The metabolism and mechanism of action of the parkinsonian syndrome inducing neurotoxin MPTP (l-methyl-4-phenyl-1,2,3,6- tetrahydropyridine) and its amine analogue 4'-amino MPTP have been studied in mouse, dog, and monkey. The identification of MPTP metabolites in mouse brain, the concentrations of the principle metabolite l-methyl-4-phenylpyridine (MPP+) in mouse and monkey brain, and the relationship between neurotoxicity and MPP+ concentration supports the causal relationship between MPP+ accumulation in target brain cells and neural degeneration. Structurally related environmental neurotoxins are being sought using an immunoassay to MPP+; functionally related neurotoxins are being sought with a cultured cell system. Low doses of MPTP produce long lasting (6 week) pharmacological effects in dogs suggesting that related neurotoxins might be detectable in exposed populations. The testing of 4'-amino MPTP in dogs has been completed, and it has been shown to be a less specific neurotoxin than MPTP, perhaps producing a better animal model of the human disease. A gas chromatography-mass spectrometric assay of plant extracts containing the putative neurotoxic amino acid beta-N- methylaminoalanine (BMAA) has been developed. The assay is being applied to cycad seeds from Guam in order to test the hypothesis that BMAA causes the high incidence of amyotrophic lateral sclerosis/Parkinsonism dementia among native Guamanians.
