Riluzole prolongs survival time and alters nuclear inclusion formation in a transgenic mouse model of Huntington's disease
Identifieur interne : 004303 ( Main/Exploration ); précédent : 004302; suivant : 004304Riluzole 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.
Descripteurs français
- Pascal (Inist)
- Wicri :
- topic : Animal transgénique.
English descriptors
- KwdEn :
- Animal model, Animals, Antagonist, Benzothiazole, Cell Nucleus (genetics), Cell Nucleus (pathology), Cell Nucleus (physiology), Cell inclusion, Cell nucleus, Cerebral Cortex (pathology), Cerebral Cortex (physiopathology), Chemotherapy, Corpus Striatum (pathology), Corpus Striatum (physiopathology), Excitatory Amino Acid Antagonists (pharmacology), Exons, Glutamate receptor, Glutamic Acid (physiology), Humans, Huntington Disease (genetics), Huntington Disease (pathology), Huntington Disease (physiopathology), Huntington disease, Immunoenzyme Techniques, Immunohistochemistry, Mice, Mice, Transgenic, Motor Skills (physiology), Mouse, Nerve Tissue Proteins (genetics), Neuroprotective Agents (pharmacology), Neuroprotective agent, Nuclear Proteins (genetics), Prognosis, Riluzole, Riluzole (pharmacology), Survival, Survival Analysis, Transgenic animal, Treatment, Trinucleotide Repeats, excitotoxicity, glutamate antagonism, neurodegenerative disease, neuroprotection, polyglutamine disease.
- MESH :
- chemical , genetics : Nerve Tissue Proteins, Nuclear Proteins.
- chemical , pharmacology : Excitatory Amino Acid Antagonists, Neuroprotective Agents, Riluzole.
- genetics : Cell Nucleus, Huntington Disease.
- pathology : Cell Nucleus, Cerebral Cortex, Corpus Striatum, Huntington Disease.
- physiology : Cell Nucleus, Glutamic Acid, Motor Skills.
- physiopathology : Cerebral Cortex, Corpus Striatum, Huntington Disease.
- Animals, Exons, Humans, Immunoenzyme Techniques, Mice, Mice, Transgenic, Survival Analysis, Trinucleotide Repeats.
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
Url:
DOI: 10.1002/mds.10229
Affiliations:
- Allemagne
- Bade-Wurtemberg, District de Cologne, District de Tübingen, Rhénanie-du-Nord-Westphalie
- Aix-la-Chapelle, Ulm
- Université d'Ulm
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Le document en format XML
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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>Animal model</term><term>Animals</term><term>Antagonist</term><term>Benzothiazole</term><term>Cell Nucleus (genetics)</term><term>Cell Nucleus (pathology)</term><term>Cell Nucleus (physiology)</term><term>Cell inclusion</term><term>Cell nucleus</term><term>Cerebral Cortex (pathology)</term><term>Cerebral Cortex (physiopathology)</term><term>Chemotherapy</term><term>Corpus Striatum (pathology)</term><term>Corpus Striatum (physiopathology)</term><term>Excitatory Amino Acid Antagonists (pharmacology)</term><term>Exons</term><term>Glutamate receptor</term><term>Glutamic Acid (physiology)</term><term>Humans</term><term>Huntington Disease (genetics)</term><term>Huntington Disease (pathology)</term><term>Huntington Disease (physiopathology)</term><term>Huntington disease</term><term>Immunoenzyme Techniques</term><term>Immunohistochemistry</term><term>Mice</term><term>Mice, Transgenic</term><term>Motor Skills (physiology)</term><term>Mouse</term><term>Nerve Tissue Proteins (genetics)</term><term>Neuroprotective Agents (pharmacology)</term><term>Neuroprotective agent</term><term>Nuclear Proteins (genetics)</term><term>Prognosis</term><term>Riluzole</term><term>Riluzole (pharmacology)</term><term>Survival</term><term>Survival Analysis</term><term>Transgenic animal</term><term>Treatment</term><term>Trinucleotide Repeats</term><term>excitotoxicity</term><term>glutamate antagonism</term><term>neurodegenerative disease</term><term>neuroprotection</term><term>polyglutamine disease</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Nerve Tissue Proteins</term><term>Nuclear Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Excitatory Amino Acid Antagonists</term><term>Neuroprotective Agents</term><term>Riluzole</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Cell Nucleus</term><term>Huntington Disease</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Cell Nucleus</term><term>Cerebral Cortex</term><term>Corpus Striatum</term><term>Huntington Disease</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Cell Nucleus</term><term>Glutamic Acid</term><term>Motor Skills</term></keywords><keywords scheme="MESH" qualifier="physiopathology" xml:lang="en"><term>Cerebral Cortex</term><term>Corpus Striatum</term><term>Huntington Disease</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Exons</term><term>Humans</term><term>Immunoenzyme Techniques</term><term>Mice</term><term>Mice, Transgenic</term><term>Survival Analysis</term><term>Trinucleotide Repeats</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Animal transgénique</term><term>Antagoniste</term><term>Benzothiazole</term><term>Chimiothérapie</term><term>Chorée Huntington</term><term>Immunohistochimie</term><term>Inclusion cellulaire</term><term>Modèle animal</term><term>Neuroprotecteur</term><term>Noyau cellulaire</term><term>Pronostic</term><term>Riluzole</term><term>Récepteur glutamate</term><term>Souris</term><term>Survie</term><term>Traitement</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Animal transgénique</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><affiliations><list><country><li>Allemagne</li></country><region><li>Bade-Wurtemberg</li><li>District de Cologne</li><li>District de Tübingen</li><li>Rhénanie-du-Nord-Westphalie</li></region><settlement><li>Aix-la-Chapelle</li><li>Ulm</li></settlement><orgName><li>Université d'Ulm</li></orgName></list><tree><country name="Allemagne"><region name="Rhénanie-du-Nord-Westphalie"><name sortKey="Schiefer, Johannes" sort="Schiefer, Johannes" uniqKey="Schiefer J" first="Johannes" last="Schiefer">Johannes Schiefer</name></region><name sortKey="Kosinski, Christoph M" sort="Kosinski, Christoph M" uniqKey="Kosinski C" first="Christoph M." last="Kosinski">Christoph M. Kosinski</name><name sortKey="Landwehrmeyer, G Bernhard" sort="Landwehrmeyer, G Bernhard" uniqKey="Landwehrmeyer G" first="G. Bernhard" last="Landwehrmeyer">G. Bernhard Landwehrmeyer</name><name sortKey="Luesse, Hans Erd" sort="Luesse, Hans Erd" uniqKey="Luesse H" first="Hans-Gerd" last="Lüesse">Hans-Gerd Lüesse</name><name sortKey="Milkereit, Anna" sort="Milkereit, Anna" uniqKey="Milkereit A" first="Anna" last="Milkereit">Anna Milkereit</name><name sortKey="Milkereit, Eva" sort="Milkereit, Eva" uniqKey="Milkereit E" first="Eva" last="Milkereit">Eva Milkereit</name><name sortKey="Puls, Christiane" sort="Puls, Christiane" uniqKey="Puls C" first="Christiane" last="Puls">Christiane Puls</name><name sortKey="Sprunken, Arne" sort="Sprunken, Arne" uniqKey="Sprunken A" first="Arne" last="Sprünken">Arne Sprünken</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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