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

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 D(1) 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.

• Authors: Ronald K B Pearce, Lance A Smith, Michael J Jackson, Tara Banerji, Jorgen Scheel-Krüger, Peter Jenner
• Journal: Movement disorders : official journal of the Movement Disorder Society (Mov Disord) Vol. 17 Issue 5 Pg. 877-86 (Sep 2002) ISSN: 0885-3185 [Print] United States
• PMID: 12360536 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2002 Movement Disorder Society

Chemical References

• Dopamine Agents
• Heterocyclic Compounds, 2-Ring
• Oximes
• brasofensine
• 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

Topics

• 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (therapeutic use)
• Animals
• Callithrix
• Disability Evaluation
• Dopamine Agents (therapeutic use)
• Female
• Heterocyclic Compounds, 2-Ring (therapeutic use)
• Male
• Movement Disorders (diagnosis, drug therapy)
• Oximes (therapeutic use)
• Parkinson Disease (diagnosis, drug therapy)
• Random Allocation
• Severity of Illness Index