WIN55,212‐2, a cannabinoid receptor agonist, protects against nigrostriatal cell loss in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine mouse model of Parkinson’s disease
Identifieur interne : 002D94 ( Main/Corpus ); précédent : 002D93; suivant : 002D95WIN55,212‐2, a cannabinoid receptor agonist, protects against nigrostriatal cell loss in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine mouse model of Parkinson’s disease
Auteurs : David A. Price ; Alex A. Martinez ; Alexandre Seillier ; Wouter Koek ; Yolanda Acosta ; Elizabeth Fernandez ; Randy Strong ; Beat Lutz ; Giovanni Marsicano ; James L. Roberts ; Andrea GiuffridaSource :
- European Journal of Neuroscience [ 0953-816X ] ; 2009-06.
English descriptors
Abstract
Parkinson’s disease (PD) is characterized by the progressive loss of nigrostriatal dopamine neurons leading to motor disturbances and cognitive impairment. Current pharmacotherapies relieve PD symptoms temporarily but fail to prevent or slow down the disease progression. In this study, we investigated the molecular mechanisms by which the non‐selective cannabinoid receptor agonist WIN55,212‐2 (WIN) protects mouse nigrostriatal neurons from 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced neurotoxicity and neuroinflammation. Stereological analyses showed that chronic treatment with WIN (4 mg/kg, intraperitoneal), initiated 24 h after MPTP administration, protected against MPTP‐induced loss of tyrosine hydroxylase‐positive neurons in the substantia nigra pars compacta independently of CB1 cannabinoid receptor activation. The neuroprotective effect of WIN was accompanied by increased dopamine and 3,4‐dihydroxyphenylacetic acid levels in the substantia nigra pars compacta and dorsal striatum of MPTP‐treated mice. At 3 days post‐MPTP, we found significant microglial activation and up‐regulation of CB2 cannabinoid receptors in the ventral midbrain. Treatment with WIN or the CB2 receptor agonist JWH015 (4 mg/kg, intraperitoneal) reduced MPTP‐induced microglial activation, whereas genetic ablation of CB2 receptors exacerbated MPTP systemic toxicity. Furthermore, chronic WIN reversed MPTP‐associated motor deficits, as revealed by the analysis of forepaw step width and percentage of faults using the inverted grid test. In conclusion, our data indicate that agonism at CB2 cannabinoid receptors protects against MPTP‐induced nigrostriatal degeneration by inhibiting microglial activation/infiltration and suggest that CB2 receptors represent a new therapeutic target to slow the degenerative process occurring in PD.
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DOI: 10.1111/j.1460-9568.2009.06764.x
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Price</name><affiliation><mods:affiliation>Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive ‐ MC 6205, San Antonio, TX 78229‐3900, USA</mods:affiliation></affiliation></author><author><name sortKey="Martinez, Alex A" sort="Martinez, Alex A" uniqKey="Martinez A" first="Alex A." last="Martinez">Alex A. Martinez</name><affiliation><mods:affiliation>Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive ‐ MC 6205, San Antonio, TX 78229‐3900, USA</mods:affiliation></affiliation></author><author><name sortKey="Seillier, Alexandre" sort="Seillier, Alexandre" uniqKey="Seillier A" first="Alexandre" last="Seillier">Alexandre Seillier</name><affiliation><mods:affiliation>Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive ‐ MC 6205, San Antonio, TX 78229‐3900, USA</mods:affiliation></affiliation></author><author><name sortKey="Koek, Wouter" sort="Koek, Wouter" uniqKey="Koek W" first="Wouter" last="Koek">Wouter Koek</name><affiliation><mods:affiliation>Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive ‐ MC 6205, San Antonio, TX 78229‐3900, USA</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Psychiatry, University of Texas Health Science Center, San Antonio, TX, USA</mods:affiliation></affiliation></author><author><name sortKey="Acosta, Yolanda" sort="Acosta, Yolanda" uniqKey="Acosta Y" first="Yolanda" last="Acosta">Yolanda Acosta</name><affiliation><mods:affiliation>Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive ‐ MC 6205, San Antonio, TX 78229‐3900, USA</mods:affiliation></affiliation></author><author><name sortKey="Fernandez, Elizabeth" sort="Fernandez, Elizabeth" uniqKey="Fernandez E" first="Elizabeth" last="Fernandez">Elizabeth Fernandez</name><affiliation><mods:affiliation>Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive ‐ MC 6205, San Antonio, TX 78229‐3900, USA</mods:affiliation></affiliation><affiliation><mods:affiliation>Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, TX, USA</mods:affiliation></affiliation></author><author><name sortKey="Strong, Randy" sort="Strong, Randy" uniqKey="Strong R" first="Randy" last="Strong">Randy Strong</name><affiliation><mods:affiliation>Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive ‐ MC 6205, San Antonio, TX 78229‐3900, USA</mods:affiliation></affiliation><affiliation><mods:affiliation>Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, TX, USA</mods:affiliation></affiliation></author><author><name sortKey="Lutz, Beat" sort="Lutz, Beat" uniqKey="Lutz B" first="Beat" last="Lutz">Beat Lutz</name><affiliation><mods:affiliation>Institute of Physiological Chemistry and Pathobiochemistry, Johannes Gutenberg‐University, Mainz, Germany</mods:affiliation></affiliation></author><author><name sortKey="Marsicano, Giovanni" sort="Marsicano, Giovanni" uniqKey="Marsicano G" first="Giovanni" last="Marsicano">Giovanni Marsicano</name><affiliation><mods:affiliation>NeuroCentre Magendie, U682 INSERM, University of Bordeaux 2, Avenir Group, Bordeaux, France</mods:affiliation></affiliation></author><author><name sortKey="Roberts, James L" sort="Roberts, James L" uniqKey="Roberts J" first="James L." last="Roberts">James L. Roberts</name><affiliation><mods:affiliation>Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive ‐ MC 6205, San Antonio, TX 78229‐3900, USA</mods:affiliation></affiliation><affiliation><mods:affiliation>Audie L. Murphy Veteran Affairs Medical Center, San Antonio, TX, USA</mods:affiliation></affiliation></author><author><name sortKey="Giuffrida, Andrea" sort="Giuffrida, Andrea" uniqKey="Giuffrida A" first="Andrea" last="Giuffrida">Andrea Giuffrida</name><affiliation><mods:affiliation>Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive ‐ MC 6205, San Antonio, TX 78229‐3900, USA</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">European Journal of Neuroscience</title><idno type="ISSN">0953-816X</idno><idno type="eISSN">1460-9568</idno><imprint><publisher>Blackwell Publishing Ltd</publisher><pubPlace>Oxford, UK</pubPlace><date type="published" when="2009-06">2009-06</date><biblScope unit="volume">29</biblScope><biblScope unit="issue">11</biblScope><biblScope unit="page" from="2177">2177</biblScope><biblScope unit="page" to="2186">2186</biblScope></imprint><idno type="ISSN">0953-816X</idno></series><idno type="istex">28C8FFA08ABC3BA2D9EA00E5AE9C14069EDB31A8</idno><idno type="DOI">10.1111/j.1460-9568.2009.06764.x</idno><idno type="ArticleID">EJN6764</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0953-816X</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>cannabinoid receptors</term><term>neuroinflammation</term><term>neurotoxicity</term><term>striatum</term><term>substantia nigra</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Parkinson’s disease (PD) is characterized by the progressive loss of nigrostriatal dopamine neurons leading to motor disturbances and cognitive impairment. Current pharmacotherapies relieve PD symptoms temporarily but fail to prevent or slow down the disease progression. In this study, we investigated the molecular mechanisms by which the non‐selective cannabinoid receptor agonist WIN55,212‐2 (WIN) protects mouse nigrostriatal neurons from 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced neurotoxicity and neuroinflammation. Stereological analyses showed that chronic treatment with WIN (4 mg/kg, intraperitoneal), initiated 24 h after MPTP administration, protected against MPTP‐induced loss of tyrosine hydroxylase‐positive neurons in the substantia nigra pars compacta independently of CB1 cannabinoid receptor activation. The neuroprotective effect of WIN was accompanied by increased dopamine and 3,4‐dihydroxyphenylacetic acid levels in the substantia nigra pars compacta and dorsal striatum of MPTP‐treated mice. At 3 days post‐MPTP, we found significant microglial activation and up‐regulation of CB2 cannabinoid receptors in the ventral midbrain. Treatment with WIN or the CB2 receptor agonist JWH015 (4 mg/kg, intraperitoneal) reduced MPTP‐induced microglial activation, whereas genetic ablation of CB2 receptors exacerbated MPTP systemic toxicity. Furthermore, chronic WIN reversed MPTP‐associated motor deficits, as revealed by the analysis of forepaw step width and percentage of faults using the inverted grid test. In conclusion, our data indicate that agonism at CB2 cannabinoid receptors protects against MPTP‐induced nigrostriatal degeneration by inhibiting microglial activation/infiltration and suggest that CB2 receptors represent a new therapeutic target to slow the degenerative process occurring in PD.</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>David A. Price</name><affiliations><json:string>Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive ‐ MC 6205, San Antonio, TX 78229‐3900, USA</json:string></affiliations></json:item><json:item><name>Alex A. Martinez</name><affiliations><json:string>Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive ‐ MC 6205, San Antonio, TX 78229‐3900, USA</json:string></affiliations></json:item><json:item><name>Alexandre Seillier</name><affiliations><json:string>Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive ‐ MC 6205, San Antonio, TX 78229‐3900, USA</json:string></affiliations></json:item><json:item><name>Wouter Koek</name><affiliations><json:string>Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive ‐ MC 6205, San Antonio, TX 78229‐3900, USA</json:string><json:string>Department of Psychiatry, University of Texas Health Science Center, San Antonio, TX, USA</json:string></affiliations></json:item><json:item><name>Yolanda Acosta</name><affiliations><json:string>Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive ‐ MC 6205, San Antonio, TX 78229‐3900, USA</json:string></affiliations></json:item><json:item><name>Elizabeth Fernandez</name><affiliations><json:string>Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive ‐ MC 6205, San Antonio, TX 78229‐3900, USA</json:string><json:string>Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, TX, USA</json:string></affiliations></json:item><json:item><name>Randy Strong</name><affiliations><json:string>Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive ‐ MC 6205, San Antonio, TX 78229‐3900, USA</json:string><json:string>Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, TX, USA</json:string></affiliations></json:item><json:item><name>Beat Lutz</name><affiliations><json:string>Institute of Physiological Chemistry and Pathobiochemistry, Johannes Gutenberg‐University, Mainz, Germany</json:string></affiliations></json:item><json:item><name>Giovanni Marsicano</name><affiliations><json:string>NeuroCentre Magendie, U682 INSERM, University of Bordeaux 2, Avenir Group, Bordeaux, France</json:string></affiliations></json:item><json:item><name>James L. Roberts</name><affiliations><json:string>Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive ‐ MC 6205, San Antonio, TX 78229‐3900, USA</json:string><json:string>Audie L. Murphy Veteran Affairs Medical Center, San Antonio, TX, USA</json:string></affiliations></json:item><json:item><name>Andrea Giuffrida</name><affiliations><json:string>Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive ‐ MC 6205, San Antonio, TX 78229‐3900, USA</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>cannabinoid receptors</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>neuroinflammation</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>neurotoxicity</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>striatum</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>substantia nigra</value></json:item></subject><articleId><json:string>EJN6764</json:string></articleId><language><json:string>eng</json:string></language><abstract>Parkinson’s disease (PD) is characterized by the progressive loss of nigrostriatal dopamine neurons leading to motor disturbances and cognitive impairment. Current pharmacotherapies relieve PD symptoms temporarily but fail to prevent or slow down the disease progression. In this study, we investigated the molecular mechanisms by which the non‐selective cannabinoid receptor agonist WIN55,212‐2 (WIN) protects mouse nigrostriatal neurons from 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced neurotoxicity and neuroinflammation. Stereological analyses showed that chronic treatment with WIN (4 mg/kg, intraperitoneal), initiated 24 h after MPTP administration, protected against MPTP‐induced loss of tyrosine hydroxylase‐positive neurons in the substantia nigra pars compacta independently of CB1 cannabinoid receptor activation. The neuroprotective effect of WIN was accompanied by increased dopamine and 3,4‐dihydroxyphenylacetic acid levels in the substantia nigra pars compacta and dorsal striatum of MPTP‐treated mice. At 3 days post‐MPTP, we found significant microglial activation and up‐regulation of CB2 cannabinoid receptors in the ventral midbrain. Treatment with WIN or the CB2 receptor agonist JWH015 (4 mg/kg, intraperitoneal) reduced MPTP‐induced microglial activation, whereas genetic ablation of CB2 receptors exacerbated MPTP systemic toxicity. Furthermore, chronic WIN reversed MPTP‐associated motor deficits, as revealed by the analysis of forepaw step width and percentage of faults using the inverted grid test. In conclusion, our data indicate that agonism at CB2 cannabinoid receptors protects against MPTP‐induced nigrostriatal degeneration by inhibiting microglial activation/infiltration and suggest that CB2 receptors represent a new therapeutic target to slow the degenerative process occurring in PD.</abstract><qualityIndicators><score>7.76</score><pdfVersion>1.3</pdfVersion><pdfPageSize>595.276 x 810.709 pts</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>5</keywordCount><abstractCharCount>1842</abstractCharCount><pdfWordCount>8266</pdfWordCount><pdfCharCount>52350</pdfCharCount><pdfPageCount>10</pdfPageCount><abstractWordCount>230</abstractWordCount></qualityIndicators><title>WIN55,212‐2, a cannabinoid receptor agonist, protects against nigrostriatal cell loss in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine mouse model of Parkinson’s 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Curl Drive ‐ MC 6205, San Antonio, TX 78229‐3900, USA</affiliation></author><author><persName><forename type="first">Alex A.</forename><surname>Martinez</surname></persName><affiliation>Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive ‐ MC 6205, San Antonio, TX 78229‐3900, USA</affiliation></author><author><persName><forename type="first">Alexandre</forename><surname>Seillier</surname></persName><affiliation>Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive ‐ MC 6205, San Antonio, TX 78229‐3900, USA</affiliation></author><author><persName><forename type="first">Wouter</forename><surname>Koek</surname></persName><affiliation>Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive ‐ MC 6205, San Antonio, TX 78229‐3900, USA</affiliation><affiliation>Department of Psychiatry, University of Texas Health Science Center, San Antonio, TX, USA</affiliation></author><author><persName><forename type="first">Yolanda</forename><surname>Acosta</surname></persName><affiliation>Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive ‐ MC 6205, San Antonio, TX 78229‐3900, USA</affiliation></author><author><persName><forename type="first">Elizabeth</forename><surname>Fernandez</surname></persName><affiliation>Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive ‐ MC 6205, San Antonio, TX 78229‐3900, USA</affiliation><affiliation>Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, TX, USA</affiliation></author><author><persName><forename type="first">Randy</forename><surname>Strong</surname></persName><affiliation>Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive ‐ MC 6205, San Antonio, TX 78229‐3900, USA</affiliation><affiliation>Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, TX, USA</affiliation></author><author><persName><forename type="first">Beat</forename><surname>Lutz</surname></persName><affiliation>Institute of Physiological Chemistry and Pathobiochemistry, Johannes Gutenberg‐University, Mainz, Germany</affiliation></author><author><persName><forename type="first">Giovanni</forename><surname>Marsicano</surname></persName><affiliation>NeuroCentre Magendie, U682 INSERM, University of Bordeaux 2, Avenir Group, Bordeaux, France</affiliation></author><author><persName><forename type="first">James L.</forename><surname>Roberts</surname></persName><affiliation>Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive ‐ MC 6205, San Antonio, TX 78229‐3900, USA</affiliation><affiliation>Audie L. Murphy Veteran Affairs Medical Center, San Antonio, TX, USA</affiliation></author><author><persName><forename type="first">Andrea</forename><surname>Giuffrida</surname></persName><affiliation>Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive ‐ MC 6205, San Antonio, TX 78229‐3900, USA</affiliation></author></analytic><monogr><title level="j">European Journal of Neuroscience</title><idno type="pISSN">0953-816X</idno><idno type="eISSN">1460-9568</idno><idno type="DOI">10.1111/(ISSN)1460-9568</idno><imprint><publisher>Blackwell Publishing Ltd</publisher><pubPlace>Oxford, UK</pubPlace><date type="published" when="2009-06"></date><biblScope unit="volume">29</biblScope><biblScope unit="issue">11</biblScope><biblScope unit="page" from="2177">2177</biblScope><biblScope unit="page" to="2186">2186</biblScope></imprint></monogr><idno type="istex">28C8FFA08ABC3BA2D9EA00E5AE9C14069EDB31A8</idno><idno type="DOI">10.1111/j.1460-9568.2009.06764.x</idno><idno type="ArticleID">EJN6764</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2009</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Parkinson’s disease (PD) is characterized by the progressive loss of nigrostriatal dopamine neurons leading to motor disturbances and cognitive impairment. Current pharmacotherapies relieve PD symptoms temporarily but fail to prevent or slow down the disease progression. In this study, we investigated the molecular mechanisms by which the non‐selective cannabinoid receptor agonist WIN55,212‐2 (WIN) protects mouse nigrostriatal neurons from 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced neurotoxicity and neuroinflammation. Stereological analyses showed that chronic treatment with WIN (4 mg/kg, intraperitoneal), initiated 24 h after MPTP administration, protected against MPTP‐induced loss of tyrosine hydroxylase‐positive neurons in the substantia nigra pars compacta independently of CB1 cannabinoid receptor activation. The neuroprotective effect of WIN was accompanied by increased dopamine and 3,4‐dihydroxyphenylacetic acid levels in the substantia nigra pars compacta and dorsal striatum of MPTP‐treated mice. At 3 days post‐MPTP, we found significant microglial activation and up‐regulation of CB2 cannabinoid receptors in the ventral midbrain. Treatment with WIN or the CB2 receptor agonist JWH015 (4 mg/kg, intraperitoneal) reduced MPTP‐induced microglial activation, whereas genetic ablation of CB2 receptors exacerbated MPTP systemic toxicity. Furthermore, chronic WIN reversed MPTP‐associated motor deficits, as revealed by the analysis of forepaw step width and percentage of faults using the inverted grid test. In conclusion, our data indicate that agonism at CB2 cannabinoid receptors protects against MPTP‐induced nigrostriatal degeneration by inhibiting microglial activation/infiltration and suggest that CB2 receptors represent a new therapeutic target to slow the degenerative process occurring in PD.</p></abstract><textClass xml:lang="en"><keywords scheme="keyword"><list><head>Keywords</head><item><term>cannabinoid receptors</term></item><item><term>neuroinflammation</term></item><item><term>neurotoxicity</term></item><item><term>striatum</term></item><item><term>substantia nigra</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2009-06">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/28C8FFA08ABC3BA2D9EA00E5AE9C14069EDB31A8/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Wiley, elements deleted: body"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="yes"</istex:xmlDeclaration><istex:document><component version="2.0" type="serialArticle" xml:lang="en"><header><publicationMeta level="product"><publisherInfo><publisherName>Blackwell Publishing Ltd</publisherName><publisherLoc>Oxford, UK</publisherLoc></publisherInfo><doi origin="wiley" registered="yes">10.1111/(ISSN)1460-9568</doi><issn type="print">0953-816X</issn><issn type="electronic">1460-9568</issn><idGroup><id type="product" value="EJN"></id><id type="publisherDivision" value="ST"></id></idGroup><titleGroup><title type="main" sort="EUROPEAN JOURNAL OF NEUROSCIENCE">European Journal of Neuroscience</title></titleGroup></publicationMeta><publicationMeta level="part" position="06011"><doi origin="wiley">10.1111/ejn.2009.29.issue-11</doi><numberingGroup><numbering type="journalVolume" number="29">29</numbering><numbering type="journalIssue" number="11">11</numbering></numberingGroup><coverDate startDate="2009-06">June 2009</coverDate></publicationMeta><publicationMeta level="unit" type="article" position="8" status="forIssue"><doi origin="wiley">10.1111/j.1460-9568.2009.06764.x</doi><idGroup><id type="unit" value="EJN6764"></id></idGroup><countGroup><count type="pageTotal" number="11"></count></countGroup><titleGroup><title type="tocHeading1">NEUROSYSTEMS</title></titleGroup><copyright>© The Authors (2009). Journal Compilation © Federation of European Neuroscience Societies and Blackwell Publishing Ltd</copyright><eventGroup><event type="firstOnline" date="2009-05-21"></event><event type="publishedOnlineFinalForm" date="2009-06-01"></event><event type="xmlConverted" agent="Converter:BPG_TO_WML3G version:2.3.2 mode:FullText source:FullText result:FullText" date="2010-03-02"></event><event type="xmlConverted" agent="Converter:WILEY_ML3G_TO_WILEY_ML3GV2 version:4.0.1" date="2014-03-12"></event><event type="xmlConverted" agent="Converter:WML3G_To_WML3G version:4.1.7 mode:FullText,remove_FC" date="2014-10-17"></event></eventGroup><numberingGroup><numbering type="pageFirst" number="2177">2177</numbering><numbering type="pageLast" number="2186">2186</numbering></numberingGroup><correspondenceTo>Dr Andrea Giuffrida, as above.
E‐mail: <email>giuffrida@uthscsa.edu</email></correspondenceTo><linkGroup><link type="toTypesetVersion" href="file:EJN.EJN6764.pdf"></link></linkGroup></publicationMeta><contentMeta><unparsedEditorialHistory>Received 11 July 2008, revised 23 March 2009, accepted 24 March 2009</unparsedEditorialHistory><countGroup><count type="figureTotal" number="6"></count><count type="tableTotal" number="0"></count></countGroup><titleGroup><title type="main">WIN55,212‐2, a cannabinoid receptor agonist, protects against nigrostriatal cell loss in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine mouse model of Parkinson’s disease</title><title type="shortAuthors">D. A. Price <i>et al.</i></title><title type="short">Cannabinoids protect against MPTP‐induced DA cell loss</title></titleGroup><creators><creator creatorRole="author" xml:id="cr1" affiliationRef="#a1" noteRef="#fn1"><personName><givenNames>David A.</givenNames><familyName>Price</familyName></personName></creator><creator creatorRole="author" xml:id="cr2" affiliationRef="#a1"><personName><givenNames>Alex A.</givenNames><familyName>Martinez</familyName></personName></creator><creator creatorRole="author" xml:id="cr3" affiliationRef="#a1"><personName><givenNames>Alexandre</givenNames><familyName>Seillier</familyName></personName></creator><creator creatorRole="author" xml:id="cr4" affiliationRef="#a1 #a2"><personName><givenNames>Wouter</givenNames><familyName>Koek</familyName></personName></creator><creator creatorRole="author" xml:id="cr5" affiliationRef="#a1"><personName><givenNames>Yolanda</givenNames><familyName>Acosta</familyName></personName></creator><creator creatorRole="author" xml:id="cr6" affiliationRef="#a1 #a3"><personName><givenNames>Elizabeth</givenNames><familyName>Fernandez</familyName></personName></creator><creator creatorRole="author" xml:id="cr7" affiliationRef="#a1 #a3"><personName><givenNames>Randy</givenNames><familyName>Strong</familyName></personName></creator><creator creatorRole="author" xml:id="cr8" affiliationRef="#a4"><personName><givenNames>Beat</givenNames><familyName>Lutz</familyName></personName></creator><creator creatorRole="author" xml:id="cr9" affiliationRef="#a5"><personName><givenNames>Giovanni</givenNames><familyName>Marsicano</familyName></personName></creator><creator creatorRole="author" xml:id="cr10" affiliationRef="#a1 #a6"><personName><givenNames>James L.</givenNames><familyName>Roberts</familyName></personName></creator><creator creatorRole="author" xml:id="cr11" affiliationRef="#a1"><personName><givenNames>Andrea</givenNames><familyName>Giuffrida</familyName></personName></creator></creators><affiliationGroup><affiliation xml:id="a1" countryCode="US"><unparsedAffiliation>Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive ‐ MC 6205, San Antonio, TX 78229‐3900, USA</unparsedAffiliation></affiliation><affiliation xml:id="a2" countryCode="US"><unparsedAffiliation>Department of Psychiatry, University of Texas Health Science Center, San Antonio, TX, USA</unparsedAffiliation></affiliation><affiliation xml:id="a3" countryCode="US"><unparsedAffiliation>Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, TX, USA</unparsedAffiliation></affiliation><affiliation xml:id="a4" countryCode="DE"><unparsedAffiliation>Institute of Physiological Chemistry and Pathobiochemistry, Johannes Gutenberg‐University, Mainz, Germany</unparsedAffiliation></affiliation><affiliation xml:id="a5" countryCode="FR"><unparsedAffiliation>NeuroCentre Magendie, U682 INSERM, University of Bordeaux 2, Avenir Group, Bordeaux, France</unparsedAffiliation></affiliation><affiliation xml:id="a6" countryCode="US"><unparsedAffiliation>Audie L. Murphy Veteran Affairs Medical Center, San Antonio, TX, USA</unparsedAffiliation></affiliation></affiliationGroup><keywordGroup xml:lang="en"><keyword xml:id="k1">cannabinoid receptors</keyword><keyword xml:id="k2">neuroinflammation</keyword><keyword xml:id="k3">neurotoxicity</keyword><keyword xml:id="k4">striatum</keyword><keyword xml:id="k5">substantia nigra</keyword></keywordGroup><abstractGroup><abstract type="main" xml:lang="en"><title type="main">Abstract</title><p>Parkinson’s disease (PD) is characterized by the progressive loss of nigrostriatal dopamine neurons leading to motor disturbances and cognitive impairment. Current pharmacotherapies relieve PD symptoms temporarily but fail to prevent or slow down the disease progression. In this study, we investigated the molecular mechanisms by which the non‐selective cannabinoid receptor agonist WIN55,212‐2 (WIN) protects mouse nigrostriatal neurons from 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced neurotoxicity and neuroinflammation. Stereological analyses showed that chronic treatment with WIN (4 mg/kg, intraperitoneal), initiated 24 h after MPTP administration, protected against MPTP‐induced loss of tyrosine hydroxylase‐positive neurons in the substantia nigra pars compacta independently of CB<sub>1</sub> cannabinoid receptor activation. The neuroprotective effect of WIN was accompanied by increased dopamine and 3,4‐dihydroxyphenylacetic acid levels in the substantia nigra pars compacta and dorsal striatum of MPTP‐treated mice. At 3 days post‐MPTP, we found significant microglial activation and up‐regulation of CB<sub>2</sub> cannabinoid receptors in the ventral midbrain. Treatment with WIN or the CB<sub>2</sub> receptor agonist JWH015 (4 mg/kg, intraperitoneal) reduced MPTP‐induced microglial activation, whereas genetic ablation of CB<sub>2</sub> receptors exacerbated MPTP systemic toxicity. Furthermore, chronic WIN reversed MPTP‐associated motor deficits, as revealed by the analysis of forepaw step width and percentage of faults using the inverted grid test. In conclusion, our data indicate that agonism at CB<sub>2</sub> cannabinoid receptors protects against MPTP‐induced nigrostriatal degeneration by inhibiting microglial activation/infiltration and suggest that CB<sub>2</sub> receptors represent a new therapeutic target to slow the degenerative process occurring in PD.</p></abstract></abstractGroup></contentMeta><noteGroup><note xml:id="fn1"><label>*</label><p><i>Present address</i>: Department of Pharmacology, University of Colorado Denver, Denver, CO, USA.</p></note></noteGroup></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>WIN55,212‐2, a cannabinoid receptor agonist, protects against nigrostriatal cell loss in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine mouse model of Parkinson’s disease</title></titleInfo><titleInfo type="abbreviated"><title>Cannabinoids protect against MPTP‐induced DA cell loss</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>WIN55,212‐2, a cannabinoid receptor agonist, protects against nigrostriatal cell loss in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine mouse model of Parkinson’s disease</title></titleInfo><name type="personal"><namePart type="given">David A.</namePart><namePart type="family">Price</namePart><affiliation>Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive ‐ MC 6205, San Antonio, TX 78229‐3900, USA</affiliation><description>Present address: Department of Pharmacology, University of Colorado Denver, Denver, CO, USA.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Alex A.</namePart><namePart type="family">Martinez</namePart><affiliation>Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive ‐ MC 6205, San Antonio, TX 78229‐3900, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Alexandre</namePart><namePart type="family">Seillier</namePart><affiliation>Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive ‐ MC 6205, San Antonio, TX 78229‐3900, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Wouter</namePart><namePart type="family">Koek</namePart><affiliation>Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive ‐ MC 6205, San Antonio, TX 78229‐3900, USA</affiliation><affiliation>Department of Psychiatry, University of Texas Health Science Center, San Antonio, TX, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Yolanda</namePart><namePart type="family">Acosta</namePart><affiliation>Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive ‐ MC 6205, San Antonio, TX 78229‐3900, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Elizabeth</namePart><namePart type="family">Fernandez</namePart><affiliation>Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive ‐ MC 6205, San Antonio, TX 78229‐3900, USA</affiliation><affiliation>Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, TX, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Randy</namePart><namePart type="family">Strong</namePart><affiliation>Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive ‐ MC 6205, San Antonio, TX 78229‐3900, USA</affiliation><affiliation>Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, TX, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Beat</namePart><namePart type="family">Lutz</namePart><affiliation>Institute of Physiological Chemistry and Pathobiochemistry, Johannes Gutenberg‐University, Mainz, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Giovanni</namePart><namePart type="family">Marsicano</namePart><affiliation>NeuroCentre Magendie, U682 INSERM, University of Bordeaux 2, Avenir Group, Bordeaux, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">James L.</namePart><namePart type="family">Roberts</namePart><affiliation>Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive ‐ MC 6205, San Antonio, TX 78229‐3900, USA</affiliation><affiliation>Audie L. Murphy Veteran Affairs Medical Center, San Antonio, TX, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Andrea</namePart><namePart type="family">Giuffrida</namePart><affiliation>Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive ‐ MC 6205, San Antonio, TX 78229‐3900, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article"></genre><originInfo><publisher>Blackwell Publishing Ltd</publisher><place><placeTerm type="text">Oxford, UK</placeTerm></place><dateIssued encoding="w3cdtf">2009-06</dateIssued><edition>Received 11 July 2008, revised 23 March 2009, accepted 24 March 2009</edition><copyrightDate encoding="w3cdtf">2009</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></physicalDescription><abstract lang="en">Parkinson’s disease (PD) is characterized by the progressive loss of nigrostriatal dopamine neurons leading to motor disturbances and cognitive impairment. Current pharmacotherapies relieve PD symptoms temporarily but fail to prevent or slow down the disease progression. In this study, we investigated the molecular mechanisms by which the non‐selective cannabinoid receptor agonist WIN55,212‐2 (WIN) protects mouse nigrostriatal neurons from 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced neurotoxicity and neuroinflammation. Stereological analyses showed that chronic treatment with WIN (4 mg/kg, intraperitoneal), initiated 24 h after MPTP administration, protected against MPTP‐induced loss of tyrosine hydroxylase‐positive neurons in the substantia nigra pars compacta independently of CB1 cannabinoid receptor activation. The neuroprotective effect of WIN was accompanied by increased dopamine and 3,4‐dihydroxyphenylacetic acid levels in the substantia nigra pars compacta and dorsal striatum of MPTP‐treated mice. At 3 days post‐MPTP, we found significant microglial activation and up‐regulation of CB2 cannabinoid receptors in the ventral midbrain. Treatment with WIN or the CB2 receptor agonist JWH015 (4 mg/kg, intraperitoneal) reduced MPTP‐induced microglial activation, whereas genetic ablation of CB2 receptors exacerbated MPTP systemic toxicity. Furthermore, chronic WIN reversed MPTP‐associated motor deficits, as revealed by the analysis of forepaw step width and percentage of faults using the inverted grid test. In conclusion, our data indicate that agonism at CB2 cannabinoid receptors protects against MPTP‐induced nigrostriatal degeneration by inhibiting microglial activation/infiltration and suggest that CB2 receptors represent a new therapeutic target to slow the degenerative process occurring in PD.</abstract><subject lang="en"><genre>Keywords</genre><topic>cannabinoid receptors</topic><topic>neuroinflammation</topic><topic>neurotoxicity</topic><topic>striatum</topic><topic>substantia nigra</topic></subject><relatedItem type="host"><titleInfo><title>European Journal of Neuroscience</title></titleInfo><genre type="Journal">journal</genre><identifier type="ISSN">0953-816X</identifier><identifier type="eISSN">1460-9568</identifier><identifier type="DOI">10.1111/(ISSN)1460-9568</identifier><identifier type="PublisherID">EJN</identifier><part><date>2009</date><detail type="volume"><caption>vol.</caption><number>29</number></detail><detail type="issue"><caption>no.</caption><number>11</number></detail><extent unit="pages"><start>2177</start><end>2186</end><total>11</total></extent></part></relatedItem><identifier type="istex">28C8FFA08ABC3BA2D9EA00E5AE9C14069EDB31A8</identifier><identifier type="DOI">10.1111/j.1460-9568.2009.06764.x</identifier><identifier type="ArticleID">EJN6764</identifier><accessCondition type="use and reproduction" contentType="copyright">© The Authors (2009). Journal Compilation © Federation of European Neuroscience Societies and Blackwell Publishing Ltd</accessCondition><recordInfo><recordContentSource>WILEY</recordContentSource><recordOrigin>Blackwell Publishing Ltd</recordOrigin></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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