February	39	9	48
2021 January	44	20	64
2020 December	51	22	73
2020 November	46	23	69
2020 October	17	7	24
2020 September	27	13	40
2020 August	24	7	31
2020 July	22	12	34
2020 June	23	14	37
2020 May	21	16	37
2020 April	6	7	13
2020 March	9	7	16
2020 February	5	5	10
2020 January	6	3	9
2019 December	11	5	16
2019 November	12	7	19
2019 October	4	3	7
2019 September	9	4	13
2019 August	3	0	3
2019 July	14	12	26
2019 June	7	16	23
2019 May	27	17	44
2019 April	2	1	3

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