MPTP: A neurotoxin relevant to the pathophysiology of Parkinson’s disease: The 1985 George C. Cotzias Lecture

MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) elicits selective destruction of nigrostriatal dopamine neurons in humans and animals along with clinical symptoms of parkinsonism. Recent studies clarify mechanisms accounting for this neurotoxicity. MPTP binds with high affinity to monoamine oxidase, which transforms it to the pyridinium MPP ⁺. MPP ⁺ is selectively concentrated by the dopamine neuronal uptake system. In nigral cells, binding by melanin of MPP ⁺ affords a “depot” release mechanism to maintain prolonged high intracellular concentrations sufficient to destroy cells. PC-12 cells provide a model catecholamine cell culture for screening environmentally occurring substances that may be relevant in the etiology of idiopathic Parkinson’s disease.