Role for monoamine oxidase-A (MAO-A) in the bioactivation and nigrostriatal dopaminergic neurotoxicity of the MPTP analog, 2'Me-MPTP.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration leads to the selective destruction of the dopaminergic neurons of the nigrostriatal pathway in experimental animals including monkeys and mice. The neurotoxicity of MPTP is dependent upon its monoamine oxidase-B (MAO-B)-catalyzed conversion to the 1-methyl-4-phenylpyridinium species (MPP+). A methylated analog of MPTP. A methylated analog of MPTP, namely 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'Me-MPTP), is a more potent dopaminergic neurotoxin than MPTP in mice. Although the selective inhibition of MAO-B is sufficient to protect mice against MPTP-induced neurotoxicity, it is reported here that complete inhibition of MAO-B failed to prevent 2'Me-MPTP-induced dopaminergic neurotoxicity. However, the neurotoxicity of 2'Me-MPTP was completely prevented and 2'Me-MPP+ formation was markedly attenuated in mice in which both MAO-A and MAO-B were almost totally inhibited. This information about the role of MAO-A in the bioactivation of 2'Me-MPTP may be of relevance to those who speculate that the MAO-B catalyzed bioactivation of MPTP or a similar compound may be the cause of idiopathic Parkinson's disease.