IRC-082451, a novel multitargeting molecule, reduces L-DOPA-induced dyskinesias in MPTP Parkinsonian primates
| العنوان: | IRC-082451, a novel multitargeting molecule, reduces L-DOPA-induced dyskinesias in MPTP Parkinsonian primates |
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| المؤلفون: | Aron Badin, Romina, Spinnewyn, Brigitte, Gaillard, Marie-Claude, Jan, Caroline, Malgorn, Carole, Van Camp, Nadja, Dollé, Frédéric, Guillermier, Martine, Boulet, Sabrina, Bertrand, Anne, Savasta, Marc, Auguet, Michel, Brouillet, Emmanuel, Chabrier, Pierre-Etienne, Hantraye, Philippe |
| المساهمون: | Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), IPSEN Innovation, Service Hospitalier Frédéric Joliot (SHFJ), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), INSERM U836, équipe 10, Dynamique des réseaux neuronaux du mouvement, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), IPSEN Innovation-IPSEN Innovation, The research reported in this manuscript has been funded by MIRCen and IPSEN Innovation (http://www.ipsen.com/fr). 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., Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS) |
| المصدر: | PLoS ONE PLoS ONE, Public Library of Science, 2013, 8 (1), pp.e52680. ⟨10.1371/journal.pone.0052680⟩ PLoS ONE, 2013, 8 (1), pp.e52680. ⟨10.1371/journal.pone.0052680⟩ |
| بيانات النشر: | HAL CCSD, 2013. |
| سنة النشر: | 2013 |
| مصطلحات موضوعية: | MESH: Levodopa, MESH: Oxidative Stress, MESH: Dyskinesias, MESH: Antioxidants, MESH: Antiparkinson Agents, MESH: Neurons, MESH: Dopamine Agents, MESH: Thiazoles, MESH: Immunohistochemistry, MESH: Amantadine, MESH: Male, MESH: Positron-Emission Tomography, nervous system diseases, MESH: Magnetic Resonance Imaging, MESH: Cyclooxygenase Inhibitors, MESH: Macaca fascicularis, MESH: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, MESH: Behavior, Animal, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], MESH: Animals, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Disease Models, Animal, MESH: Chromatography, High Pressure Liquid, MESH: Parkinson Disease |
| الوصف: | International audience; 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. |
| اللغة: | English |
| تدمد: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0052680⟩ |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=dedup_wf_001::4950abb110b169e4d11b715fa6bac069 https://www.hal.inserm.fr/inserm-00857944 |
| رقم الانضمام: | edsair.dedup.wf.001..4950abb110b169e4d11b715fa6bac069 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19326203 |
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| DOI: | 10.1371/journal.pone.0052680⟩ |