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Synergistic antidyskinetic effects of topiramate and amantadine in animal models of Parkinson's disease§

Authors

  • Christopher Kobylecki MRCP, PhD,

    Corresponding author
    1. Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom
    2. Faculty of Medical and Human Sciences, University of Manchester, Manchester, United Kingdom
    3. Department of Neurology, Greater Manchester Neurosciences Centre, Salford, United Kingdom
    • Department of Neurology, Greater Manchester Neurosciences Centre, Salford Royal Hospital, Stott Lane, Salford M6 8HD, UK
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  • Michael P. Hill PhD,

    1. Toronto Western Research Institute, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada
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  • Alan R. Crossman PhD, DSc,

    1. Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom
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  • Paula Ravenscroft PhD

    1. Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom
    2. Toronto Western Research Institute, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada
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  • Funding agencies: This research was supported by the Edmonds Bequest for Parkinson's Disease Research.

  • Relevant conflicts of interest/financial disclosures: Alan R. Crossman holds equity in a company holding a use patent for topiramate in L-dopa-induced dyskinesia.

  • §

    Full financial disclosures and author roles may be found in the online version of this article.

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. © 2011 Movement Disorder Society

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