title: Synergistic antidyskinetic effects of topiramate and amantadine in animal models of Parkinson's disease.
abstract: L-Dopa-induced dyskinesia in patients with Parkinson's disease can be alleviated by amantadine, an antagonist at N-methyl-D-aspartate glutamate receptors. The antiepileptic drug topiramate, which blocks α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, has also been shown to reduce dyskinesia. The purpose of this study was to examine the behavioral pharmacology of topiramate alone and in combination with amantadine in animal models of PD and L-dopa-induced dyskinesia. The effects of topiramate (5-20 mg/kg) and amantadine (5-20 mg/kg) on abnormal involuntary movements (the rat homologue of dyskinesia) and Rotarod performance were assessed alone and in combination in the 6-hydroxydopamine-lesioned rat following chronic L-dopa treatment. Dyskinesia, parkinsonian disability, and "on-time" were assessed in the MPTP-lesioned nonhuman primate following administration of topiramate (5-20 mg/kg) and amantadine (0.1-1.0 mg/kg) alone and in combination. Topiramate and amantadine dose-dependently reduced dyskinesia in the 6-hydroxydopamine-lesioned rat, whereas topiramate reduced Rotarod performance; there was no effect on parkinsonian disability in the MPTP-lesioned nonhuman primate, in which both drugs reduced dyskinesia. Topiramate and amantadine exhibited differential antidyskinetic effects on dyskinesia elicited by the dopamine D1 receptor agonist SKF 38393 (2 mg/kg). Subthreshold doses of both drugs in combination had a synergistic effect on dyskinesia in the 6-hydroxydopamine-lesioned rat, with no worsening of motor performance; this effect was confirmed in the MPTP-lesioned nonhuman primate, with a selective reduction in "bad on-time." These data confirm the antidyskinetic potential of topiramate and suggest that combination with low-dose amantadine may allow better reduction of dyskinesia with no adverse motor effects.
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom. christopher.kobylecki@manchester.ac.uk
authors.forename: Christopher
authors.initials: C
authors.lastname: Kobylecki
authors.forename: Michael P
authors.initials: MP
authors.lastname: Hill
authors.forename: Alan R
authors.initials: AR
authors.lastname: Crossman
authors.forename: Paula
authors.initials: P
authors.lastname: Ravenscroft
mesh_terms: D000547:Amantadine / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use* / Q000633:toxicity; D001522:Behavior, Animal / Q000187:drug effects*; D002144:Callithrix; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000008:administration & dosage / Q000633:toxicity; D004357:Drug Synergism; D004409:Dyskinesia, Drug-Induced / Q000175:diagnosis / Q000188:drug therapy*; D005632:Fructose / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D007980:Levodopa / Q000633:toxicity; D020267:MPTP Poisoning / Q000188:drug therapy*; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010300:Parkinson Disease / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077236:Topiramate
chemical_list: D000978:Antiparkinson Agents; D018491:Dopamine Agonists; D018696:Neuroprotective Agents; D000077236:Topiramate; D005632:Fructose; D007980:Levodopa; D000547:Amantadine