Low‐dose 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine causes inflammatory activation of astrocytes in nuclear factor‐κB reporter mice prior to loss of dopaminergic neurons
Identifieur interne : 002C16 ( Main/Corpus ); précédent : 002C15; suivant : 002C17Low‐dose 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine causes inflammatory activation of astrocytes in nuclear factor‐κB reporter mice prior to loss of dopaminergic neurons
Auteurs : James A. Miller ; Briana R. Trout ; Kelly A. Sullivan ; Russell A. Bialecki ; Ruth A. Roberts ; Ronald B. TjalkensSource :
- Journal of Neuroscience Research [ 0360-4012 ] ; 2011-03.
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- KwdEn :
Abstract
Neuroinflammation is implicated in the progression of numerous disease states of the CNS, but early inflammatory signaling events in glial cells that may predispose neurons to injury are not easily characterized in vivo. To address this question, we exposed transgenic mice expressing a nuclear factor‐κB (NF‐κB)‐driven enhanced green fluorescent protein (EGFP) reporter construct to low doses of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) and examined inflammatory activation of astrocytes in relation to neurobehavioral and neuropathological outcomes. The highest dose of MPTP (60 mg/kg total dose) caused a decrease in locomotor activity and a reduction in stride length. No significant loss of dopaminergic neurons in the substantia nigra was apparent at any dose. In contrast, expression of tyrosine hydroxylase in striatal fibers was reduced at 60 mg/kg MPTP, as were levels of dopamine and DOPAC. Colocalized expression of EGFP and inducible nitric oxide synthase (NOS2) occurred in astrocytes at 30 and 60 mg/kg MPTP and was associated with increased protein nitration in nigral dopaminergic neurons. Inhibition of NF‐κB in primary astrocytes by expression of mutant IκBα suppressed expression of NOS2 and protected cocultured neurons from astrocyte‐mediated apoptosis. These data indicate that inflammatory activation of astrocytes and enhanced nitrosative stress occurs at low doses of MPTP prior to loss of dopaminergic neurons. NF‐κB‐mediated expression of NOS2 appears to be a sensitive indicator of neuroinflammation that correlates with MPTP‐induced neurochemical and neurobehavioral deficits prior to loss of dopaminergic neurons in the subtantia nigra. © 2011 Wiley‐Liss, Inc.
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DOI: 10.1002/jnr.22549
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To address this question, we exposed transgenic mice expressing a nuclear factor‐κB (NF‐κB)‐driven enhanced green fluorescent protein (EGFP) reporter construct to low doses of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) and examined inflammatory activation of astrocytes in relation to neurobehavioral and neuropathological outcomes. The highest dose of MPTP (60 mg/kg total dose) caused a decrease in locomotor activity and a reduction in stride length. No significant loss of dopaminergic neurons in the substantia nigra was apparent at any dose. In contrast, expression of tyrosine hydroxylase in striatal fibers was reduced at 60 mg/kg MPTP, as were levels of dopamine and DOPAC. Colocalized expression of EGFP and inducible nitric oxide synthase (NOS2) occurred in astrocytes at 30 and 60 mg/kg MPTP and was associated with increased protein nitration in nigral dopaminergic neurons. Inhibition of NF‐κB in primary astrocytes by expression of mutant IκBα suppressed expression of NOS2 and protected cocultured neurons from astrocyte‐mediated apoptosis. These data indicate that inflammatory activation of astrocytes and enhanced nitrosative stress occurs at low doses of MPTP prior to loss of dopaminergic neurons. NF‐κB‐mediated expression of NOS2 appears to be a sensitive indicator of neuroinflammation that correlates with MPTP‐induced neurochemical and neurobehavioral deficits prior to loss of dopaminergic neurons in the subtantia nigra. © 2011 Wiley‐Liss, Inc.</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>James A. 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To address this question, we exposed transgenic mice expressing a nuclear factor‐κB (NF‐κB)‐driven enhanced green fluorescent protein (EGFP) reporter construct to low doses of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) and examined inflammatory activation of astrocytes in relation to neurobehavioral and neuropathological outcomes. The highest dose of MPTP (60 mg/kg total dose) caused a decrease in locomotor activity and a reduction in stride length. No significant loss of dopaminergic neurons in the substantia nigra was apparent at any dose. In contrast, expression of tyrosine hydroxylase in striatal fibers was reduced at 60 mg/kg MPTP, as were levels of dopamine and DOPAC. Colocalized expression of EGFP and inducible nitric oxide synthase (NOS2) occurred in astrocytes at 30 and 60 mg/kg MPTP and was associated with increased protein nitration in nigral dopaminergic neurons. Inhibition of NF‐κB in primary astrocytes by expression of mutant IκBα suppressed expression of NOS2 and protected cocultured neurons from astrocyte‐mediated apoptosis. These data indicate that inflammatory activation of astrocytes and enhanced nitrosative stress occurs at low doses of MPTP prior to loss of dopaminergic neurons. NF‐κB‐mediated expression of NOS2 appears to be a sensitive indicator of neuroinflammation that correlates with MPTP‐induced neurochemical and neurobehavioral deficits prior to loss of dopaminergic neurons in the subtantia nigra. © 2011 Wiley‐Liss, Inc.</abstract><qualityIndicators><score>7.88</score><pdfVersion>1.3</pdfVersion><pdfPageSize>612 x 810 pts</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>5</keywordCount><abstractCharCount>1702</abstractCharCount><pdfWordCount>6307</pdfWordCount><pdfCharCount>41564</pdfCharCount><pdfPageCount>12</pdfPageCount><abstractWordCount>240</abstractWordCount></qualityIndicators><title>Low‐dose 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine causes inflammatory activation of astrocytes in nuclear factor‐κB reporter mice prior to loss of dopaminergic neurons</title><genre><json:string>article</json:string></genre><host><volume>89</volume><publisherId><json:string>JNR</json:string></publisherId><pages><total>12</total><last>417</last><first>406</first></pages><issn><json:string>0360-4012</json:string></issn><issue>3</issue><subject><json:item><value>Research Article</value></json:item></subject><genre><json:string>Journal</json:string></genre><language><json:string>unknown</json:string></language><eissn><json:string>1097-4547</json:string></eissn><title>Journal of Neuroscience Research</title><doi><json:string>10.1002/(ISSN)1097-4547</json:string></doi></host><publicationDate>2011</publicationDate><copyrightDate>2011</copyrightDate><doi><json:string>10.1002/jnr.22549</json:string></doi><id>75DE47640D2C4903AA211CA1B641BD4146238097</id><fulltext><json:item><original>true</original><mimetype>application/pdf</mimetype><extension>pdf</extension><uri>https://api.istex.fr/document/75DE47640D2C4903AA211CA1B641BD4146238097/fulltext/pdf</uri></json:item><json:item><original>false</original><mimetype>application/zip</mimetype><extension>zip</extension><uri>https://api.istex.fr/document/75DE47640D2C4903AA211CA1B641BD4146238097/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/75DE47640D2C4903AA211CA1B641BD4146238097/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">Low‐dose 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine causes inflammatory activation of astrocytes in nuclear factor‐κB reporter mice prior to loss of dopaminergic neurons</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><availability><p>WILEY</p></availability><date>2011</date></publicationStmt><notesStmt><note>AstraZeneca Pharmaceuticals</note><note>The Michael J. 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Inhibition of NF‐κB in primary astrocytes by expression of mutant IκBα suppressed expression of NOS2 and protected cocultured neurons from astrocyte‐mediated apoptosis. These data indicate that inflammatory activation of astrocytes and enhanced nitrosative stress occurs at low doses of MPTP prior to loss of dopaminergic neurons. 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Res.</title></titleGroup></publicationMeta><publicationMeta level="part" position="30"><doi origin="wiley" registered="yes">10.1002/jnr.v89.3</doi><numberingGroup><numbering type="journalVolume" number="89">89</numbering><numbering type="journalIssue">3</numbering></numberingGroup><coverDate startDate="2011-03">March 2011</coverDate></publicationMeta><publicationMeta level="unit" type="article" position="130" status="forIssue"><doi origin="wiley" registered="yes">10.1002/jnr.22549</doi><idGroup><id type="unit" value="JNR22549"></id></idGroup><countGroup><count type="pageTotal" number="12"></count></countGroup><titleGroup><title type="articleCategory">Research Article</title><title type="tocHeading1">Research Articles</title></titleGroup><copyright ownership="publisher">Copyright © 2011 Wiley‐Liss, Inc.</copyright><eventGroup><event type="manuscriptReceived" date="2010-08-06"></event><event type="manuscriptRevised" date="2010-10-08"></event><event type="manuscriptAccepted" date="2010-10-11"></event><event type="xmlConverted" agent="Converter:JWSART34_TO_WML3G version:2.4.4 mode:FullText" date="2011-01-21"></event><event type="publishedOnlineEarlyUnpaginated" date="2011-01-06"></event><event type="firstOnline" date="2011-01-06"></event><event type="publishedOnlineFinalForm" date="2011-01-21"></event><event type="xmlConverted" agent="Converter:WILEY_ML3G_TO_WILEY_ML3GV2 version:3.8.8" date="2014-01-31"></event><event type="xmlConverted" agent="Converter:WML3G_To_WML3G version:4.1.7 mode:FullText,remove_FC" date="2014-10-30"></event></eventGroup><numberingGroup><numbering type="pageFirst">406</numbering><numbering type="pageLast">417</numbering></numberingGroup><correspondenceTo>Department of Environmental and Radiological Health Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, 1680 Campus Delivery, Fort Collins, CO 80523‐1680</correspondenceTo><linkGroup><link type="toTypesetVersion" href="file:JNR.JNR22549.pdf"></link></linkGroup></publicationMeta><contentMeta><countGroup><count type="figureTotal" number="6"></count><count type="tableTotal" number="0"></count><count type="referenceTotal" number="53"></count><count type="wordTotal" number="6535"></count></countGroup><titleGroup><title type="main" xml:lang="en">Low‐dose 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine causes inflammatory activation of astrocytes in nuclear factor‐κB reporter mice prior to loss of dopaminergic neurons</title><title type="short" xml:lang="en">Astrocyte NF‐κB and MPTP Neurotoxicity</title></titleGroup><creators><creator xml:id="au1" creatorRole="author" affiliationRef="#af1 #af2"><personName><givenNames>James A.</givenNames><familyName>Miller</familyName></personName></creator><creator xml:id="au2" creatorRole="author" affiliationRef="#af1 #af2"><personName><givenNames>Briana R.</givenNames><familyName>Trout</familyName></personName></creator><creator xml:id="au3" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Kelly A.</givenNames><familyName>Sullivan</familyName></personName></creator><creator xml:id="au4" creatorRole="author" affiliationRef="#af3"><personName><givenNames>Russell A.</givenNames><familyName>Bialecki</familyName></personName></creator><creator xml:id="au5" creatorRole="author" affiliationRef="#af4"><personName><givenNames>Ruth A.</givenNames><familyName>Roberts</familyName></personName></creator><creator xml:id="au6" creatorRole="author" affiliationRef="#af1 #af2" corresponding="yes"><personName><givenNames>Ronald B.</givenNames><familyName>Tjalkens</familyName></personName><contactDetails><email>ron.tjalkens@colostate.edu</email></contactDetails></creator></creators><affiliationGroup><affiliation xml:id="af1" countryCode="US" type="organization"><unparsedAffiliation>Center for Environmental Medicine, Colorado State University, Fort Collins, Colorado</unparsedAffiliation></affiliation><affiliation xml:id="af2" countryCode="US" type="organization"><unparsedAffiliation>Program in Molecular, Cellular, and Integrative Neuroscience, Colorado State University, Fort Collins, Colorado</unparsedAffiliation></affiliation><affiliation xml:id="af3" countryCode="US" type="organization"><unparsedAffiliation>AstraZeneca Safety Assessment, Wilmington, Delaware</unparsedAffiliation></affiliation><affiliation xml:id="af4" countryCode="GB" type="organization"><unparsedAffiliation>AstraZeneca Safety Assessment, Alderley Park, United Kingdom</unparsedAffiliation></affiliation></affiliationGroup><keywordGroup xml:lang="en" type="author"><keyword xml:id="kwd1">astrocyte</keyword><keyword xml:id="kwd2">neuroinflammation</keyword><keyword xml:id="kwd3">neurodegeneration</keyword><keyword xml:id="kwd4">NF‐κB</keyword><keyword xml:id="kwd5">MPTP</keyword></keywordGroup><fundingInfo><fundingAgency>AstraZeneca Pharmaceuticals</fundingAgency></fundingInfo><fundingInfo><fundingAgency>The Michael J. Fox Foundation for Parkinson's Research</fundingAgency></fundingInfo><abstractGroup><abstract type="main" xml:lang="en"><title type="main">Abstract</title><p>Neuroinflammation is implicated in the progression of numerous disease states of the CNS, but early inflammatory signaling events in glial cells that may predispose neurons to injury are not easily characterized in vivo. To address this question, we exposed transgenic mice expressing a nuclear factor‐κB (NF‐κB)‐driven enhanced green fluorescent protein (EGFP) reporter construct to low doses of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) and examined inflammatory activation of astrocytes in relation to neurobehavioral and neuropathological outcomes. The highest dose of MPTP (60 mg/kg total dose) caused a decrease in locomotor activity and a reduction in stride length. No significant loss of dopaminergic neurons in the substantia nigra was apparent at any dose. In contrast, expression of tyrosine hydroxylase in striatal fibers was reduced at 60 mg/kg MPTP, as were levels of dopamine and DOPAC. Colocalized expression of EGFP and inducible nitric oxide synthase (NOS2) occurred in astrocytes at 30 and 60 mg/kg MPTP and was associated with increased protein nitration in nigral dopaminergic neurons. Inhibition of NF‐κB in primary astrocytes by expression of mutant IκBα suppressed expression of NOS2 and protected cocultured neurons from astrocyte‐mediated apoptosis. These data indicate that inflammatory activation of astrocytes and enhanced nitrosative stress occurs at low doses of MPTP prior to loss of dopaminergic neurons. NF‐κB‐mediated expression of NOS2 appears to be a sensitive indicator of neuroinflammation that correlates with MPTP‐induced neurochemical and neurobehavioral deficits prior to loss of dopaminergic neurons in the subtantia nigra. © 2011 Wiley‐Liss, Inc.</p></abstract></abstractGroup></contentMeta></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Low‐dose 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine causes inflammatory activation of astrocytes in nuclear factor‐κB reporter mice prior to loss of dopaminergic neurons</title></titleInfo><titleInfo type="abbreviated" lang="en"><title>Astrocyte NF‐κB and MPTP Neurotoxicity</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Low‐dose 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine causes inflammatory activation of astrocytes in nuclear factor‐κB reporter mice prior to loss of dopaminergic neurons</title></titleInfo><name type="personal"><namePart type="given">James A.</namePart><namePart type="family">Miller</namePart><affiliation>Center for Environmental Medicine, Colorado State University, Fort Collins, Colorado</affiliation><affiliation>Program in Molecular, Cellular, and Integrative Neuroscience, Colorado State University, Fort Collins, Colorado</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Briana R.</namePart><namePart type="family">Trout</namePart><affiliation>Center for Environmental Medicine, Colorado State University, Fort Collins, Colorado</affiliation><affiliation>Program in Molecular, Cellular, and Integrative Neuroscience, Colorado State University, Fort Collins, Colorado</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Kelly A.</namePart><namePart type="family">Sullivan</namePart><affiliation>Center for Environmental Medicine, Colorado State University, Fort Collins, Colorado</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Russell A.</namePart><namePart type="family">Bialecki</namePart><affiliation>AstraZeneca Safety Assessment, Wilmington, Delaware</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ruth A.</namePart><namePart type="family">Roberts</namePart><affiliation>AstraZeneca Safety Assessment, Alderley Park, United Kingdom</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ronald B.</namePart><namePart type="family">Tjalkens</namePart><affiliation>Center for Environmental Medicine, Colorado State University, Fort Collins, Colorado</affiliation><affiliation>Program in Molecular, Cellular, and Integrative Neuroscience, Colorado State University, Fort Collins, Colorado</affiliation><description>Correspondence: Department of Environmental and Radiological Health Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, 1680 Campus Delivery, Fort Collins, CO 80523‐1680</description><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">2011-03</dateIssued><dateCaptured encoding="w3cdtf">2010-08-06</dateCaptured><dateValid encoding="w3cdtf">2010-10-11</dateValid><copyrightDate encoding="w3cdtf">2011</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="references">53</extent><extent unit="words">6535</extent></physicalDescription><abstract lang="en">Neuroinflammation is implicated in the progression of numerous disease states of the CNS, but early inflammatory signaling events in glial cells that may predispose neurons to injury are not easily characterized in vivo. To address this question, we exposed transgenic mice expressing a nuclear factor‐κB (NF‐κB)‐driven enhanced green fluorescent protein (EGFP) reporter construct to low doses of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) and examined inflammatory activation of astrocytes in relation to neurobehavioral and neuropathological outcomes. The highest dose of MPTP (60 mg/kg total dose) caused a decrease in locomotor activity and a reduction in stride length. No significant loss of dopaminergic neurons in the substantia nigra was apparent at any dose. In contrast, expression of tyrosine hydroxylase in striatal fibers was reduced at 60 mg/kg MPTP, as were levels of dopamine and DOPAC. Colocalized expression of EGFP and inducible nitric oxide synthase (NOS2) occurred in astrocytes at 30 and 60 mg/kg MPTP and was associated with increased protein nitration in nigral dopaminergic neurons. Inhibition of NF‐κB in primary astrocytes by expression of mutant IκBα suppressed expression of NOS2 and protected cocultured neurons from astrocyte‐mediated apoptosis. These data indicate that inflammatory activation of astrocytes and enhanced nitrosative stress occurs at low doses of MPTP prior to loss of dopaminergic neurons. NF‐κB‐mediated expression of NOS2 appears to be a sensitive indicator of neuroinflammation that correlates with MPTP‐induced neurochemical and neurobehavioral deficits prior to loss of dopaminergic neurons in the subtantia nigra. © 2011 Wiley‐Liss, Inc.</abstract><note type="funding">AstraZeneca Pharmaceuticals</note><note type="funding">The Michael J. Fox Foundation for Parkinson's Research</note><subject lang="en"><genre>Keywords</genre><topic>astrocyte</topic><topic>neuroinflammation</topic><topic>neurodegeneration</topic><topic>NF‐κB</topic><topic>MPTP</topic></subject><relatedItem type="host"><titleInfo><title>Journal of Neuroscience Research</title></titleInfo><titleInfo type="abbreviated"><title>J. Neurosci. Res.</title></titleInfo><genre type="Journal">journal</genre><subject><genre>article category</genre><topic>Research Article</topic></subject><identifier type="ISSN">0360-4012</identifier><identifier type="eISSN">1097-4547</identifier><identifier type="DOI">10.1002/(ISSN)1097-4547</identifier><identifier type="PublisherID">JNR</identifier><part><date>2011</date><detail type="volume"><caption>vol.</caption><number>89</number></detail><detail type="issue"><caption>no.</caption><number>3</number></detail><extent unit="pages"><start>406</start><end>417</end><total>12</total></extent></part></relatedItem><identifier type="istex">75DE47640D2C4903AA211CA1B641BD4146238097</identifier><identifier type="DOI">10.1002/jnr.22549</identifier><identifier type="ArticleID">JNR22549</identifier><accessCondition type="use and reproduction" contentType="copyright">Copyright © 2011 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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