IRC-082451, a Novel Multitargeting Molecule, Reduces L-DOPA-Induced Dyskinesias in MPTP Parkinsonian Primates
Identifieur interne : 000809 ( Pmc/Curation ); précédent : 000808; suivant : 000810IRC-082451, a Novel Multitargeting Molecule, Reduces L-DOPA-Induced Dyskinesias in MPTP Parkinsonian Primates
Auteurs : Romina Aron Badin [France] ; Brigitte Spinnewyn [France] ; Marie-Claude Gaillard [France] ; Caroline Jan [France] ; Carole Malgorn [France] ; Nadja Van Camp [France] ; Frédéric Dollé [France] ; Martine Guillermier [France] ; Sabrina Boulet [France] ; Anne Bertrand [France] ; Marc Savasta [France] ; Michel Auguet [France] ; Emmanuel Brouillet [France] ; Pierre-Etienne Chabrier [France] ; Philippe Hantraye [France]Source :
- PLoS ONE [ 1932-6203 ] ; 2013.
Abstract
The development of dyskinesias following chronic L-DOPA replacement therapy remains a major problem in the long-term treatment of Parkinson’s disease. This study aimed at evaluating the effect of IRC-082451 (base of BN82451), a novel multitargeting hybrid molecule, on L-DOPA-induced dyskinesias (LIDs) and hypolocomotor activity in a non-human primate model of PD. IRC-082451 displays multiple properties: it inhibits neuronal excitotoxicity (sodium channel blocker), oxidative stress (antioxidant) and neuroinflammation (cyclooxygenase inhibitor) and is endowed with mitochondrial protective properties. Animals received daily MPTP injections until stably parkinsonian. A daily treatment with increasing doses of L-DOPA was administered to parkinsonian primates until the appearance of dyskinesias. Then, different treatment regimens and doses of IRC-082451 were tested and compared to the benchmark molecule amantadine. Primates were regularly filmed and videos were analyzed with specialized software. A novel approach combining the analysis of dyskinesias and locomotor activity was used to determine efficacy. This analysis yielded the quantification of the total distance travelled and the incidence of dyskinesias in 7 different body parts. A dose-dependent efficacy of IRC-082451 against dyskinesias was observed. The 5 mg/kg dose was best at attenuating the severity of fully established LIDs. Its effect was significantly different from that of amantadine since it increased spontaneous locomotor activity while reducing LIDs. This dose was effective both acutely and in a 5-day sub-chronic treatment. Moreover, positron emission tomography scans using radiolabelled dopamine demonstrated that there was no direct interference between treatment with IRC-082451 and dopamine metabolism in the brain. Finally, post-mortem analysis indicated that this reduction in dyskinesias was associated with changes in cFOS, FosB and ARC mRNA expression levels in the putamen. The data demonstrates the antidyskinetic efficacy of IRC-082451 in a primate model of PD with motor complications and opens the way to the clinical application of this treatment for the management of LIDs.
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DOI: 10.1371/journal.pone.0052680
PubMed: 23300984
PubMed Central: 3536787
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Fontenay-aux-Roses, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Molecular Imaging Research Center, Commissariat à l’énergie atomique, Fontenay-aux-Roses</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>URA CEA CNRS 2210, Commissariat à l’énergie atomique, Fontenay-aux-Roses, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>URA CEA CNRS 2210, Commissariat à l’énergie atomique, Fontenay-aux-Roses</wicri:regionArea></affiliation></author><author><name sortKey="Spinnewyn, Brigitte" sort="Spinnewyn, Brigitte" uniqKey="Spinnewyn B" first="Brigitte" last="Spinnewyn">Brigitte Spinnewyn</name><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>IPSEN Innovation, Les Ulis, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>IPSEN Innovation, Les Ulis</wicri:regionArea></affiliation></author><author><name sortKey="Gaillard, Marie Claude" sort="Gaillard, Marie Claude" uniqKey="Gaillard M" first="Marie-Claude" last="Gaillard">Marie-Claude Gaillard</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Molecular Imaging Research Center, Commissariat à l’énergie atomique, Fontenay-aux-Roses, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Molecular Imaging Research Center, Commissariat à l’énergie atomique, Fontenay-aux-Roses</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>URA CEA CNRS 2210, Commissariat à l’énergie atomique, Fontenay-aux-Roses, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>URA CEA CNRS 2210, Commissariat à l’énergie atomique, Fontenay-aux-Roses</wicri:regionArea></affiliation></author><author><name sortKey="Jan, Caroline" sort="Jan, Caroline" uniqKey="Jan C" first="Caroline" last="Jan">Caroline Jan</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Molecular Imaging Research Center, Commissariat à l’énergie atomique, Fontenay-aux-Roses, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Molecular Imaging Research Center, Commissariat à l’énergie atomique, Fontenay-aux-Roses</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>URA CEA CNRS 2210, Commissariat à l’énergie atomique, Fontenay-aux-Roses, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>URA CEA CNRS 2210, Commissariat à l’énergie atomique, Fontenay-aux-Roses</wicri:regionArea></affiliation></author><author><name sortKey="Malgorn, Carole" sort="Malgorn, Carole" uniqKey="Malgorn C" first="Carole" last="Malgorn">Carole Malgorn</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Molecular Imaging Research Center, Commissariat à l’énergie atomique, Fontenay-aux-Roses, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Molecular Imaging Research Center, Commissariat à l’énergie atomique, Fontenay-aux-Roses</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>URA CEA CNRS 2210, Commissariat à l’énergie atomique, Fontenay-aux-Roses, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>URA CEA CNRS 2210, Commissariat à l’énergie atomique, Fontenay-aux-Roses</wicri:regionArea></affiliation></author><author><name sortKey="Van Camp, Nadja" sort="Van Camp, Nadja" uniqKey="Van Camp N" first="Nadja" last="Van Camp">Nadja Van Camp</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Molecular Imaging Research Center, Commissariat à l’énergie atomique, Fontenay-aux-Roses, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Molecular Imaging Research Center, Commissariat à l’énergie atomique, Fontenay-aux-Roses</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>URA CEA CNRS 2210, Commissariat à l’énergie atomique, Fontenay-aux-Roses, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>URA CEA CNRS 2210, Commissariat à l’énergie atomique, Fontenay-aux-Roses</wicri:regionArea></affiliation></author><author><name sortKey="Dolle, Frederic" sort="Dolle, Frederic" uniqKey="Dolle F" first="Frédéric" last="Dollé">Frédéric Dollé</name><affiliation wicri:level="1"><nlm:aff id="aff4"><addr-line>Service Hospitalier Frédéric Joliot, Institut d’Imagerie BioMédicale – Commissariat à l’énergie atomique, Orsay, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Service Hospitalier Frédéric Joliot, Institut d’Imagerie BioMédicale – Commissariat à l’énergie atomique, Orsay</wicri:regionArea></affiliation></author><author><name sortKey="Guillermier, Martine" sort="Guillermier, Martine" uniqKey="Guillermier M" first="Martine" last="Guillermier">Martine Guillermier</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Molecular Imaging Research Center, Commissariat à l’énergie atomique, Fontenay-aux-Roses, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Molecular Imaging Research Center, Commissariat à l’énergie atomique, Fontenay-aux-Roses</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>URA CEA CNRS 2210, Commissariat à l’énergie atomique, Fontenay-aux-Roses, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>URA CEA CNRS 2210, Commissariat à l’énergie atomique, Fontenay-aux-Roses</wicri:regionArea></affiliation></author><author><name sortKey="Boulet, Sabrina" sort="Boulet, Sabrina" uniqKey="Boulet S" first="Sabrina" last="Boulet">Sabrina Boulet</name><affiliation wicri:level="1"><nlm:aff id="aff5"><addr-line>INSERM U836, Grenoble Institut des Neurosciences Team #10, Grenoble, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>INSERM U836, Grenoble Institut des Neurosciences Team #10, Grenoble</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff6"><addr-line>Université Joseph Fourier, Grenoble, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Université Joseph Fourier, Grenoble</wicri:regionArea></affiliation></author><author><name sortKey="Bertrand, Anne" sort="Bertrand, Anne" uniqKey="Bertrand A" first="Anne" last="Bertrand">Anne Bertrand</name><affiliation wicri:level="1"><nlm:aff id="aff5"><addr-line>INSERM U836, Grenoble Institut des Neurosciences Team #10, Grenoble, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>INSERM U836, Grenoble Institut des Neurosciences Team #10, Grenoble</wicri:regionArea></affiliation></author><author><name sortKey="Savasta, Marc" sort="Savasta, Marc" uniqKey="Savasta M" first="Marc" last="Savasta">Marc Savasta</name><affiliation wicri:level="1"><nlm:aff id="aff5"><addr-line>INSERM U836, Grenoble Institut des Neurosciences Team #10, Grenoble, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>INSERM U836, Grenoble Institut des Neurosciences Team #10, Grenoble</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff6"><addr-line>Université Joseph Fourier, Grenoble, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Université Joseph Fourier, Grenoble</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff7"><addr-line>Centre Hospitalier Universitaire, Grenoble, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Centre Hospitalier Universitaire, Grenoble</wicri:regionArea></affiliation></author><author><name sortKey="Auguet, Michel" sort="Auguet, Michel" uniqKey="Auguet M" first="Michel" last="Auguet">Michel Auguet</name><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>IPSEN Innovation, Les Ulis, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>IPSEN Innovation, Les Ulis</wicri:regionArea></affiliation></author><author><name sortKey="Brouillet, Emmanuel" sort="Brouillet, Emmanuel" uniqKey="Brouillet E" first="Emmanuel" last="Brouillet">Emmanuel Brouillet</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Molecular Imaging Research Center, Commissariat à l’énergie atomique, Fontenay-aux-Roses, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Molecular Imaging Research Center, Commissariat à l’énergie atomique, Fontenay-aux-Roses</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>URA CEA CNRS 2210, Commissariat à l’énergie atomique, Fontenay-aux-Roses, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>URA CEA CNRS 2210, Commissariat à l’énergie atomique, Fontenay-aux-Roses</wicri:regionArea></affiliation></author><author><name sortKey="Chabrier, Pierre Etienne" sort="Chabrier, Pierre Etienne" uniqKey="Chabrier P" first="Pierre-Etienne" last="Chabrier">Pierre-Etienne Chabrier</name><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>IPSEN Innovation, Les Ulis, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>IPSEN Innovation, Les Ulis</wicri:regionArea></affiliation></author><author><name sortKey="Hantraye, Philippe" sort="Hantraye, Philippe" uniqKey="Hantraye P" first="Philippe" last="Hantraye">Philippe Hantraye</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Molecular Imaging Research Center, Commissariat à l’énergie atomique, Fontenay-aux-Roses, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Molecular Imaging Research Center, Commissariat à l’énergie atomique, Fontenay-aux-Roses</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>URA CEA CNRS 2210, Commissariat à l’énergie atomique, Fontenay-aux-Roses, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>URA CEA CNRS 2210, Commissariat à l’énergie atomique, Fontenay-aux-Roses</wicri:regionArea></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2013">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>The development of dyskinesias following chronic L-DOPA replacement therapy remains a major problem in the long-term treatment of Parkinson’s disease. This study aimed at evaluating the effect of IRC-082451 (base of BN82451), a novel multitargeting hybrid molecule, on L-DOPA-induced dyskinesias (LIDs) and hypolocomotor activity in a non-human primate model of PD. IRC-082451 displays multiple properties: it inhibits neuronal excitotoxicity (sodium channel blocker), oxidative stress (antioxidant) and neuroinflammation (cyclooxygenase inhibitor) and is endowed with mitochondrial protective properties. Animals received daily MPTP injections until stably parkinsonian. A daily treatment with increasing doses of L-DOPA was administered to parkinsonian primates until the appearance of dyskinesias. Then, different treatment regimens and doses of IRC-082451 were tested and compared to the benchmark molecule amantadine. Primates were regularly filmed and videos were analyzed with specialized software. A novel approach combining the analysis of dyskinesias and locomotor activity was used to determine efficacy. This analysis yielded the quantification of the total distance travelled and the incidence of dyskinesias in 7 different body parts. A dose-dependent efficacy of IRC-082451 against dyskinesias was observed. The 5 mg/kg dose was best at attenuating the severity of fully established LIDs. Its effect was significantly different from that of amantadine since it increased spontaneous locomotor activity while reducing LIDs. This dose was effective both acutely and in a 5-day sub-chronic treatment. Moreover, positron emission tomography scans using radiolabelled dopamine demonstrated that there was no direct interference between treatment with IRC-082451 and dopamine metabolism in the brain. Finally, post-mortem analysis indicated that this reduction in dyskinesias was associated with changes in cFOS, FosB and ARC mRNA expression levels in the putamen. The data demonstrates the antidyskinetic efficacy of IRC-082451 in a primate model of PD with motor complications and opens the way to the clinical application of this treatment for the management of LIDs.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="De Lau, Lm" uniqKey="De Lau L">LM de Lau</name></author><author><name sortKey="Breteler, Mm" uniqKey="Breteler M">MM Breteler</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cotzias, Gc" uniqKey="Cotzias G">GC Cotzias</name></author><author><name sortKey="Papavasiliou, Ps" uniqKey="Papavasiliou P">PS Papavasiliou</name></author><author><name sortKey="Gellene, R" uniqKey="Gellene R">R Gellene</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Marsden, Cd" uniqKey="Marsden C">CD Marsden</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chase, Tn" uniqKey="Chase T">TN 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<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS One</journal-id><journal-id journal-id-type="iso-abbrev">PLoS ONE</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plosone</journal-id><journal-title-group><journal-title>PLoS ONE</journal-title></journal-title-group><issn pub-type="epub">1932-6203</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">23300984</article-id><article-id pub-id-type="pmc">3536787</article-id><article-id pub-id-type="publisher-id">PONE-D-12-23199</article-id><article-id pub-id-type="doi">10.1371/journal.pone.0052680</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="Discipline-v2"><subject>Biology</subject><subj-group><subject>Neuroscience</subject><subj-group><subject>Neuroimaging</subject><subj-group><subject>Pet</subject></subj-group></subj-group><subj-group><subject>Behavioral Neuroscience</subject><subject>Neurobiology of Disease and Regeneration</subject></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v2"><subject>Medicine</subject><subj-group><subject>Drugs and Devices</subject><subj-group><subject>Drug Research and Development</subject><subj-group><subject>Drug Discovery</subject></subj-group></subj-group></subj-group><subj-group><subject>Neurology</subject><subj-group><subject>Movement Disorders</subject><subject>Parkinson Disease</subject></subj-group></subj-group><subj-group><subject>Radiology</subject><subj-group><subject>Diagnostic Radiology</subject><subj-group><subject>Magnetic Resonance Imaging</subject></subj-group></subj-group></subj-group></subj-group></article-categories><title-group><article-title>IRC-082451, a Novel Multitargeting Molecule, Reduces L-DOPA-Induced Dyskinesias in MPTP Parkinsonian Primates</article-title><alt-title alt-title-type="running-head">New Anti-Dyskinetic Treatment for PD</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Aron Badin</surname><given-names>Romina</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff2"><sup>2</sup></xref><xref ref-type="corresp" rid="cor1"><sup>*</sup></xref></contrib><contrib contrib-type="author"><name><surname>Spinnewyn</surname><given-names>Brigitte</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Gaillard</surname><given-names>Marie-Claude</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Jan</surname><given-names>Caroline</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Malgorn</surname><given-names>Carole</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Van Camp</surname><given-names>Nadja</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Dollé</surname><given-names>Frédéric</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Guillermier</surname><given-names>Martine</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Boulet</surname><given-names>Sabrina</given-names></name><xref ref-type="aff" rid="aff5"><sup>5</sup></xref><xref ref-type="aff" rid="aff6"><sup>6</sup></xref></contrib><contrib contrib-type="author"><name><surname>Bertrand</surname><given-names>Anne</given-names></name><xref ref-type="aff" rid="aff5"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Savasta</surname><given-names>Marc</given-names></name><xref ref-type="aff" rid="aff5"><sup>5</sup></xref><xref ref-type="aff" rid="aff6"><sup>6</sup></xref><xref ref-type="aff" rid="aff7"><sup>7</sup></xref></contrib><contrib contrib-type="author"><name><surname>Auguet</surname><given-names>Michel</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Brouillet</surname><given-names>Emmanuel</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Chabrier</surname><given-names>Pierre-Etienne</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hantraye</surname><given-names>Philippe</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib></contrib-group><aff id="aff1"><label>1</label><addr-line>Molecular Imaging Research Center, Commissariat à l’énergie atomique, Fontenay-aux-Roses, France</addr-line></aff><aff id="aff2"><label>2</label><addr-line>URA CEA CNRS 2210, Commissariat à l’énergie atomique, Fontenay-aux-Roses, France</addr-line></aff><aff id="aff3"><label>3</label><addr-line>IPSEN Innovation, Les Ulis, France</addr-line></aff><aff id="aff4"><label>4</label><addr-line>Service Hospitalier Frédéric Joliot, Institut d’Imagerie BioMédicale – Commissariat à l’énergie atomique, Orsay, France</addr-line></aff><aff id="aff5"><label>5</label><addr-line>INSERM U836, Grenoble Institut des Neurosciences Team #10, Grenoble, France</addr-line></aff><aff id="aff6"><label>6</label><addr-line>Université Joseph Fourier, Grenoble, France</addr-line></aff><aff id="aff7"><label>7</label><addr-line>Centre Hospitalier Universitaire, Grenoble, France</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Sgambato-Faure</surname><given-names>Veronique</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1"><addr-line>INSERM/CNRS, France</addr-line></aff><author-notes><corresp id="cor1">* E-mail: <email>romina.aron-badin@cea.fr</email></corresp><fn fn-type="conflict"><p><bold>Competing Interests: </bold>The authors have declared that no competing interests exist.</p></fn><fn fn-type="con"><p>Conceived and designed the experiments: PH EB RAB PEC MA BS. Performed the experiments: RAB MG MCG CM CJ NVC. Analyzed the data: RAB BS SB AB MS. Contributed reagents/materials/analysis tools: MS BS. Wrote the paper: RAB. PET radiotracers synthesis: FD.</p></fn></author-notes><pub-date pub-type="collection"><year>2013</year></pub-date><pub-date pub-type="epub"><day>3</day><month>1</month><year>2013</year></pub-date><volume>8</volume><issue>1</issue><elocation-id>e52680</elocation-id><history><date date-type="received"><day>27</day><month>7</month><year>2012</year></date><date date-type="accepted"><day>19</day><month>11</month><year>2012</year></date></history><permissions><copyright-year>2013</copyright-year><copyright-holder>Aron Badin et al</copyright-holder><license><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</license-p></license></permissions><abstract><p>The development of dyskinesias following chronic L-DOPA replacement therapy remains a major problem in the long-term treatment of Parkinson’s disease. This study aimed at evaluating the effect of IRC-082451 (base of BN82451), a novel multitargeting hybrid molecule, on L-DOPA-induced dyskinesias (LIDs) and hypolocomotor activity in a non-human primate model of PD. IRC-082451 displays multiple properties: it inhibits neuronal excitotoxicity (sodium channel blocker), oxidative stress (antioxidant) and neuroinflammation (cyclooxygenase inhibitor) and is endowed with mitochondrial protective properties. Animals received daily MPTP injections until stably parkinsonian. A daily treatment with increasing doses of L-DOPA was administered to parkinsonian primates until the appearance of dyskinesias. Then, different treatment regimens and doses of IRC-082451 were tested and compared to the benchmark molecule amantadine. Primates were regularly filmed and videos were analyzed with specialized software. A novel approach combining the analysis of dyskinesias and locomotor activity was used to determine efficacy. This analysis yielded the quantification of the total distance travelled and the incidence of dyskinesias in 7 different body parts. A dose-dependent efficacy of IRC-082451 against dyskinesias was observed. The 5 mg/kg dose was best at attenuating the severity of fully established LIDs. Its effect was significantly different from that of amantadine since it increased spontaneous locomotor activity while reducing LIDs. This dose was effective both acutely and in a 5-day sub-chronic treatment. Moreover, positron emission tomography scans using radiolabelled dopamine demonstrated that there was no direct interference between treatment with IRC-082451 and dopamine metabolism in the brain. Finally, post-mortem analysis indicated that this reduction in dyskinesias was associated with changes in cFOS, FosB and ARC mRNA expression levels in the putamen. The data demonstrates the antidyskinetic efficacy of IRC-082451 in a primate model of PD with motor complications and opens the way to the clinical application of this treatment for the management of LIDs.</p></abstract><funding-group><funding-statement>The research reported in this manuscript has been funded by MIRCen and IPSEN Innovation (<ext-link ext-link-type="uri" xlink:href="http://www.ipsen.com/fr">http://www.ipsen.com/fr</ext-link>). The funders had no role in study design, data collection or decision to publish. Their support was requested for data analysis and their advice for preparation and critical evaluation of the manuscript.</funding-statement></funding-group><counts><page-count count="13"></page-count></counts></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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