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Cellular changes in motor neuron cell culture produced by cytotoxic cerebrospinal fluid from patients with amyotrophic lateral sclerosis
Cambios celulares producidos por la citotoxicidad del líquido cefalorraquídeo de pacientes con esclerosis lateral amiotrófica sobre cultivos de neuronas motoras
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Gomez-Pinedo, M. Yáñez, J. Matías-Guiu, L. Galán, A. Guerrero-Sola, M.S. Benito-Martin, Á. Vela, J.A. Arranz-Tagarro, A.G. García" "autores" => array:9 [ 0 => array:4 [ "nombre" => "U." "apellidos" => "Gomez-Pinedo" "email" => array:3 [ 0 => "inc.hcsc@salud.madrid.org" 1 => "u.gomez.pinedo@gmail.com" 2 => "ulisesalfonso.gomez@salud.madrid.org" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">¿</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "M." "apellidos" => "Yáñez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "J." "apellidos" => "Matías-Guiu" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "L." "apellidos" => "Galán" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 4 => array:3 [ "nombre" => "A." "apellidos" => "Guerrero-Sola" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 5 => array:3 [ "nombre" => "M.S." "apellidos" => "Benito-Martin" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 6 => array:3 [ "nombre" => "Á." "apellidos" => "Vela" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 7 => array:3 [ "nombre" => "J.A." "apellidos" => "Arranz-Tagarro" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 8 => array:3 [ "nombre" => "A.G." "apellidos" => "García" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Instituto de Neurociencias, IdISSC, Hospital Clínico San Carlos, Universidad Complutense, Madrid, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Instituto Teófilo Hernando, Departamento de Farmacología, Universidad Autónoma de Madrid, Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Cambios celulares producidos por la citotoxicidad del líquido cefalorraquídeo de pacientes con esclerosis lateral amiotrófica sobre cultivos de neuronas motoras" ] ] "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" => 4004 "Ancho" => 2406 "Tamanyo" => 436400 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Cellular changes in motor neuron cell culture in control (baseline) and after exposure to CSF-control, 100<span class="elsevierStyleHsp" style=""></span>μM glutamate, and CSF-ALS. In the control image, the black arrow indicates pyknotic cells. In the culture exposed to glutamate, white arrows indicate autophagic vacuoles and black arrows show chromatin condensation. In the culture exposed to CSF-ALS, black arrows indicate maintenance of the cytoplasmic membrane.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">One specific trait of cerebrospinal fluid from patients with amyotrophic lateral sclerosis (CSF-ALS) is its ability to decrease cell survival in motor neuron cell cultures. This is referred to as the cytotoxic effect.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> This effect is limited to the CSF<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2–8</span></a> and it has been demonstrated by repeated studies.<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9–13</span></a> In a previous study,<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> we observed this mechanism in neuronal cell cultures and found it to be glutamate-independent after exposing cultures to different antagonists. The purpose of this study is to determine which cellular changes occur in neuronal cell cultures exposed to CSF-ALS.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Materials and methods</span><p id="par0010" class="elsevierStylePara elsevierViewall">Using lumbar puncture, we extracted CSF from 3 patients diagnosed with ALS according to the El Escorial/Airlie House Diagnostic Criteria.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> We extracted 1.5 to 3<span class="elsevierStyleHsp" style=""></span>cc and centrifuged, quantised, and stored the sample at −80° until it was exposed to the culture. We also extracted CSF from 3 controls who had undergone lumbar puncture as part of the diagnostic procedure after headache or epileptic attack. All patients and controls signed an informed consent form.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Extraction and maintenance procedures for cultures of motor neurons from embryonic rats followed the protocol previously described by Yáñez et al.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> Firstly, cultures were exposed to CSF-ALS, CSF-control and 100<span class="elsevierStyleHsp" style=""></span>μM glutamate, and we also kept a baseline culture. They were incubated for 24<span class="elsevierStyleHsp" style=""></span>hours and analysed with an optical microscope and immunohistochemical methods.</p><p id="par0020" class="elsevierStylePara elsevierViewall">Immunohistochemical studies after cell fixation involved using anti-caspase-3 antibodies (1:200, Millipore, 04-1090), anti-TNF antibodiesα (1:100, Abcam ab66579), anti-peripherin antibodies (1:500, Millipore, AB9282), and the FluoroPan Neuronal Marker to label all cells of neural origin (1:100, Millipore MAB2300×). Cells were then incubated with pertinent secondary antibodies (Alexa 488, 555, or 647, 1:500, Invitrogen). Nuclei were later contrasted with DRAQ5 (1:3000, Abcam, ab108410). Phase contrast and immunofluorescence imaging were performed with an Olympus inverted microscope attached to an Olympus FV1000<span class="elsevierStyleSup">®</span> confocal microscopy system. Quantitative analysis was performed using ImageJ analysis software (version 1.42) (<a id="intr0010" class="elsevierStyleInterRef" href="http://rsbweb.nih.gov/ij/">http://rsbweb.nih.gov/ij/</a>). The measurements were made following a double-blind method. We used GraphPad Prism 5 software for statistical analysis and the values are presented as mean<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>standard error of the mean (SEM).</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Results</span><p id="par0025" class="elsevierStylePara elsevierViewall">Cellular changes observed under the optical microscope and provoked in the motor neuron cell cultures after exposure to glutamate (100<span class="elsevierStyleHsp" style=""></span>μM) present signs of autophagic degradation, characterised by autophagic vacuolation of the cytoplasm and granulovacuolar degeneration, in addition to pyknotic cells and obvious condensation of chromatin. On the contrary, in the culture exposed to CSF-ALS, we observed cells with shortened cellular projections, decreased cellular volume, nuclear fragmentation (karyorrhexis), or chromatin condensation (pyknosis). Cells may show a little to no structural modification of cytoplasmic organelles, plasma membrane blebbing or maintenance of the plasma membrane (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Comparison of the two images showed that cellular changes provoked by CSF-ALS and glutamate were different.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">When we compared the number of cells marked using immunohistochemical methods between the control (baseline) culture, those exposed to CSF-control, and cultures exposed to CSF-ALS, we observed a significant increase in caspase-3 and TNFα in the latter (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). No differences were observed between the control (baseline) culture and CSF-control. Caspase-3 labelling yielded a mean<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>SD of 27.8<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>7.9 when exposed to CSF-ALS vs. 7.1<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>3.4 and 10.3<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>6.6 in the other 2 cultures. Mean TNFα<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>SD after exposure to CSF-ALS was 4.9<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1.3 vs. 2.2<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.7 and 2.4<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.1 for the other groups. Comparison of these data therefore shows that exposure to CSF-ALS provokes an increase in caspase-3 and TNFα at 24<span class="elsevierStyleHsp" style=""></span>hours of incubation.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">Peripherin expression was observed only in the culture exposed to CSF-ALS and not in other cultures. Expression of this protein as small cytoplasmic precipitates was observed in the group of cells exposed to CSF-ALS (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). We observed cells expressing caspase-3 that did not co-express peripherin as well as caspase-3 positive cells that did express peripherin (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>). No TNFα labelling can be observed in some cells expressing peripherin, which leads us to suggest that peripherin expression may precede the increase in TNFα (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>). Consequently, comparison of these cultures shows that exposure to CSF-ALS induces overexpression of peripherin that precedes the increase in TNFα at 24<span class="elsevierStyleHsp" style=""></span>hours after exposure.</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Discussion</span><p id="par0040" class="elsevierStylePara elsevierViewall">Cytotoxicity in primary motor neuron cells exposed to CSF-ALS has historically been based on laboratory techniques which have varied between different research groups. For example, researchers have used intracellular LDH determination,<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> ChAT expression,<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> cell viability by MTT assay or a similar technique,<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14,17</span></a> live cell count,<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9,10,17</span></a> intracellular calcium levels,<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> or expression of phosphorylated neurofilaments.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> Our study confirms that, according to cell viability by MTT assay, cytotoxicity is associated with an increase in caspase-3 and therefore correlates with the process of apoptosis.</p><p id="par0045" class="elsevierStylePara elsevierViewall">Our study shows that cellular changes observed as a result of exposing a motor neuron cell culture to CSF-ALS differ from those caused by exposure to 100<span class="elsevierStyleHsp" style=""></span>μM glutamate. These changes lead to apoptosis with an increase in TNFα. Some authors report that glutamate-induced excitotoxicity is one of the mechanisms in ALS and the mutant SOD1 mouse model of ALS.<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">19,20</span></a> This idea is supported by the fact that excitatory neurotransmission by spinal motor neurons are especially dependent on AMPA receptors. This may explain the specific vulnerability of these cells.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a>This mechanism is also supported by the fact that riluzole, the only drug to have shown a discrete protective effect by prolonging the patient's life by a few months,<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22,23</span></a> blocks presynaptic glutamate release, inhibits calcium entry, regulates AMPA receptors, and inhibits the effect of NMDA and AMPA receptors.<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">24–26</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">There are little data in the literature regarding cellular changes produced by cytotoxic CSF from patients with ALS. Researchers have described changes ranging from astrogliosis<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">27–29</span></a> in <span class="elsevierStyleItalic">in vivo</span> models or mixed neuron-astrocyte cultures, vacuoles,<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">30,31</span></a> pre- or pro-apoptotic signs,<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32–34</span></a> or signs of cellular death.<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> Our data show that changes differ from those observed after cultures are exposed to glutamate, thereby supporting our conclusions from a previous study that demonstrated that the CSF-ALS mechanism is glutamate-independent by exposing cultures to different antagonists.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Observed cellular changes suggest that when cells are exposed to CSF-ALS, nuclear impairment occurs earlier than impairment of the cell membrane or cytoplasmic organelles. This phenomenon has already been observed in the disease,<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> the transgenic mouse model of ALS,<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> and in the autosomal dominant form of familial ALS (ALS8).<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">38,39</span></a> The latter produces a mutant protein which contributes to the formation of cytoplasmic ER membranes with observable nuclear envelope defects. This blocks transport of nucleoporins to the nuclear envelope, and these proteins remain sequestered in the cytoplasm.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> Our findings suggest that the cytotoxic mechanism might initially penetrate motor neurons without damaging the cell membrane, a process that is probably also due to anomalous accumulation of protein in the cytoplasm. This would explain why the apoptosis mechanism shown by the increase of caspase-3 would be associated with increased TNFα.<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> Expression would probably have been even higher if the culture had been incubated for more than 24<span class="elsevierStyleHsp" style=""></span>hours.</p><p id="par0060" class="elsevierStylePara elsevierViewall">Peripherin is a neuronal intermediate-filament protein that predominates in the peripheral nervous system, although it has also been found in some neuron populations of the central nervous system. Overexpression of the protein has been described in multiple neurodegenerative disorders. In the case of ALS, peripherin gene mutations are normally sporadic and gene overexpression results in motor neuron disease in mice.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a> Mizuno et al.<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> have described presence of this protein in Bunina bodies, which are typical of those forms of the disease not related to SOD1.<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> A mouse model developed with a TDP-43 mutation shows clinical signs of frontotemporal degeneration similar to those of ALS and presents peripherin overexpression.<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> Presence of this protein in cultures exposed to CSF-ALS supports the hypothesis presented by Mizuno et al.<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> stating that peripherin could play a role in the development of ALS. Considering that it reduces the effect of BDNF<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> and that riluzole acts on BDNF receptors, this mechanism might explain how this drug could act independently of glutamate. The increase in peripherin preceding the increase in TNFα suggests that the protein may play an early role in the process of apoptosis. This supports the observation that it co-localises with caspase-3.</p><p id="par0065" class="elsevierStylePara elsevierViewall">In summary, our study supports the idea that cytotoxic CSF-ALS is not related to glutamate, which causes early nuclear impairment without damaging the cytoplasmic membrane. This provokes cytoplasmic apoptosis that results in an increase in caspase-3 which is co-localised with anomalously overexpressed peripherin.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Funding</span><p id="par0070" class="elsevierStylePara elsevierViewall">The research behind our study was funded within the project “<span class="elsevierStyleItalic">Vulnerabilidad selectiva de la motoneurona a los efectos neurotóxicos del líquido cefalorraquídeo de pacientes en esclerosis lateral amiotrófica (ELA)</span>” by <span class="elsevierStyleGrantSponsor" id="gs1">Fundación Mutua Madrileña</span> 2008, 2009.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Conflicts of interest</span><p id="par0075" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:2 [ "identificador" => "xres354342" "titulo" => array:5 [ 0 => "Abstract" 1 => "Introduction" 2 => "Materials and methods" 3 => "Results" 4 => "Conclusions" ] ] 1 => array:2 [ "identificador" => "xpalclavsec335690" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres354341" "titulo" => array:5 [ 0 => "Resumen" 1 => "Introducción" 2 => "Material y métodos" 3 => "Resultados" 4 => "Conclusiones" ] ] 3 => array:2 [ "identificador" => "xpalclavsec335689" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Materials and methods" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Funding" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Conflicts of interest" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2013-08-05" "fechaAceptado" => "2013-08-20" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec335690" "palabras" => array:7 [ 0 => "Amyotrophic lateral sclerosis" 1 => "Cerebrospinal fluid" 2 => "Neurotoxicity" 3 => "Peripherin" 4 => "Caspase-3" 5 => "TNFα" 6 => "Glutamate" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec335689" "palabras" => array:7 [ 0 => "Esclerosis lateral amiotrófica" 1 => "Líquido cefalorraquídeo" 2 => "Neurotoxicidad" 3 => "Periferina" 4 => "Caspasa-3" 5 => "TNFα" 6 => "Glutamato" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">The neurotoxic effects of cerebrospinal fluid (CSF) from patients with amyotrophic lateral sclerosis (ALS) have been reported by various authors who have attributed this neurotoxicity to the glutamate in CSF-ALS.</p> <span class="elsevierStyleSectionTitle" id="sect0015">Materials and methods</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Cultures of rat embryonic cortical neurons were exposed to CSF from ALS patients during an incubation period of 24<span class="elsevierStyleHsp" style=""></span>hours. Optical microscopy was used to compare cellular changes to those elicited by exposure to 100<span class="elsevierStyleHsp" style=""></span>μm glutamate, and confocal microscopy was used to evaluate immunohistochemistry for caspase-3, TNFα, and peripherin.</p> <span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">In the culture exposed to CSF-ALS, we observed cells with nuclear fragmentation and scarce or null structural modifications to the cytoplasmic organelles or to plasma membrane maintenance. This did not occur in the culture exposed to glutamate. The culture exposed to CSF-ALS also demonstrated increases in caspase-3, TNFα, and in peripherin co-locating with caspase-3, but not with TNFα, suggesting that TNFα may play an early role in the process of apoptosis.</p> <span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">CFS-ALS cytotoxicity is not related to glutamate. It initially affects the nucleus without altering the cytoplasmic membrane. It causes cytoplasmic apoptosis that involves an increase in caspase-3 co-located with peripherin, which is also overexpressed.</p>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0035">Introducción</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Los efectos neurotóxicos del líquido cefalorraquídeo (LCR) procedentes de pacientes con esclerosis lateral amiotrófica (ELA) han sido descritos por varios autores que han atribuido esta neurotoxicidad al efecto de glutamato del LCR-ELA.</p> <span class="elsevierStyleSectionTitle" id="sect0040">Material y métodos</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Se han expuesto cultivos de neuronas embrionarias corticales de rata con un incubación de 24<span class="elsevierStyleHsp" style=""></span>h y el LCR procedente de pacientes con ELA, valorando las alteraciones celulares a través de microscopía óptica en comparación con aquellas que produce con 100<span class="elsevierStyleHsp" style=""></span>mM de glutamato y la inmunohistoquímica de caspasa-3, TNF y periferina a través de microscopia confocal.</p> <span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">En el cultivo expuesto a LCR-ELA se observan células con fragmentación del núcleo con escasa o nula modificación estructural de los organelos citoplasmáticos y mantenimiento de la membrana plasmática, lo que no ocurre con la exposición a glutamato. Se observa un aumento de caspasa-3 y de TNFα y un incremento de periferina que co-localiza con caspasa-3 pero no con TNFα, lo hace sugerir que puede tener un papel precoz en el desarrollo de la apoptosis.</p> <span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">La citotoxicidad por LCR-ELA no se relaciona con el glutamato, que provoca una afectación nuclear precoz sin alteración de la membrana citoplasmática produciendo una apoptosis citoplasmática que conlleva un incremento de caspasa-3 que co-localiza con sobreexpresión anómala de periferina.</p>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Please cite this article as: Gomez-Pinedo U, Yáñez M, Matías-Guiu J, Galán L, Guerrero-Sola A, Benito-Martin MS, et al. Cambios celulares producidos por la citotoxicidad del líquido cefalorraquídeo de pacientes con esclerosis lateral amiotrófica sobre cultivos de neuronas motoras. Neurología. 2014;29:346–352.</p>" ] ] "multimedia" => array:5 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 4004 "Ancho" => 2406 "Tamanyo" => 436400 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Cellular changes in motor neuron cell culture in control (baseline) and after exposure to CSF-control, 100<span class="elsevierStyleHsp" style=""></span>μM glutamate, and CSF-ALS. In the control image, the black arrow indicates pyknotic cells. In the culture exposed to glutamate, white arrows indicate autophagic vacuoles and black arrows show chromatin condensation. In the culture exposed to CSF-ALS, black arrows indicate maintenance of the cytoplasmic membrane.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1119 "Ancho" => 2167 "Tamanyo" => 117943 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Co-expression of caspase-3 and peripherin in the culture exposed to CSF-ALS (A–C). Labelling of caspase-3 (red), peripherin (green, arrows) and nuclei (blue) (A–C). Peripherin expression was observed as small cytoplasmic precipitates (arrows, B and C) and caspase-3 positive cells (asterisk). Bar: (A) 30 microns, (B) 15 microns, and (C) 5 microns.</p>" ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1461 "Ancho" => 2167 "Tamanyo" => 140039 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Co-expression of caspase-3 and peripherin in the culture exposed to CSF-ALS (A–C). Labelling of caspase-3 (red-asterisk), peripherin (green-arrows) and nuclei (blue) (A–C). Image B shows inclusions that express peripherin (asterisks) and expression of caspase-3 marked with arrows (B and C). Bar: (A) 60 microns, (B) 40 microns, and (C) 20 microns.</p>" ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1601 "Ancho" => 1625 "Tamanyo" => 53191 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Co-expression of TNFα and peripherin in the culture exposed to CSF-ALS. Arrows indicate positive peripherin inclusions in cells not expressing TNFα and in cells positive (+) for TNFα. Asterisks indicate cells with nuclear degradation. Bar: 30 microns.</p>" ] ] 4 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Mean<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>SD data expressed as percentages.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Group \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Neuron cells<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Caspase-3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">TNFα \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Control (baseline) \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">99.0<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>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">7.10<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>3.4 \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">2.2<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.7 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CSF-CTL \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">98.7<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.6 \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">10.3<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>6.6 \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">2.4<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CSF-ALS \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">98.6<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>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">27.8<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>7.9 \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 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 2 | 0 | 2 |
| 2024 October | 37 | 4 | 41 |
| 2024 September | 56 | 5 | 61 |
| 2024 August | 30 | 3 | 33 |
| 2024 July | 29 | 5 | 34 |
| 2024 June | 30 | 4 | 34 |
| 2024 May | 25 | 4 | 29 |
| 2024 April | 25 | 15 | 40 |
| 2024 March | 46 | 10 | 56 |
| 2024 February | 31 | 11 | 42 |
| 2024 January | 30 | 7 | 37 |
| 2023 December | 24 | 6 | 30 |
| 2023 November | 21 | 9 | 30 |
| 2023 October | 38 | 8 | 46 |
| 2023 September | 24 | 3 | 27 |
| 2023 August | 19 | 6 | 25 |
| 2023 July | 28 | 10 | 38 |
| 2023 June | 27 | 1 | 28 |
| 2023 May | 46 | 8 | 54 |
| 2023 April | 61 | 9 | 70 |
| 2023 March | 61 | 4 | 65 |
| 2023 February | 30 | 3 | 33 |
| 2023 January | 24 | 12 | 36 |
| 2022 December | 56 | 3 | 59 |
| 2022 November | 70 | 17 | 87 |
| 2022 October | 34 | 9 | 43 |
| 2022 September | 43 | 12 | 55 |
| 2022 August | 29 | 16 | 45 |
| 2022 July | 23 | 10 | 33 |
| 2022 June | 46 | 7 | 53 |
| 2022 May | 35 | 11 | 46 |
| 2022 April | 47 | 18 | 65 |
| 2022 March | 37 | 14 | 51 |
| 2022 February | 21 | 9 | 30 |
| 2022 January | 27 | 11 | 38 |
| 2021 December | 27 | 14 | 41 |
| 2021 November | 44 | 12 | 56 |
| 2021 October | 44 | 11 | 55 |
| 2021 September | 22 | 19 | 41 |
| 2021 August | 21 | 6 | 27 |
| 2021 July | 23 | 14 | 37 |
| 2021 June | 23 | 14 | 37 |
| 2021 May | 28 | 11 | 39 |
| 2021 April | 73 | 17 | 90 |
| 2021 March | 43 | 20 | 63 |
| 2021 February | 23 | 8 | 31 |
| 2021 January | 32 | 17 | 49 |
| 2020 December | 44 | 14 | 58 |
| 2020 November | 39 | 13 | 52 |
| 2020 October | 36 | 7 | 43 |
| 2020 September | 23 | 8 | 31 |
| 2020 August | 33 | 8 | 41 |
| 2020 July | 26 | 5 | 31 |
| 2020 June | 23 | 14 | 37 |
| 2020 May | 32 | 23 | 55 |
| 2020 April | 25 | 4 | 29 |
| 2020 March | 33 | 6 | 39 |
| 2020 February | 27 | 3 | 30 |
| 2020 January | 30 | 28 | 58 |
| 2019 December | 25 | 7 | 32 |
| 2019 November | 25 | 11 | 36 |
| 2019 October | 27 | 7 | 34 |
| 2019 September | 37 | 5 | 42 |
| 2019 August | 27 | 3 | 30 |
| 2019 July | 20 | 14 | 34 |
| 2019 June | 46 | 11 | 57 |
| 2019 May | 98 | 32 | 130 |
| 2019 April | 49 | 3 | 52 |
| 2019 March | 15 | 6 | 21 |
| 2019 February | 28 | 12 | 40 |
| 2019 January | 9 | 3 | 12 |
| 2018 December | 16 | 10 | 26 |
| 2018 November | 18 | 9 | 27 |
| 2018 October | 37 | 21 | 58 |
| 2018 September | 20 | 9 | 29 |
| 2018 August | 7 | 1 | 8 |
| 2018 July | 9 | 1 | 10 |
| 2018 June | 5 | 1 | 6 |
| 2018 May | 17 | 5 | 22 |
| 2018 April | 10 | 5 | 15 |
| 2018 March | 11 | 4 | 15 |
| 2018 February | 8 | 1 | 9 |
| 2018 January | 10 | 8 | 18 |
| 2017 December | 10 | 3 | 13 |
| 2017 November | 15 | 1 | 16 |
| 2017 October | 12 | 6 | 18 |
| 2017 September | 23 | 7 | 30 |
| 2017 August | 22 | 4 | 26 |
| 2017 July | 18 | 2 | 20 |
| 2017 June | 49 | 4 | 53 |
| 2017 May | 28 | 10 | 38 |
| 2017 April | 23 | 2 | 25 |
| 2017 March | 22 | 24 | 46 |
| 2017 February | 19 | 5 | 24 |
| 2017 January | 18 | 5 | 23 |
| 2016 December | 28 | 15 | 43 |
| 2016 November | 28 | 5 | 33 |
| 2016 October | 51 | 8 | 59 |
| 2016 September | 58 | 7 | 65 |
| 2016 August | 28 | 9 | 37 |
| 2016 July | 24 | 4 | 28 |
| 2016 June | 30 | 8 | 38 |
| 2016 May | 28 | 23 | 51 |
| 2016 April | 18 | 68 | 86 |
| 2016 March | 31 | 73 | 104 |
| 2016 February | 25 | 30 | 55 |
| 2016 January | 16 | 14 | 30 |
| 2015 December | 22 | 16 | 38 |
| 2015 November | 17 | 20 | 37 |
| 2015 October | 29 | 15 | 44 |
| 2015 September | 22 | 10 | 32 |
| 2015 August | 47 | 7 | 54 |
| 2015 July | 39 | 11 | 50 |
| 2015 June | 18 | 2 | 20 |
| 2015 May | 38 | 12 | 50 |
| 2015 April | 45 | 15 | 60 |
| 2015 March | 38 | 14 | 52 |
| 2015 February | 36 | 8 | 44 |
| 2015 January | 45 | 11 | 56 |
| 2014 December | 52 | 19 | 71 |
| 2014 November | 29 | 9 | 38 |
| 2014 October | 43 | 10 | 53 |
| 2014 September | 79 | 28 | 107 |
| 2014 August | 69 | 36 | 105 |
| 2014 July | 4 | 3 | 7 |
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