The antiapoptotic effect of guanosine is mediated by the activation of the PI 3‐kinase/AKT/PKB pathway in cultured rat astrocytes
Identifieur interne : 001518 ( Istex/Corpus ); précédent : 001517; suivant : 001519The antiapoptotic effect of guanosine is mediated by the activation of the PI 3‐kinase/AKT/PKB pathway in cultured rat astrocytes
Auteurs : Patrizia Di Iorio ; Patrizia Ballerini ; Ugo Traversa ; Ferdinando Nicoletti ; Iolanda D'Alimonte ; Sonya Kleywegt ; Eva S. Werstiuk ; Michel P. Rathbone ; Francesco Caciagli ; Renata CiccarelliSource :
- Glia [ 0894-1491 ] ; 2004-06.
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Abstract
Guanosine has many trophic effects in the CNS, including the stimulation of neurotrophic factor synthesis and release by astrocytes, which protect neurons against excitotoxic death. Therefore, we questioned whether guanosine protected astrocytes against apoptosis induced by staurosporine. We evaluated apoptosis in cultured rat brain astrocytes, following exposure (3 h) to 100 nM staurosporine by acridine orange staining or by oligonucleosome, or caspase‐3 ELISA assays. Staurosporine promoted apoptosis rapidly, reaching its maximal effect (∼ 10‐fold over basal apoptotic values) in 18–24 h after its administration to astrocytes. Guanosine, added to the culture medium for 4 h, starting from 1 h prior to staurosporine, reduced the proportion of apoptotic cells in a concentration‐dependent manner. The IC50 value for the inhibitory effect of guanosine is 7.5 × 10−5 M. The protective effect of guanosine was not affected by inhibiting the nucleoside transporters by propentophylline, or by the selective antagonists of the adenosine A1 or A2 receptors (DPCPX or DMPX), or by an antagonist of the P2X and P2Y purine receptors (suramin). In contrast, pretreatment of astrocytes with pertussis toxin, which uncouples Gi‐proteins from their receptors, abolished the antiapoptotic effect of guanosine. The protective effect of guanosine was also reduced by pretreatment of astrocytes with inhibitors of the phosphoinositide 3‐kinase (PI3K; LY294002, 30 μM) or the MAPK pathway (PD98059, 10 μM). Addition of guanosine caused a rapid phosphorylation of Akt/PKB, and glycogen synthase kinase‐3β (GSK‐3β) and induced an upregulation of Bcl‐2 mRNA and protein expression. These data demonstrate that guanosine protects astrocytes against staurosporine‐induced apoptosis by activating multiple pathways, and these are mediated by a Gi‐protein‐coupled putative guanosine receptor. © 2004 Wiley‐Liss, Inc.
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DOI: 10.1002/glia.20002
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Therefore, we questioned whether guanosine protected astrocytes against apoptosis induced by staurosporine. We evaluated apoptosis in cultured rat brain astrocytes, following exposure (3 h) to 100 nM staurosporine by acridine orange staining or by oligonucleosome, or caspase‐3 ELISA assays. Staurosporine promoted apoptosis rapidly, reaching its maximal effect (∼ 10‐fold over basal apoptotic values) in 18–24 h after its administration to astrocytes. Guanosine, added to the culture medium for 4 h, starting from 1 h prior to staurosporine, reduced the proportion of apoptotic cells in a concentration‐dependent manner. The IC50 value for the inhibitory effect of guanosine is 7.5 × 10−5 M. The protective effect of guanosine was not affected by inhibiting the nucleoside transporters by propentophylline, or by the selective antagonists of the adenosine A1 or A2 receptors (DPCPX or DMPX), or by an antagonist of the P2X and P2Y purine receptors (suramin). In contrast, pretreatment of astrocytes with pertussis toxin, which uncouples Gi‐proteins from their receptors, abolished the antiapoptotic effect of guanosine. The protective effect of guanosine was also reduced by pretreatment of astrocytes with inhibitors of the phosphoinositide 3‐kinase (PI3K; LY294002, 30 μM) or the MAPK pathway (PD98059, 10 μM). Addition of guanosine caused a rapid phosphorylation of Akt/PKB, and glycogen synthase kinase‐3β (GSK‐3β) and induced an upregulation of Bcl‐2 mRNA and protein expression. These data demonstrate that guanosine protects astrocytes against staurosporine‐induced apoptosis by activating multiple pathways, and these are mediated by a Gi‐protein‐coupled putative guanosine receptor. © 2004 Wiley‐Liss, Inc.</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>Patrizia Di Iorio</name><affiliations><json:string>Department of Biomedical Sciences, School of Medicine, University of Chieti, Chieti, Italy</json:string></affiliations></json:item><json:item><name>Patrizia Ballerini</name><affiliations><json:string>Department of Biomedical Sciences, School of Medicine, University of Chieti, Chieti, Italy</json:string></affiliations></json:item><json:item><name>Ugo Traversa</name><affiliations><json:string>Department of Biomedical Sciences, School of Pharmacy, University of Trieste, Trieste, Italy</json:string></affiliations></json:item><json:item><name>Ferdinando Nicoletti</name><affiliations><json:string>Department of Physiology and Pharmacology, School of Medicine, University of Roma “La Sapienza,” Rome, Italy</json:string></affiliations></json:item><json:item><name>Iolanda D'Alimonte</name><affiliations><json:string>Department of Biomedical Sciences, School of Medicine, University of Chieti, Chieti, Italy</json:string></affiliations></json:item><json:item><name>Sonya Kleywegt</name><affiliations><json:string>Department of Biomedical Sciences, School of Medicine, University of Chieti, Chieti, Italy</json:string><json:string>Department of Medicine, McMaster University, Health Sciences Centre, Hamilton, Ontario, Canada</json:string></affiliations></json:item><json:item><name>Eva S. 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Therefore, we questioned whether guanosine protected astrocytes against apoptosis induced by staurosporine. We evaluated apoptosis in cultured rat brain astrocytes, following exposure (3 h) to 100 nM staurosporine by acridine orange staining or by oligonucleosome, or caspase‐3 ELISA assays. Staurosporine promoted apoptosis rapidly, reaching its maximal effect (∼ 10‐fold over basal apoptotic values) in 18–24 h after its administration to astrocytes. Guanosine, added to the culture medium for 4 h, starting from 1 h prior to staurosporine, reduced the proportion of apoptotic cells in a concentration‐dependent manner. The IC50 value for the inhibitory effect of guanosine is 7.5 × 10−5 M. The protective effect of guanosine was not affected by inhibiting the nucleoside transporters by propentophylline, or by the selective antagonists of the adenosine A1 or A2 receptors (DPCPX or DMPX), or by an antagonist of the P2X and P2Y purine receptors (suramin). In contrast, pretreatment of astrocytes with pertussis toxin, which uncouples Gi‐proteins from their receptors, abolished the antiapoptotic effect of guanosine. The protective effect of guanosine was also reduced by pretreatment of astrocytes with inhibitors of the phosphoinositide 3‐kinase (PI3K; LY294002, 30 μM) or the MAPK pathway (PD98059, 10 μM). Addition of guanosine caused a rapid phosphorylation of Akt/PKB, and glycogen synthase kinase‐3β (GSK‐3β) and induced an upregulation of Bcl‐2 mRNA and protein expression. 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xml:id="author-9"><persName><forename type="first">Francesco</forename><surname>Caciagli</surname></persName><affiliation>Department of Biomedical Sciences, School of Medicine, University of Chieti, Chieti, Italy</affiliation></author><author xml:id="author-10"><persName><forename type="first">Renata</forename><surname>Ciccarelli</surname></persName><affiliation>Department of Biomedical Sciences, School of Medicine, University of Chieti, Chieti, Italy</affiliation></author></analytic><monogr><title level="j">Glia</title><title level="j" type="abbrev">Glia</title><idno type="pISSN">0894-1491</idno><idno type="eISSN">1098-1136</idno><idno type="DOI">10.1002/(ISSN)1098-1136</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2004-06"></date><biblScope unit="volume">46</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="356">356</biblScope><biblScope unit="page" 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Therefore, we questioned whether guanosine protected astrocytes against apoptosis induced by staurosporine. We evaluated apoptosis in cultured rat brain astrocytes, following exposure (3 h) to 100 nM staurosporine by acridine orange staining or by oligonucleosome, or caspase‐3 ELISA assays. Staurosporine promoted apoptosis rapidly, reaching its maximal effect (∼ 10‐fold over basal apoptotic values) in 18–24 h after its administration to astrocytes. Guanosine, added to the culture medium for 4 h, starting from 1 h prior to staurosporine, reduced the proportion of apoptotic cells in a concentration‐dependent manner. The IC50 value for the inhibitory effect of guanosine is 7.5 × 10−5 M. The protective effect of guanosine was not affected by inhibiting the nucleoside transporters by propentophylline, or by the selective antagonists of the adenosine A1 or A2 receptors (DPCPX or DMPX), or by an antagonist of the P2X and P2Y purine receptors (suramin). In contrast, pretreatment of astrocytes with pertussis toxin, which uncouples Gi‐proteins from their receptors, abolished the antiapoptotic effect of guanosine. The protective effect of guanosine was also reduced by pretreatment of astrocytes with inhibitors of the phosphoinositide 3‐kinase (PI3K; LY294002, 30 μM) or the MAPK pathway (PD98059, 10 μM). Addition of guanosine caused a rapid phosphorylation of Akt/PKB, and glycogen synthase kinase‐3β (GSK‐3β) and induced an upregulation of Bcl‐2 mRNA and protein expression. These data demonstrate that guanosine protects astrocytes against staurosporine‐induced apoptosis by activating multiple pathways, and these are mediated by a Gi‐protein‐coupled putative guanosine receptor. © 2004 Wiley‐Liss, Inc.</p></abstract><textClass xml:lang="en"><keywords scheme="keyword"><list><head>keywords</head><item><term>guanosine</term></item><item><term>cell survival</term></item><item><term>antiapoptosis</term></item><item><term>PI 3‐kinase</term></item><item><term>AKT/PKB</term></item><item><term>astrocytes</term></item></list></keywords></textClass><textClass><keywords scheme="Journal Subject"><list><head>article-category</head><item><term>Original Article</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2003-05-06">Received</change><change when="2003-10-27">Registration</change><change 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type="publishedOnlineEarlyUnpaginated" date="2004-03-10"></event><event type="firstOnline" date="2004-03-10"></event><event type="publishedOnlineFinalForm" date="2004-04-13"></event><event type="xmlConverted" agent="Converter:JWSART34_TO_WML3G version:2.3.2 mode:FullText source:FullText result:FullText" date="2010-03-06"></event><event type="xmlConverted" agent="Converter:WILEY_ML3G_TO_WILEY_ML3GV2 version:3.8.8" date="2014-01-26"></event><event type="xmlConverted" agent="Converter:WML3G_To_WML3G version:4.1.7 mode:FullText,remove_FC" date="2014-10-23"></event></eventGroup><numberingGroup><numbering type="pageFirst">356</numbering><numbering type="pageLast">368</numbering></numberingGroup><correspondenceTo>Department of Medicine, McMaster University, Health Sciences Centre, 4N‐39, 1200 Main Street West, Hamilton, ON L8N 3Z5, Canada</correspondenceTo><linkGroup><link type="toTypesetVersion" href="file:GLIA.GLIA20002.pdf"></link></linkGroup></publicationMeta><contentMeta><countGroup><count type="figureTotal" number="6"></count><count type="tableTotal" number="1"></count><count type="referenceTotal" number="80"></count><count type="wordTotal" number="10358"></count></countGroup><titleGroup><title type="main" xml:lang="en">The antiapoptotic effect of guanosine is mediated by the activation of the PI 3‐kinase/AKT/PKB pathway in cultured rat astrocytes</title><title type="short" xml:lang="en">Guanosine is Antiapoptotic</title></titleGroup><creators><creator xml:id="au1" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Patrizia</givenNames><familyName>Di Iorio</familyName></personName></creator><creator xml:id="au2" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Patrizia</givenNames><familyName>Ballerini</familyName></personName></creator><creator xml:id="au3" creatorRole="author" affiliationRef="#af2"><personName><givenNames>Ugo</givenNames><familyName>Traversa</familyName></personName></creator><creator xml:id="au4" creatorRole="author" affiliationRef="#af3"><personName><givenNames>Ferdinando</givenNames><familyName>Nicoletti</familyName></personName></creator><creator xml:id="au5" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Iolanda</givenNames><familyName>D'Alimonte</familyName></personName></creator><creator xml:id="au6" creatorRole="author" affiliationRef="#af1 #af4"><personName><givenNames>Sonya</givenNames><familyName>Kleywegt</familyName></personName></creator><creator xml:id="au7" creatorRole="author" affiliationRef="#af4" corresponding="yes"><personName><givenNames>Eva S.</givenNames><familyName>Werstiuk</familyName></personName></creator><creator xml:id="au8" creatorRole="author" affiliationRef="#af4"><personName><givenNames>Michel P.</givenNames><familyName>Rathbone</familyName></personName></creator><creator xml:id="au9" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Francesco</givenNames><familyName>Caciagli</familyName></personName></creator><creator xml:id="au10" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Renata</givenNames><familyName>Ciccarelli</familyName></personName></creator></creators><affiliationGroup><affiliation xml:id="af1" countryCode="IT" type="organization"><unparsedAffiliation>Department of Biomedical Sciences, School of Medicine, University of Chieti, Chieti, Italy</unparsedAffiliation></affiliation><affiliation xml:id="af2" countryCode="IT" type="organization"><unparsedAffiliation>Department of Biomedical Sciences, School of Pharmacy, University of Trieste, Trieste, Italy</unparsedAffiliation></affiliation><affiliation xml:id="af3" countryCode="IT" type="organization"><unparsedAffiliation>Department of Physiology and Pharmacology, School of Medicine, University of Roma “La Sapienza,” Rome, Italy</unparsedAffiliation></affiliation><affiliation xml:id="af4" countryCode="CA" type="organization"><unparsedAffiliation>Department of Medicine, McMaster University, Health Sciences Centre, Hamilton, Ontario, Canada</unparsedAffiliation></affiliation></affiliationGroup><keywordGroup xml:lang="en" type="author"><keyword xml:id="kwd1">guanosine</keyword><keyword xml:id="kwd2">cell survival</keyword><keyword xml:id="kwd3">antiapoptosis</keyword><keyword xml:id="kwd4">PI 3‐kinase</keyword><keyword xml:id="kwd5">AKT/PKB</keyword><keyword xml:id="kwd6">astrocytes</keyword></keywordGroup><fundingInfo><fundingAgency>Neurological Technologies Inc</fundingAgency></fundingInfo><fundingInfo><fundingAgency>Ministero Università e Ricerca Scientifica e Technologica (MURST) of Italy</fundingAgency></fundingInfo><abstractGroup><abstract type="main" xml:lang="en"><title type="main">Abstract</title><p>Guanosine has many trophic effects in the CNS, including the stimulation of neurotrophic factor synthesis and release by astrocytes, which protect neurons against excitotoxic death. Therefore, we questioned whether guanosine protected astrocytes against apoptosis induced by staurosporine. We evaluated apoptosis in cultured rat brain astrocytes, following exposure (3 h) to 100 nM staurosporine by acridine orange staining or by oligonucleosome, or caspase‐3 ELISA assays. Staurosporine promoted apoptosis rapidly, reaching its maximal effect (∼ 10‐fold over basal apoptotic values) in 18–24 h after its administration to astrocytes. Guanosine, added to the culture medium for 4 h, starting from 1 h prior to staurosporine, reduced the proportion of apoptotic cells in a concentration‐dependent manner. The IC<sub>50</sub> value for the inhibitory effect of guanosine is 7.5 × 10<sup>−5</sup> M. The protective effect of guanosine was not affected by inhibiting the nucleoside transporters by propentophylline, or by the selective antagonists of the adenosine A<sub>1</sub> or A<sub>2</sub> receptors (DPCPX or DMPX), or by an antagonist of the P2X and P2Y purine receptors (suramin). In contrast, pretreatment of astrocytes with pertussis toxin, which uncouples G<sub>i</sub>‐proteins from their receptors, abolished the antiapoptotic effect of guanosine. The protective effect of guanosine was also reduced by pretreatment of astrocytes with inhibitors of the phosphoinositide 3‐kinase (PI3K; LY294002, 30 μM) or the MAPK pathway (PD98059, 10 μM). Addition of guanosine caused a rapid phosphorylation of Akt/PKB, and glycogen synthase kinase‐3β (GSK‐3β) and induced an upregulation of Bcl‐2 mRNA and protein expression. These data demonstrate that guanosine protects astrocytes against staurosporine‐induced apoptosis by activating multiple pathways, and these are mediated by a G<sub>i</sub>‐protein‐coupled putative guanosine receptor. © 2004 Wiley‐Liss, Inc.</p></abstract></abstractGroup></contentMeta></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>The antiapoptotic effect of guanosine is mediated by the activation of the PI 3‐kinase/AKT/PKB pathway in cultured rat astrocytes</title></titleInfo><titleInfo type="abbreviated" lang="en"><title>Guanosine is Antiapoptotic</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>The antiapoptotic effect of guanosine is mediated by the activation of the PI 3‐kinase/AKT/PKB pathway in cultured rat astrocytes</title></titleInfo><name type="personal"><namePart type="given">Patrizia</namePart><namePart type="family">Di Iorio</namePart><affiliation>Department of Biomedical Sciences, School of Medicine, University of Chieti, Chieti, Italy</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Patrizia</namePart><namePart type="family">Ballerini</namePart><affiliation>Department of Biomedical Sciences, School of Medicine, University of Chieti, Chieti, Italy</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ugo</namePart><namePart type="family">Traversa</namePart><affiliation>Department of Biomedical Sciences, School of Pharmacy, University of Trieste, Trieste, Italy</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ferdinando</namePart><namePart type="family">Nicoletti</namePart><affiliation>Department of Physiology and Pharmacology, School of Medicine, University of Roma “La Sapienza,” Rome, Italy</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Iolanda</namePart><namePart type="family">D'Alimonte</namePart><affiliation>Department of Biomedical Sciences, School of Medicine, University of Chieti, Chieti, Italy</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Sonya</namePart><namePart type="family">Kleywegt</namePart><affiliation>Department of Biomedical Sciences, School of Medicine, University of Chieti, Chieti, Italy</affiliation><affiliation>Department of Medicine, McMaster University, Health Sciences Centre, Hamilton, Ontario, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Eva S.</namePart><namePart type="family">Werstiuk</namePart><affiliation>Department of Medicine, McMaster University, Health Sciences Centre, Hamilton, Ontario, Canada</affiliation><affiliation>Department of Medicine, McMaster University, Health Sciences Centre, 4N‐39, 1200 Main Street West, Hamilton, ON L8N 3Z5, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Michel P.</namePart><namePart type="family">Rathbone</namePart><affiliation>Department of Medicine, McMaster University, Health Sciences Centre, Hamilton, Ontario, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Francesco</namePart><namePart type="family">Caciagli</namePart><affiliation>Department of Biomedical Sciences, School of Medicine, University of Chieti, Chieti, Italy</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Renata</namePart><namePart type="family">Ciccarelli</namePart><affiliation>Department of Biomedical Sciences, School of Medicine, University of Chieti, Chieti, Italy</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article"></genre><originInfo><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><place><placeTerm type="text">Hoboken</placeTerm></place><dateIssued encoding="w3cdtf">2004-06</dateIssued><dateCaptured encoding="w3cdtf">2003-05-06</dateCaptured><dateValid encoding="w3cdtf">2003-10-27</dateValid><copyrightDate encoding="w3cdtf">2004</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType><extent unit="figures">6</extent><extent unit="tables">1</extent><extent unit="references">80</extent><extent unit="words">10358</extent></physicalDescription><abstract lang="en">Guanosine has many trophic effects in the CNS, including the stimulation of neurotrophic factor synthesis and release by astrocytes, which protect neurons against excitotoxic death. Therefore, we questioned whether guanosine protected astrocytes against apoptosis induced by staurosporine. We evaluated apoptosis in cultured rat brain astrocytes, following exposure (3 h) to 100 nM staurosporine by acridine orange staining or by oligonucleosome, or caspase‐3 ELISA assays. Staurosporine promoted apoptosis rapidly, reaching its maximal effect (∼ 10‐fold over basal apoptotic values) in 18–24 h after its administration to astrocytes. Guanosine, added to the culture medium for 4 h, starting from 1 h prior to staurosporine, reduced the proportion of apoptotic cells in a concentration‐dependent manner. The IC50 value for the inhibitory effect of guanosine is 7.5 × 10−5 M. The protective effect of guanosine was not affected by inhibiting the nucleoside transporters by propentophylline, or by the selective antagonists of the adenosine A1 or A2 receptors (DPCPX or DMPX), or by an antagonist of the P2X and P2Y purine receptors (suramin). In contrast, pretreatment of astrocytes with pertussis toxin, which uncouples Gi‐proteins from their receptors, abolished the antiapoptotic effect of guanosine. The protective effect of guanosine was also reduced by pretreatment of astrocytes with inhibitors of the phosphoinositide 3‐kinase (PI3K; LY294002, 30 μM) or the MAPK pathway (PD98059, 10 μM). Addition of guanosine caused a rapid phosphorylation of Akt/PKB, and glycogen synthase kinase‐3β (GSK‐3β) and induced an upregulation of Bcl‐2 mRNA and protein expression. These data demonstrate that guanosine protects astrocytes against staurosporine‐induced apoptosis by activating multiple pathways, and these are mediated by a Gi‐protein‐coupled putative guanosine receptor. © 2004 Wiley‐Liss, Inc.</abstract><note type="funding">Neurological Technologies Inc</note><note type="funding">Ministero Università e Ricerca Scientifica e Technologica (MURST) of Italy</note><subject lang="en"><genre>keywords</genre><topic>guanosine</topic><topic>cell survival</topic><topic>antiapoptosis</topic><topic>PI 3‐kinase</topic><topic>AKT/PKB</topic><topic>astrocytes</topic></subject><relatedItem type="host"><titleInfo><title>Glia</title></titleInfo><titleInfo type="abbreviated"><title>Glia</title></titleInfo><genre type="journal">journal</genre><subject><genre>article-category</genre><topic>Original Article</topic></subject><identifier type="ISSN">0894-1491</identifier><identifier type="eISSN">1098-1136</identifier><identifier type="DOI">10.1002/(ISSN)1098-1136</identifier><identifier type="PublisherID">GLIA</identifier><part><date>2004</date><detail type="volume"><caption>vol.</caption><number>46</number></detail><detail type="issue"><caption>no.</caption><number>4</number></detail><extent unit="pages"><start>356</start><end>368</end><total>13</total></extent></part></relatedItem><identifier type="istex">E0D88F8D28C74D212FEC9CCBB8748DAD5267D31C</identifier><identifier type="DOI">10.1002/glia.20002</identifier><identifier type="ArticleID">GLIA20002</identifier><accessCondition type="use and reproduction" contentType="copyright">Copyright © 2004 Wiley‐Liss, Inc.</accessCondition><recordInfo><recordContentSource>WILEY</recordContentSource><recordOrigin>Wiley Subscription Services, Inc., A Wiley Company</recordOrigin></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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