Biochemical mechanism of action of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

The various biochemical mechanisms considered to explain the selective dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are reviewed. MPTP is metabolized by monoamine oxidase in the brain, ultimately yielding 1-methyl-4-phenylpyridinium cation (MPP+), which is accumulated in dopamine cells by the high-affinity dopamine uptake pump. Cell death appears to reflect a compromise in energy production arising as a result of the Nernstian concentration of MPP+ inside mitochondria and persistent inhibition of Site 1 of the respiratory chain. The structural features underlying each biochemical step involved in the expression of neurotoxicity are described, and the implications of the MPTP phenomenon to efforts aimed at elucidating the pathogenesis of idiopathic parkinsonism are discussed.