Intake of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) leads to symptoms of Parkinson's disease and produces degeneration of nigrostriatal dopaminergic neurons in humans, giving rise to the hypothesis that this disorder may be caused by endogenous or environmental toxins. Excitation mediated by dicarboxylic amino acids such as L-glutamate or L-aspartate, has been claimed to be involved in pathogenesis of neurodegenerative disorders. We therefore sought to determine whether antagonists active at the NMDA or quisqualate subtypes of L-glutamate receptors prevent toxicity of either MPP+ (1-methyl-4-phenyl-pyridinium ion, the active metabolite of MPTP) or the selective dopaminergic neurotoxin 6-OHDA in the rat substantia nigra pars compacta. We report here that certain selective NMDA antagonists (AP7, CPP, MK-801), but not the preferential quisqualate antagonists CNQX and NBQX, provided short-term (up to 24 h) protection against MPP+ toxicity when coadministered into the substantia nigra. Systemic administration of CPP or MK-801 also offered temporary protection for up to 4 h against MPP+ toxicity. Repeated systemic administration of either compound prolonged protection against MPP+ challenge. Repeated administration for at least 24 h also led to permanent protection, still evident 7 days after intranigral administration of MPP+.

Summary. Degeneration of dopaminergic nigrostriatal neurons in Parkinson's disease results in an overactivity of excitatory glutamatergic projections from the subthalamic nucleus to the output nuclei of the basal ganglia resulting in rigidity and akinesia. In theory pharmacological blockade of these overactive systems should improve parkinsonian symptomatology. The selective AMPAantagonist NBQX and the competitive NMDA-antagonist CPP are not effective in animal models of Parkinson's disease when given alone but ameliorate parkinsonian symptomatology and stimulate locomotor activity when co-administered with a threshold dose of L-Dopa. These synergistic effects are seen in the MPTP-treated (1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine) common marmoset and the rat with unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra. Therefore competitive NMDA and non-NMDA antagonists may offer a new therapeutic strategy for the treatment of Parkinson's disease.

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