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NEUROPHARMACOLOGY

Levetiracetam Potentiates the Antidyskinetic Action of Amantadine in the 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-Lesioned Primate Model of Parkinson's Disease

Motac Neuroscience Ltd, Manchester, United Kingdom (M.P.H., P.R., A.R.C.); Basal Gang, Laboratoire de Neurophysiologie, Universite Victor Segalen-Bordeaux 2, Bordeaux, France (E.B.); University of Manchester, School of Biological Sciences, Manchester, United Kingdom (A.R.C.); Toronto Western Research Institute, Toronto Western Hospital, Toronto, Canada (J.M.B.); and UCB S.A., Pharma Sector, Preclinical CNS Research, Braine L'Alleud, Belgium (A.M., R.G., H.K.)

Levetiracetam (LEV) (Keppra; UCB Pharma, Brussels, Belgium) has recently been reported to have antidyskinetic activity against levodopa (L-DOPA)-induced dyskinesia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset and macaque models of Parkinson's disease. Amantadine is frequently used as adjunctive therapy for L-DOPA-induced dyskinesia, but adverse effects limit its clinical utility. The current study was designed to investigate whether LEV can potentiate the antidyskinetic action of amantadine. The antiparkinsonian and antidyskinetic effects of LEV (13 and 60 mg/kg) and amantadine (0.01, 0.03, 0.1, and 0.3 mg/kg), administered alone and in combination, were assessed in the MPTP-lesioned marmoset model of L-DOPA-induced dyskinesia (n = 12). LEV (60 mg/kg) and amantadine (0.3 mg/kg) administered alone significantly reduced L-DOPA-induced dyskinesia without compromising the antiparkinsonian action of L-DOPA. Lower doses were without any significant effects. The combination of LEV (60 mg/kg) and amantadine (0.01, 0.03, 0.1, and 0.3 mg/kg) significantly decreased dyskinesia severity, without compromising the antiparkinsonian action of L-DOPA, more efficaciously than LEV or amantadine monotherapy. These results support the concept that normalization of different pathophysiological mechanisms (i.e., altered synchronization between neurons and enhanced N-methyl-D-aspartate transmission) has a greater efficacy. Combined LEV/amantadine therapy might be useful as an adjunct to L-DOPA to treat dyskinetic side effects and to expand the population of Parkinson's disease patients who benefit from treatment with amantadine alone.

Address correspondence to: Henrik Klitgaard, UCB S.A. Pharma Sector, Preclinical CNS Research, Chemin du Foriest, B-1420 Braine-l'Alleud, Belgium. E-mail: henrik.klitgaard{at}ucb-group.com

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