Antiparkinsonian and neuroprotective effects of modafinil in the mptp-treated common marmoset

The psychostimulant drug, modafinil, protects rodents against 1-methyl-4-ph enyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity, striatal ischemia and part ial transection of the nigro-striatal pathway. We now report on the ability of modafinil to reverse motor disability in MPTP-treated common marmosets and to prevent MPTP-induced nigral cell death in this species. Tn the initi al experiments, adult common marmosets were treated with MPTP to produce st able motor deficits. The subsequent administration of modafinil (10, 30 or 100 mg/kg/day, p.o.) produced a dose-dependent reversal of motor disability . In a subsequent experiment, normal common marmosets were concurrently tre ated with 10, 30 or 100 mg/kg of modafinil once daily by gavage during acut e MPTP administration (daily for 5 days), continuing for 2 weeks after the last dose of MPTP. Modafinil dose-dependently prevented the decline in moto r activity normally produced by MPTP treatment. MPTP treatment caused a 76% loss of nigral tyrosine-hydroxylase-immunoreactive cells in placebo-treate d animals, and this was dose-dependently prevented by modafinil. At the hig hest dose (100 mg/kg/day) of modafinil, there was no significant loss of ty rosine-hydroxylase-immunoreactive cells in the substantia nigra compared wi th normal animals. MPTP treatment also reduced striatal dopamine uptake sit es by 95%, as measured by specific [H-3]-mazindol binding, compared with no rmal controls. Modafinil treatment dose-dependently reduced the loss of spe cific [H-3]-mazindol binding. Behavioural and morphological evidence in the present study indicate a potential antiparkinsonian and neuroprotective ro le for modafinil, which may form a new pharmacological approach to the trea tment of Parkinson's disease.