The mechanism of action of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is being studied in several animal species. In primates, MPTP produces a persistent parkinsonian syndrome. In dogs, MPTP destroys cells in the A-9 cell group in the substantia nigra, and does not kill other cell types. In the rat, no nigral cell death has been induced, but in mice long-lasting impairment of nigral neuronal function has been documented. The metabolic fate of MPTP in the monkey and rodent is consistent with species difference in metabolism being important for susceptability. MPTP is converted to the pyridinium ion MPP+ in all species, but trapped intraneuronally for long times in the monkey. Blockade of the oxidation of MPTP to MPP+ with monoamine oxidase type B inhibitors prevents the toxicity of MPTP in mice and dogs. The oxidation of MPTP to MPP+ has been studied in vitro in primate tissue. The role of oxidative stress produced by trapped MPP+ has been studied in the rodent. MPP+ administered peripherally causes lung damage to the rat, similar to that produced by its structural analog paraquat. Furthermore, it caused an increase in plasma glutathione disulfide 60-90 minutes after administration. Selenium deficient mice which are especially susceptible to oxidative stress exhibited lowered LD50 levels toward MPP+. This oxidative stress mechanism may play a role in the CNS toxicity of MPTP. A sensitive and specific gas chromatographic-mass spectrometric quantitative assay for MPTP and MPP+ has been developed and applied to the studies of its toxic mechanism. The synthesis of analogs of MPTP and MPP+, and the synthesis of antigens for antibody preparation to MPTP and MPP+ is in progress.
