The monoamine reuptake blocker brasofensine reverses akinesia without dyskinesia in MPTP-treated and levodopa-primed common marmosets.
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.
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000627:therapeutic use*; D000818:Animals; D002144:Callithrix; D004185:Disability Evaluation; D015259:Dopamine Agents / Q000627:therapeutic use*; D005260:Female; D006574:Heterocyclic Compounds, 2-Ring / Q000627:therapeutic use*; D008297:Male; D009069:Movement Disorders / Q000175:diagnosis / Q000188:drug therapy*; D010091:Oximes / Q000627:therapeutic use*; D010300:Parkinson Disease / Q000175:diagnosis / Q000188:drug therapy*; D011897:Random Allocation; D012720:Severity of Illness Index
D015259:Dopamine Agents; D006574:Heterocyclic Compounds, 2-Ring; D010091:Oximes; C415103:brasofensine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine