Riluzole prolongs survival time and alters nuclear inclusion formation in a transgenic mouse model of Huntington's disease
Identifieur interne : 000019 ( Istex/Curation ); précédent : 000018; suivant : 000020Riluzole prolongs survival time and alters nuclear inclusion formation in a transgenic mouse model of Huntington's disease
Auteurs : Johannes Schiefer [Allemagne] ; G. Bernhard Landwehrmeyer [Allemagne] ; Hans-Gerd Lüesse [Allemagne] ; Arne Sprünken [Allemagne] ; Christiane Puls [Allemagne] ; Anna Milkereit [Allemagne] ; Eva Milkereit [Allemagne] ; Christoph M. Kosinski [Allemagne]Source :
- Movement Disorders [ 0885-3185 ] ; 2002-07.
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Abstract
Glutamate excitotoxicity has been suggested to contribute to the pathogenesis of Huntington's disease (HD). Riluzole is a substance with glutamate antagonistic properties that is used for neuroprotective treatment in amyotrophic lateral sclerosis and which is currently tested in clinical trials for treatment of HD. R6/2 transgenic mice, which express exon 1 of the human HD gene with an expanded CAG triplet repeat, serve as a well‐characterized mouse model for HD with progressing neurological abnormalities and limited survival. We treated R6/2 HD transgenic mice with riluzole orally beginning at a presymptomatic stage until death to investigate its potential neuroprotective effects in this mouse model and found that survival time in the riluzole group was significantly increased in comparison to placebo‐treated transgenic controls. Additionally, the progressive weight loss was delayed and significantly reduced by riluzole treatment; behavioral testing of motor coordination and spontaneous locomotor activity, however, showed no statistically significant differences. We also examined the formation of the HD characteristic neuronal intranuclear inclusions (NII) immunohistologically. At a late disease stage, striatal NII from riluzole‐treated transgenic mice showed profound changes in ubiquitination, i.e., NII were less ubiquitinated and surrounded by ubiquitinated micro‐aggregates. Staining with antibodies directed against the mutated huntingtin revealed no significant difference in this component of NII. Taken together, these data suggest that riluzole is a promising candidate for neuroprotective treatment in human HD. © 2002 Movement Disorder Society
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DOI: 10.1002/mds.10229
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Bernhard Landwehrmeyer</name><affiliation wicri:level="1"><mods:affiliation>University of Ulm, Department of Neurology, Ulm, Germany</mods:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>University of Ulm, Department of Neurology, Ulm</wicri:regionArea></affiliation></author><author><name sortKey="Luesse, Hans Erd" sort="Luesse, Hans Erd" uniqKey="Luesse H" first="Hans-Gerd" last="Lüesse">Hans-Gerd Lüesse</name><affiliation wicri:level="1"><mods:affiliation>University Hospital RWTH Aachen, Department of Neurology, Aachen, Germany</mods:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>University Hospital RWTH Aachen, Department of Neurology, Aachen</wicri:regionArea></affiliation></author><author><name sortKey="Sprunken, Arne" sort="Sprunken, Arne" uniqKey="Sprunken A" first="Arne" last="Sprünken">Arne Sprünken</name><affiliation wicri:level="1"><mods:affiliation>University Hospital RWTH Aachen, Department of Neurology, Aachen, Germany</mods:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>University Hospital RWTH Aachen, Department of Neurology, Aachen</wicri:regionArea></affiliation></author><author><name sortKey="Puls, Christiane" sort="Puls, Christiane" uniqKey="Puls C" first="Christiane" last="Puls">Christiane Puls</name><affiliation wicri:level="1"><mods:affiliation>University Hospital RWTH Aachen, Department of Neurology, Aachen, Germany</mods:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>University Hospital RWTH Aachen, Department of Neurology, Aachen</wicri:regionArea></affiliation></author><author><name sortKey="Milkereit, Anna" sort="Milkereit, Anna" uniqKey="Milkereit A" first="Anna" last="Milkereit">Anna Milkereit</name><affiliation wicri:level="1"><mods:affiliation>University Hospital RWTH Aachen, Department of Neurology, Aachen, Germany</mods:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>University Hospital RWTH Aachen, Department of Neurology, Aachen</wicri:regionArea></affiliation></author><author><name sortKey="Milkereit, Eva" sort="Milkereit, Eva" uniqKey="Milkereit E" first="Eva" last="Milkereit">Eva Milkereit</name><affiliation wicri:level="1"><mods:affiliation>University Hospital RWTH Aachen, Department of Neurology, Aachen, Germany</mods:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>University Hospital RWTH Aachen, Department of Neurology, Aachen</wicri:regionArea></affiliation></author><author><name sortKey="Kosinski, Christoph M" sort="Kosinski, Christoph M" uniqKey="Kosinski C" first="Christoph M." last="Kosinski">Christoph M. 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Disord.</title><idno type="ISSN">0885-3185</idno><idno type="eISSN">1531-8257</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>New York</pubPlace><date type="published" when="2002-07">2002-07</date><biblScope unit="vol">17</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="748">748</biblScope><biblScope unit="page" to="757">757</biblScope></imprint><idno type="ISSN">0885-3185</idno></series><idno type="istex">1CC05411A34792F85059884719BD40FA39186252</idno><idno type="DOI">10.1002/mds.10229</idno><idno type="ArticleID">MDS10229</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0885-3185</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>excitotoxicity</term><term>glutamate antagonism</term><term>neurodegenerative disease</term><term>neuroprotection</term><term>polyglutamine disease</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Glutamate excitotoxicity has been suggested to contribute to the pathogenesis of Huntington's disease (HD). Riluzole is a substance with glutamate antagonistic properties that is used for neuroprotective treatment in amyotrophic lateral sclerosis and which is currently tested in clinical trials for treatment of HD. R6/2 transgenic mice, which express exon 1 of the human HD gene with an expanded CAG triplet repeat, serve as a well‐characterized mouse model for HD with progressing neurological abnormalities and limited survival. We treated R6/2 HD transgenic mice with riluzole orally beginning at a presymptomatic stage until death to investigate its potential neuroprotective effects in this mouse model and found that survival time in the riluzole group was significantly increased in comparison to placebo‐treated transgenic controls. Additionally, the progressive weight loss was delayed and significantly reduced by riluzole treatment; behavioral testing of motor coordination and spontaneous locomotor activity, however, showed no statistically significant differences. We also examined the formation of the HD characteristic neuronal intranuclear inclusions (NII) immunohistologically. At a late disease stage, striatal NII from riluzole‐treated transgenic mice showed profound changes in ubiquitination, i.e., NII were less ubiquitinated and surrounded by ubiquitinated micro‐aggregates. Staining with antibodies directed against the mutated huntingtin revealed no significant difference in this component of NII. Taken together, these data suggest that riluzole is a promising candidate for neuroprotective treatment in human HD. © 2002 Movement Disorder Society</div></front></TEI></record>Pour manipuler ce document sous Unix (Dilib)
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