Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure

This report provides the first detailed neuropathological study of 1-methyl -4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in humans. All 3 subjects self-administered the drug under the impression it was "syn thetic heroin" and subsequently developed severe and unremitting parkinsoni sm, which was L-dopa responsive, at least in the earlier stages of illness, Survival times ranged from 3 to 16 years. Neuropathological examination re vealed moderate to severe depletion of pigmented nerve cells in the substan tia nigra ia each case. Lewy bodies were nor present. In Patients 1 and 2, there was gliosis and clustering of microglia around nerve cells, Patient 3 had a similar picture and also showed large amounts of extraneuronal melan in. These findings are indicative of active, ongoing nerve cell loss, sugge sting that a time-limited insult to the nigrostriatal system can set in mot ion a self-perpetuating process of neurodegeneration. Although the mechanis m by which this occurs is far from clear, the precedent set by the cases co uld have broad implications for human neurodegenerative disease.