The monoamine reuptake blocker brasofensine reverses akinesia without dyskinesia in MPTP-treated and levodopa-primed common marmosets

Authors

  • Ronald K.B. Pearce MD, PhD, FRCPC,

    1. Division of Pharmacology & Therapeutics, Guy's, King's and St. Thomas’ School of Biomedical Sciences, London, United Kingdom
    2. Department of Neurology, Charing Cross Hospital, London, United Kingdom
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  • Lance A. Smith MSc PhD,

    1. Division of Pharmacology & Therapeutics, Guy's, King's and St. Thomas’ School of Biomedical Sciences, London, United Kingdom
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  • Michael J. Jackson BSc,

    1. Division of Pharmacology & Therapeutics, Guy's, King's and St. Thomas’ School of Biomedical Sciences, London, United Kingdom
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  • Tara Banerji MBBS, BSc,

    1. Division of Pharmacology & Therapeutics, Guy's, King's and St. Thomas’ School of Biomedical Sciences, London, United Kingdom
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  • Jorgen Scheel-Krüger PhD,

    1. NeuroSearch, Smedeland, Glostrup, Denmark
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  • Peter Jenner PhD, DSc

    Corresponding author
    1. Division of Pharmacology & Therapeutics, Guy's, King's and St. Thomas’ School of Biomedical Sciences, London, United Kingdom
    • Division of Pharmacology & Therapeutics, Guy's, King's and St Thomas' School of Biomedical Sciences, King's College, London SE1 1UL, United Kingdom
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Abstract

The common marmoset develops motor deficits after MPTP treatment and exhibits dyskinesia after chronic levodopa (L-dopa) dosing and subsequent re-challenge with L-dopa and other dopaminergic agents. We report on the actions of the potent monoamine reuptake blocker brasofensine on motor disability, locomotor activity, and dyskinesia in the 1-methyl-4-1, 2,3,6-tetrahydropyridine (MPTP) -treated marmoset model of Parkinson's disease. Oral administration of brasofensine (0.25, 0.5, 1.0, or 2.5 mg/kg) to MPTP-treated marmosets produced a long-lasting, dose-dependent increase in locomotor activity and reduction in disability scores. In addition, coadministration of the lowest dose of brasofensine (0.25 mg/kg orally) with a threshold oral dose of L-dopa (2.5 mg/kg) caused a marked increase in locomotor activity, greater than that produced by either drug alone. In other MPTP-treated marmosets previously primed to exhibit dyskinesia by repeated L-dopa dosing, brasofensine effectively reversed akinesia with a naturalistic and prolonged motor response without the appearance of dyskinesia or stereotypy. This finding contrasts with the severe dyskinesia, stereotypy, and hyperkinesis produced by equivalent doses of L-dopa. The ability of brasofensine to produce a prolonged and naturalistic antiparkinsonian response without eliciting dyskinesia after previous L-dopa priming may relate to actions on D1 receptor-linked pathways. These findings suggest that monoamine reuptake blockade may be of value in the treatment of Parkinson's disease, both early in the disease course and when L-dopa–induced dyskinesias complicate treatment. © 2002 Movement Disorder Society

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