The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been shown to induce parkinsonism in man and non-human primates. Hypotheses concerning the mechanism of action of MPTP have been related to the pathogenesis of nigral cell death in Parkinson´s disease. For instance, alterations of calcium influxes have been reported to be implicated in both MPTP-induced parkinsonism and Parkinson´s disease. Recently, we reported that nimodipine, a blocker of L-type calcium channels, prevents dopaminergic MPTP-induced neurotoxicity in C57Bl/6 black mice (2). The present study extended these rodent findings to the non-human primate model of Parkinson´s disease and assessed the effects of nimodipine, continuously applied by pellet for 18 days, on behavioural, biochemical and histological parameters, following systemic application of MPTP in common marmosets (Callithrix jacchus).
The experimental design involved 5 groups of common marmosets and a total of 24 animals. Monkeys assigned to group I (n=4) received subcutaneously implanted vehicle pellets 7 days prior to subcutaneous saline injections (control). Monkeys of group II (n=4) were treated with nimodipine pellets (80 mg) and saline injections. Marmosets in group III (n=8) were treated with vehicle pellets and received 4 times MPTP (MPTP-HCl, 2 mg/kg body weight subcutaneously, separated by an interval of 24 hours for a total of 4 days). Monkeys in group IV (n=4) and V (n=4) were treated as group III-animals except for the implantation of nimodipine pellets (80 mg and 120 mg, respectively) 7 days prior to toxin exposure.
In common marmosets MPTP induced severe parkinsonian symptoms, a pronounced dopamine depletion in the caudate-putamen (> 99 % of control) and a loss of tyrosine hydroxylase immunoreactive cells in the substantia nigra (50 % percent of control) 7 days after MPTP-administration. Pretreatment with nimodipine (120 mg pellets) did neither attenuate the behavioural impairments in MPTP-treated animals nor antagonize the striatal neurotoxin-induced dopamine depletion, but almost completely prevented (in a dose-dependent manner) the MPTP-induced decrease of nigral tyrosine hydroxylase immunoreactive cells.
This data (3) shows that application of nimodipine, a clinically available drug, protects against MPTP-induced neurotoxicity (2, 3) at the cellular nigral level, but not at the synaptic striatal level. The different levels of neuroprotection implicate differential mechanisms of actions of MPTP-induced neurotoxicity at the nigral versus the striatal level. Interestingly, nimodipine was not effective in another animal model of Parkinson´s disease, i.e. the 6-hydroxydopamine model of the rat (4), which could suggest that a combination of drugs may be required to slow down the on-going cell death in the human disease.
Nevertheless, the crucial clinical question, whether calcium channel blockers (1) like nimodipine may be of therapeutic value in the treatment of Parkinson´s disease seems to be a promising target for future clinical studies.