Protection of substantia nigra from MPP⁺ neurotoxicity by N-methyl-D-aspartate antagonists

Abstract

INTAKE of MPTP (l-methyl-4-phenyl-l,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^1–3. Excitation mediated by dicarboxylic amino acids such as L-glutamate or L-aspartate, has been claimed to be involved in pathogenesis of neurodegenerative disorders⁴. We therefore sought to determine whether antagonists active at the NMDA or quisqualate subtypes of L-glutamate receptors prevent toxicity of either MPP⁺ (l-methyl-4-phenyl-pyridinium ion⁵, the active metabolite of MPTP⁶) 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)⁷, but not the preferential quisqualate antagonists CNQX and NBQX,⁸ 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⁺.