The Role of Glial Reaction and Inflammation in Parkinson's Disease
Identifieur interne : 001F05 ( Istex/Corpus ); précédent : 001F04; suivant : 001F06The Role of Glial Reaction and Inflammation in Parkinson's Disease
Auteurs : E. C. Hirsch ; T. Breidert ; E. Rousselet ; S. Hunot ; A. Hartmann ; P. P. MichelSource :
- Annals of the New York Academy of Sciences [ 0077-8923 ] ; 2003-06.
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Abstract
Abstract: The glial reaction is generally considered to be a consequence of neuronal death in neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, and Parkinson's disease. In Parkinson's disease, postmortem examination reveals a loss of dopaminergic neurons in the substantia nigra associated with a massive astrogliosis and the presence of activated microglial cells. Recent evidence suggests that the disease may progress even when the initial cause of neuronal degeneration has disappeared, suggesting that toxic substances released by the glial cells may be involved in the propagation and perpetuation of neuronal degeneration. Glial cells can release deleterious compounds such as proinflammatory cytokines (TNF‐α, Il‐1β, IFN‐γ), which may act by stimulating nitric oxide production in glial cells, or which may exert a more direct deleterious effect on dopaminergic neurons by activating receptors that contain intracytoplasmic death domains involved in apoptosis. In line with this possibility, an activation of proteases such as caspase‐3 and caspase‐8, which are known effectors of apoptosis, has been reported in Parkinson's disease. Yet, caspase inhibitors or invalidation of TNF‐α receptors does not protect dopaminergic neurons against degeneration in experimental models of the disease, suggesting that manipulation of a single signaling pathway may not be sufficient to protect dopaminergic neurons. In contrast, the antiinflammatory drugs pioglitazone, a PPAR‐γ agonist, and the tetracycline derivative minocycline have been shown to reduce glial activation and protect the substantia nigra in an animal model of the disease. Inhibition of the glial reaction and the inflammatory processes may thus represent a therapeutic target to reduce neuronal degeneration in Parkinson's disease.
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DOI: 10.1111/j.1749-6632.2003.tb07478.x
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Hirsch</name><affiliation><mods:affiliation>INSERM U289, Experimental Neurology and Therapeutics, Hôpital de la Salpêtrière, 75651 Paris Cedex 13, France</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: hirsch@ccr.jussieu.fr</mods:affiliation></affiliation></author><author><name sortKey="Breidert, T" sort="Breidert, T" uniqKey="Breidert T" first="T." last="Breidert">T. Breidert</name><affiliation><mods:affiliation>INSERM U289, Experimental Neurology and Therapeutics, Hôpital de la Salpêtrière, 75651 Paris Cedex 13, France</mods:affiliation></affiliation></author><author><name sortKey="Rousselet, E" sort="Rousselet, E" uniqKey="Rousselet E" first="E." last="Rousselet">E. Rousselet</name><affiliation><mods:affiliation>INSERM U289, Experimental Neurology and Therapeutics, Hôpital de la Salpêtrière, 75651 Paris Cedex 13, France</mods:affiliation></affiliation></author><author><name sortKey="Hunot, S" sort="Hunot, S" uniqKey="Hunot S" first="S." last="Hunot">S. Hunot</name><affiliation><mods:affiliation>INSERM U289, Experimental Neurology and Therapeutics, Hôpital de la Salpêtrière, 75651 Paris Cedex 13, France</mods:affiliation></affiliation></author><author><name sortKey="Hartmann, A" sort="Hartmann, A" uniqKey="Hartmann A" first="A." last="Hartmann">A. Hartmann</name><affiliation><mods:affiliation>INSERM U289, Experimental Neurology and Therapeutics, Hôpital de la Salpêtrière, 75651 Paris Cedex 13, France</mods:affiliation></affiliation></author><author><name sortKey="Michel, P P" sort="Michel, P P" uniqKey="Michel P" first="P. P." last="Michel">P. P. Michel</name><affiliation><mods:affiliation>INSERM U289, Experimental Neurology and Therapeutics, Hôpital de la Salpêtrière, 75651 Paris Cedex 13, France</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Annals of the New York Academy of Sciences</title><idno type="ISSN">0077-8923</idno><idno type="eISSN">1749-6632</idno><imprint><publisher>Blackwell Publishing Ltd</publisher><pubPlace>Oxford, UK</pubPlace><date type="published" when="2003-06">2003-06</date><biblScope unit="volume">991</biblScope><biblScope unit="issue">1</biblScope><biblScope unit="page" from="214">214</biblScope><biblScope unit="page" to="228">228</biblScope></imprint><idno type="ISSN">0077-8923</idno></series><idno type="istex">7EC790141B211503BA4D587100832AD9E681C8B0</idno><idno type="DOI">10.1111/j.1749-6632.2003.tb07478.x</idno><idno type="ArticleID">NYAS214</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0077-8923</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>apoptosis</term><term>cytokines</term><term>dopamine neuron</term><term>neuroprotection</term><term>substantia nigra</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract">Abstract: The glial reaction is generally considered to be a consequence of neuronal death in neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, and Parkinson's disease. In Parkinson's disease, postmortem examination reveals a loss of dopaminergic neurons in the substantia nigra associated with a massive astrogliosis and the presence of activated microglial cells. Recent evidence suggests that the disease may progress even when the initial cause of neuronal degeneration has disappeared, suggesting that toxic substances released by the glial cells may be involved in the propagation and perpetuation of neuronal degeneration. Glial cells can release deleterious compounds such as proinflammatory cytokines (TNF‐α, Il‐1β, IFN‐γ), which may act by stimulating nitric oxide production in glial cells, or which may exert a more direct deleterious effect on dopaminergic neurons by activating receptors that contain intracytoplasmic death domains involved in apoptosis. In line with this possibility, an activation of proteases such as caspase‐3 and caspase‐8, which are known effectors of apoptosis, has been reported in Parkinson's disease. Yet, caspase inhibitors or invalidation of TNF‐α receptors does not protect dopaminergic neurons against degeneration in experimental models of the disease, suggesting that manipulation of a single signaling pathway may not be sufficient to protect dopaminergic neurons. In contrast, the antiinflammatory drugs pioglitazone, a PPAR‐γ agonist, and the tetracycline derivative minocycline have been shown to reduce glial activation and protect the substantia nigra in an animal model of the disease. Inhibition of the glial reaction and the inflammatory processes may thus represent a therapeutic target to reduce neuronal degeneration in Parkinson's disease.</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>E. C. HIRSCH</name><affiliations><json:string>INSERM U289, Experimental Neurology and Therapeutics, Hôpital de la Salpêtrière, 75651 Paris Cedex 13, France</json:string><json:string>E-mail: hirsch@ccr.jussieu.fr</json:string></affiliations></json:item><json:item><name>T. BREIDERT</name><affiliations><json:string>INSERM U289, Experimental Neurology and Therapeutics, Hôpital de la Salpêtrière, 75651 Paris Cedex 13, France</json:string></affiliations></json:item><json:item><name>E. ROUSSELET</name><affiliations><json:string>INSERM U289, Experimental Neurology and Therapeutics, Hôpital de la Salpêtrière, 75651 Paris Cedex 13, France</json:string></affiliations></json:item><json:item><name>S. HUNOT</name><affiliations><json:string>INSERM U289, Experimental Neurology and Therapeutics, Hôpital de la Salpêtrière, 75651 Paris Cedex 13, France</json:string></affiliations></json:item><json:item><name>A. HARTMANN</name><affiliations><json:string>INSERM U289, Experimental Neurology and Therapeutics, Hôpital de la Salpêtrière, 75651 Paris Cedex 13, France</json:string></affiliations></json:item><json:item><name>P. P. MICHEL</name><affiliations><json:string>INSERM U289, Experimental Neurology and Therapeutics, Hôpital de la Salpêtrière, 75651 Paris Cedex 13, France</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>cytokines</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>neuroprotection</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>apoptosis</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>dopamine neuron</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>substantia nigra</value></json:item></subject><articleId><json:string>NYAS214</json:string></articleId><language><json:string>eng</json:string></language><originalGenre><json:string>article</json:string></originalGenre><abstract>Abstract: The glial reaction is generally considered to be a consequence of neuronal death in neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, and Parkinson's disease. In Parkinson's disease, postmortem examination reveals a loss of dopaminergic neurons in the substantia nigra associated with a massive astrogliosis and the presence of activated microglial cells. Recent evidence suggests that the disease may progress even when the initial cause of neuronal degeneration has disappeared, suggesting that toxic substances released by the glial cells may be involved in the propagation and perpetuation of neuronal degeneration. Glial cells can release deleterious compounds such as proinflammatory cytokines (TNF‐α, Il‐1β, IFN‐γ), which may act by stimulating nitric oxide production in glial cells, or which may exert a more direct deleterious effect on dopaminergic neurons by activating receptors that contain intracytoplasmic death domains involved in apoptosis. In line with this possibility, an activation of proteases such as caspase‐3 and caspase‐8, which are known effectors of apoptosis, has been reported in Parkinson's disease. Yet, caspase inhibitors or invalidation of TNF‐α receptors does not protect dopaminergic neurons against degeneration in experimental models of the disease, suggesting that manipulation of a single signaling pathway may not be sufficient to protect dopaminergic neurons. In contrast, the antiinflammatory drugs pioglitazone, a PPAR‐γ agonist, and the tetracycline derivative minocycline have been shown to reduce glial activation and protect the substantia nigra in an animal model of the disease. Inhibition of the glial reaction and the inflammatory processes may thus represent a therapeutic target to reduce neuronal degeneration in Parkinson's disease.</abstract><qualityIndicators><score>8</score><pdfVersion>1.3</pdfVersion><pdfPageSize>595 x 842 pts (A4)</pdfPageSize><refBibsNative>true</refBibsNative><abstractCharCount>1827</abstractCharCount><pdfWordCount>5995</pdfWordCount><pdfCharCount>39161</pdfCharCount><pdfPageCount>16</pdfPageCount><abstractWordCount>256</abstractWordCount></qualityIndicators><title>The Role of Glial Reaction and Inflammation in Parkinson's Disease</title><refBibs><json:item><author><json:item><name>E.C. Hirsch</name></json:item></author><host><volume>334</volume><pages><last>348</last><first>345</first></pages><author></author><title>Nature</title></host><title>Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson's disease</title></json:item><json:item><author><json:item><name>R. 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C.</forename><surname>HIRSCH</surname></persName><email>hirsch@ccr.jussieu.fr</email><affiliation>INSERM U289, Experimental Neurology and Therapeutics, Hôpital de la Salpêtrière, 75651 Paris Cedex 13, France</affiliation></author><author xml:id="author-2"><persName><forename type="first">T.</forename><surname>BREIDERT</surname></persName><affiliation>INSERM U289, Experimental Neurology and Therapeutics, Hôpital de la Salpêtrière, 75651 Paris Cedex 13, France</affiliation></author><author xml:id="author-3"><persName><forename type="first">E.</forename><surname>ROUSSELET</surname></persName><affiliation>INSERM U289, Experimental Neurology and Therapeutics, Hôpital de la Salpêtrière, 75651 Paris Cedex 13, France</affiliation></author><author xml:id="author-4"><persName><forename type="first">S.</forename><surname>HUNOT</surname></persName><affiliation>INSERM U289, Experimental Neurology and Therapeutics, Hôpital de la Salpêtrière, 75651 Paris Cedex 13, France</affiliation></author><author xml:id="author-5"><persName><forename type="first">A.</forename><surname>HARTMANN</surname></persName><affiliation>INSERM U289, Experimental Neurology and Therapeutics, Hôpital de la Salpêtrière, 75651 Paris Cedex 13, France</affiliation></author><author xml:id="author-6"><persName><forename type="first">P. P.</forename><surname>MICHEL</surname></persName><affiliation>INSERM U289, Experimental Neurology and Therapeutics, Hôpital de la Salpêtrière, 75651 Paris Cedex 13, France</affiliation></author></analytic><monogr><title level="j">Annals of the New York Academy of Sciences</title><idno type="pISSN">0077-8923</idno><idno type="eISSN">1749-6632</idno><idno type="DOI">10.1111/(ISSN)1749-6632</idno><imprint><publisher>Blackwell Publishing Ltd</publisher><pubPlace>Oxford, UK</pubPlace><date type="published" when="2003-06"></date><biblScope unit="volume">991</biblScope><biblScope unit="issue">1</biblScope><biblScope unit="page" from="214">214</biblScope><biblScope unit="page" to="228">228</biblScope></imprint></monogr><idno type="istex">7EC790141B211503BA4D587100832AD9E681C8B0</idno><idno type="DOI">10.1111/j.1749-6632.2003.tb07478.x</idno><idno type="ArticleID">NYAS214</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2003</date></creation><langUsage><language ident="en">en</language></langUsage><abstract><p>Abstract: The glial reaction is generally considered to be a consequence of neuronal death in neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, and Parkinson's disease. In Parkinson's disease, postmortem examination reveals a loss of dopaminergic neurons in the substantia nigra associated with a massive astrogliosis and the presence of activated microglial cells. Recent evidence suggests that the disease may progress even when the initial cause of neuronal degeneration has disappeared, suggesting that toxic substances released by the glial cells may be involved in the propagation and perpetuation of neuronal degeneration. Glial cells can release deleterious compounds such as proinflammatory cytokines (TNF‐α, Il‐1β, IFN‐γ), which may act by stimulating nitric oxide production in glial cells, or which may exert a more direct deleterious effect on dopaminergic neurons by activating receptors that contain intracytoplasmic death domains involved in apoptosis. In line with this possibility, an activation of proteases such as caspase‐3 and caspase‐8, which are known effectors of apoptosis, has been reported in Parkinson's disease. Yet, caspase inhibitors or invalidation of TNF‐α receptors does not protect dopaminergic neurons against degeneration in experimental models of the disease, suggesting that manipulation of a single signaling pathway may not be sufficient to protect dopaminergic neurons. In contrast, the antiinflammatory drugs pioglitazone, a PPAR‐γ agonist, and the tetracycline derivative minocycline have been shown to reduce glial activation and protect the substantia nigra in an animal model of the disease. Inhibition of the glial reaction and the inflammatory processes may thus represent a therapeutic target to reduce neuronal degeneration in Parkinson's disease.</p></abstract><textClass xml:lang="en"><keywords scheme="keyword"><list><head>keywords</head><item><term>cytokines</term></item><item><term>neuroprotection</term></item><item><term>apoptosis</term></item><item><term>dopamine neuron</term></item><item><term>substantia nigra</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2003-06">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/document/7EC790141B211503BA4D587100832AD9E681C8B0/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)1749-6632</doi><issn type="print">0077-8923</issn><issn type="electronic">1749-6632</issn><idGroup><id type="product" value="NYAS"></id><id type="publisherDivision" value="ST"></id></idGroup><titleGroup><title type="main" sort="ANNALS OF NEW YORK ACADEMY SCIENCES">Annals of the New York Academy of Sciences</title></titleGroup></publicationMeta><publicationMeta level="part" position="06001"><doi origin="wiley">10.1111/nyas.2003.991.issue-1</doi><titleGroup><title type="main">PARKINSON'S DISEASE: The Life Cycle of the Dopamine Neuron</title></titleGroup><numberingGroup><numbering type="journalVolume" number="991">991</numbering><numbering type="journalIssue">1</numbering></numberingGroup><coverDate startDate="2003-06">June 2003</coverDate></publicationMeta><publicationMeta level="unit" type="article" position="22" status="forIssue"><doi origin="wiley">10.1111/j.1749-6632.2003.tb07478.x</doi><idGroup><id type="unit" value="NYAS214"></id></idGroup><countGroup><count type="pageTotal" number="15"></count></countGroup><titleGroup><title type="tocHeading1">Parkinson's Disease: The Life Cycle of the Dopamine Neuron: Part V. From Molecules to Organism: The Organism</title></titleGroup><eventGroup><event type="firstOnline" date="2006-01-24"></event><event type="publishedOnlineFinalForm" date="2006-01-24"></event><event type="xmlConverted" agent="Converter:BPG_TO_WML3G version:2.3.5 mode:FullText source:FullText result:FullText" date="2010-04-09"></event><event type="xmlConverted" agent="Converter:WILEY_ML3G_TO_WILEY_ML3GV2 version:4.0.1" date="2014-03-19"></event><event type="xmlConverted" agent="Converter:WML3G_To_WML3G version:4.1.7 mode:FullText,remove_FC" date="2014-10-14"></event></eventGroup><numberingGroup><numbering type="pageFirst" number="214">214</numbering><numbering type="pageLast" number="228">228</numbering></numberingGroup><correspondenceTo>Address for correspondence: E.C. Hirsch, INSERM U289, Experimental Neurology and Therapeutics, Hôpital de la Salpêtrière, 47 boulevard de l'Hôpital, 75651 Paris Cedex 13, France. Voice: +33 (0) 1 42 16 22 02; fax: + 33 (0) 1 44 24 36 58. <email>hirsch@ccr.jussieu.fr</email></correspondenceTo><linkGroup><link type="toTypesetVersion" href="file:NYAS.NYAS214.pdf"></link></linkGroup></publicationMeta><contentMeta><countGroup><count type="figureTotal" number="0"></count><count type="tableTotal" number="2"></count><count type="formulaTotal" number="0"></count><count type="referenceTotal" number="72"></count><count type="linksCrossRef" number="60"></count></countGroup><titleGroup><title type="main">The Role of Glial Reaction and Inflammation in Parkinson's Disease</title></titleGroup><creators><creator creatorRole="author" xml:id="cr1" affiliationRef="#a1" corresponding="yes"><personName><givenNames>E. C.</givenNames><familyName>HIRSCH</familyName></personName></creator><creator creatorRole="author" xml:id="cr2" affiliationRef="#a1"><personName><givenNames>T.</givenNames><familyName>BREIDERT</familyName></personName></creator><creator creatorRole="author" xml:id="cr3" affiliationRef="#a1"><personName><givenNames>E.</givenNames><familyName>ROUSSELET</familyName></personName></creator><creator creatorRole="author" xml:id="cr4" affiliationRef="#a1"><personName><givenNames>S.</givenNames><familyName>HUNOT</familyName></personName></creator><creator creatorRole="author" xml:id="cr5" affiliationRef="#a1"><personName><givenNames>A.</givenNames><familyName>HARTMANN</familyName></personName></creator><creator creatorRole="author" xml:id="cr6" affiliationRef="#a1"><personName><givenNames>P. P.</givenNames><familyName>MICHEL</familyName></personName></creator></creators><affiliationGroup><affiliation xml:id="a1" countryCode="FR"><unparsedAffiliation>INSERM U289, Experimental Neurology and Therapeutics, Hôpital de la Salpêtrière, 75651 Paris Cedex 13, France</unparsedAffiliation></affiliation></affiliationGroup><keywordGroup xml:lang="en"><keyword xml:id="k1">cytokines</keyword><keyword xml:id="k2">neuroprotection</keyword><keyword xml:id="k3">apoptosis</keyword><keyword xml:id="k4">dopamine neuron</keyword><keyword xml:id="k5">substantia nigra</keyword></keywordGroup><abstractGroup><abstract type="main" xml:lang="en"><p><b>A<sc>bstract</sc>: </b> The glial reaction is generally considered to be a consequence of neuronal death in neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, and Parkinson's disease. In Parkinson's disease, postmortem examination reveals a loss of dopaminergic neurons in the substantia nigra associated with a massive astrogliosis and the presence of activated microglial cells. Recent evidence suggests that the disease may progress even when the initial cause of neuronal degeneration has disappeared, suggesting that toxic substances released by the glial cells may be involved in the propagation and perpetuation of neuronal degeneration. Glial cells can release deleterious compounds such as proinflammatory cytokines (TNF‐α, Il‐1β, IFN‐γ), which may act by stimulating nitric oxide production in glial cells, or which may exert a more direct deleterious effect on dopaminergic neurons by activating receptors that contain intracytoplasmic death domains involved in apoptosis. In line with this possibility, an activation of proteases such as caspase‐3 and caspase‐8, which are known effectors of apoptosis, has been reported in Parkinson's disease. Yet, caspase inhibitors or invalidation of TNF‐α receptors does not protect dopaminergic neurons against degeneration in experimental models of the disease, suggesting that manipulation of a single signaling pathway may not be sufficient to protect dopaminergic neurons. In contrast, the antiinflammatory drugs pioglitazone, a PPAR‐γ agonist, and the tetracycline derivative minocycline have been shown to reduce glial activation and protect the substantia nigra in an animal model of the disease. Inhibition of the glial reaction and the inflammatory processes may thus represent a therapeutic target to reduce neuronal degeneration in Parkinson's disease.</p></abstract></abstractGroup></contentMeta></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>The Role of Glial Reaction and Inflammation in Parkinson's Disease</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>The Role of Glial Reaction and Inflammation in Parkinson's Disease</title></titleInfo><name type="personal"><namePart type="given">E. C.</namePart><namePart type="family">HIRSCH</namePart><affiliation>INSERM U289, Experimental Neurology and Therapeutics, Hôpital de la Salpêtrière, 75651 Paris Cedex 13, France</affiliation><affiliation>E-mail: hirsch@ccr.jussieu.fr</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">T.</namePart><namePart type="family">BREIDERT</namePart><affiliation>INSERM U289, Experimental Neurology and Therapeutics, Hôpital de la Salpêtrière, 75651 Paris Cedex 13, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">E.</namePart><namePart type="family">ROUSSELET</namePart><affiliation>INSERM U289, Experimental Neurology and Therapeutics, Hôpital de la Salpêtrière, 75651 Paris Cedex 13, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">S.</namePart><namePart type="family">HUNOT</namePart><affiliation>INSERM U289, Experimental Neurology and Therapeutics, Hôpital de la Salpêtrière, 75651 Paris Cedex 13, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">A.</namePart><namePart type="family">HARTMANN</namePart><affiliation>INSERM U289, Experimental Neurology and Therapeutics, Hôpital de la Salpêtrière, 75651 Paris Cedex 13, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">P. P.</namePart><namePart type="family">MICHEL</namePart><affiliation>INSERM U289, Experimental Neurology and Therapeutics, Hôpital de la Salpêtrière, 75651 Paris Cedex 13, France</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">2003-06</dateIssued><copyrightDate encoding="w3cdtf">2003</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="tables">2</extent><extent unit="references">72</extent></physicalDescription><abstract>Abstract: The glial reaction is generally considered to be a consequence of neuronal death in neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, and Parkinson's disease. In Parkinson's disease, postmortem examination reveals a loss of dopaminergic neurons in the substantia nigra associated with a massive astrogliosis and the presence of activated microglial cells. Recent evidence suggests that the disease may progress even when the initial cause of neuronal degeneration has disappeared, suggesting that toxic substances released by the glial cells may be involved in the propagation and perpetuation of neuronal degeneration. Glial cells can release deleterious compounds such as proinflammatory cytokines (TNF‐α, Il‐1β, IFN‐γ), which may act by stimulating nitric oxide production in glial cells, or which may exert a more direct deleterious effect on dopaminergic neurons by activating receptors that contain intracytoplasmic death domains involved in apoptosis. In line with this possibility, an activation of proteases such as caspase‐3 and caspase‐8, which are known effectors of apoptosis, has been reported in Parkinson's disease. Yet, caspase inhibitors or invalidation of TNF‐α receptors does not protect dopaminergic neurons against degeneration in experimental models of the disease, suggesting that manipulation of a single signaling pathway may not be sufficient to protect dopaminergic neurons. In contrast, the antiinflammatory drugs pioglitazone, a PPAR‐γ agonist, and the tetracycline derivative minocycline have been shown to reduce glial activation and protect the substantia nigra in an animal model of the disease. Inhibition of the glial reaction and the inflammatory processes may thus represent a therapeutic target to reduce neuronal degeneration in Parkinson's disease.</abstract><subject lang="en"><genre>keywords</genre><topic>cytokines</topic><topic>neuroprotection</topic><topic>apoptosis</topic><topic>dopamine neuron</topic><topic>substantia nigra</topic></subject><relatedItem type="host"><titleInfo><title>Annals of the New York Academy of Sciences</title></titleInfo><genre type="journal">journal</genre><identifier type="ISSN">0077-8923</identifier><identifier type="eISSN">1749-6632</identifier><identifier type="DOI">10.1111/(ISSN)1749-6632</identifier><identifier type="PublisherID">NYAS</identifier><part><date>2003</date><detail type="title"><title>PARKINSON'S DISEASE: The Life Cycle of the Dopamine Neuron</title></detail><detail type="volume"><caption>vol.</caption><number>991</number></detail><detail type="issue"><caption>no.</caption><number>1</number></detail><extent unit="pages"><start>214</start><end>228</end><total>15</total></extent></part></relatedItem><identifier type="istex">7EC790141B211503BA4D587100832AD9E681C8B0</identifier><identifier type="DOI">10.1111/j.1749-6632.2003.tb07478.x</identifier><identifier type="ArticleID">NYAS214</identifier><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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