NMDA antagonists partially protect against MPTP induced neurotoxicity in mice

Recent studies show that N-methyl-D-aspartate (NMDA) antagonists protect against neurotoxicity induced by local injections of 1-methyl-4-phenylpyridinium (MPP+) in both the substantia nigra and the striatum. The present studies examined whether either systemic administration of the non-competitive NMDA antagonist MK-801 or the competitive NMDA antagonists CGP39551 and LY274614 would protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) dopaminergic toxicity in mice. Administration of MK-801, CGP39551 or LY274614 for 24 hours partially but significantly attenuated striatal dopamine (DA) depletions induced by MPTP at both 24 h and 1 week. These results support the hypothesis that MPTP neurotoxicity involves a secondary excitotoxic mechanism mediated by NMDA receptors. Such a mechanism may play a role in the etiology of Parkinson's disease.