title: IRC-082451, a novel multitargeting molecule, reduces L-DOPA-induced dyskinesias in MPTP Parkinsonian primates.
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.
authors.affiliation: Molecular Imaging Research Center, Commissariat à l'Énergie Atomique, Fontenay-aux-Roses, France. romina.aron-badin@cea.fr
authors.forename: Romina
authors.initials: R
authors.lastname: Aron Badin
authors.forename: Brigitte
authors.initials: B
authors.lastname: Spinnewyn
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Gaillard
authors.forename: Caroline
authors.initials: C
authors.lastname: Jan
authors.forename: Carole
authors.initials: C
authors.lastname: Malgorn
authors.forename: Nadja
authors.initials: N
authors.lastname: Van Camp
authors.forename: Frédéric
authors.initials: F
authors.lastname: Dollé
authors.forename: Martine
authors.initials: M
authors.lastname: Guillermier
authors.forename: Sabrina
authors.initials: S
authors.lastname: Boulet
authors.forename: Anne
authors.initials: A
authors.lastname: Bertrand
authors.forename: Marc
authors.initials: M
authors.lastname: Savasta
authors.forename: Michel
authors.initials: M
authors.lastname: Auguet
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Brouillet
authors.forename: Pierre-Etienne
authors.initials: PE
authors.lastname: Chabrier
authors.forename: Philippe
authors.initials: P
authors.lastname: Hantraye
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D000547:Amantadine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D000978:Antiparkinson Agents / Q000494:pharmacology*; D001522:Behavior, Animal; D002851:Chromatography, High Pressure Liquid; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000494:pharmacology; D020820:Dyskinesias / Q000378:metabolism*; D007150:Immunohistochemistry; D007980:Levodopa / Q000378:metabolism*; D008252:Macaca fascicularis; D008279:Magnetic Resonance Imaging; D008297:Male; D009474:Neurons / Q000187:drug effects; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000188:drug therapy*; D049268:Positron-Emission Tomography; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D000978:Antiparkinson Agents; D016861:Cyclooxygenase Inhibitors; D015259:Dopamine Agents; C582899:IRC-082451; D013844:Thiazoles; D007980:Levodopa; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000547:Amantadine