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

• Published in: Annals of neurology Vol. 46; no. 4; pp. 598 - 605
• Main Authors: Langston, J. W., Forno, L. S., Tetrud, J., Reeves, A. G., Kaplan, J. A., Karluk, D.
• Format: Journal Article
• Language: English
• Published: New York John Wiley & Sons, Inc 01.10.1999; Willey-Liss
• Subjects: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine - adverse effects; Adult; Biological and medical sciences; Cell Death; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Humans; Male; Medical sciences; Nerve Degeneration - chemically induced; Nerve Degeneration - pathology; Neurology; Substantia Nigra - drug effects; Substantia Nigra - pathology; Case study; Human; Pathology; Nervous system diseases; Grey matter; Central nervous system disease; Parkinson disease; Exploration; Degenerative disease; Poisoning; Cerebral disorder; Extrapyramidal syndrome
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/1531-8249(199910)46:4<598::AID-ANA7>3.0.CO;2-F

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 “synthetic heroin” and subsequently developed severe and unremitting parkinsonism, which was L‐dopa responsive, at least in the earlier stages of illness. Survival times ranged from 3 to 16 years. Neuropathological examination revealed moderate to severe depletion of pigmented nerve cells in the substantia nigra in each case. Lewy bodies were not 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 melanin. These findings are indicative of active, ongoing nerve cell loss, suggesting that a time‐limited insult to the nigrostriatal system can set in motion a self‐perpetuating process of neurodegeneration. Although the mechanism by which this occurs is far from clear, the precedent set by the cases could have broad implications for human neurodegenerative disease.