Evidence for neuromelanin involvement in MPTP-induced neurotoxicity

Robert J. D'Amato, Guillermo M. Alexander, Robert J. Schwartzman, Cheryl A. Kitt, Donald L. Price, Solomon H Snyder

Research output: Contribution to journalArticle

Abstract

Exposuretol-methyl-4-phenyl-l,293,6-tetrahydropyridine(MPTP) reproduces certain clinical, pathological, and neurochemical features of Parkinson's disease1,7. MPTP is metabolized by monoamine oxidase Type B to l-methyl-4-phenylpyridine (MPP+)8, which is selectively accumulated by high-affinity uptake mechanisms into dopaminergic neurons9. Lyden et al.10 described low-affinity binding of MPTP to synthetic and retinal melanin. We showed that MPP+ binds to neuromelanin with high affinity11,12, suggesting that in MPTP neurotoxicity, MPP+ enters nigral neurons by the dopamine uptake system and binds to neuromelanin, which serves as a depot, continuously releasing MPP+ until it destroys the cells 11. This model predicts that agents which compete with MPP+ binding to neuromelanin should partially protect the dopamine neurons from MPTP-induced toxicity. The most potent identified competitor for MPP+ binding to melanin is the antimalarial drug chloroquine12, which has a high affinity for melanins13. In the present study, chloroquine, administered to monkeys in conventional anti-malarial doses before MPTP, protects them from MPTP-induced parkinsonian motor abnormalities, dopamine depletion in the striatum, and neuropathological changes in the substantia nigra.

Original languageEnglish (US)
Pages (from-to)324-326
Number of pages3
JournalNature
Volume327
Issue number6120
Publication statusPublished - 1987

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Cite this

D'Amato, R. J., Alexander, G. M., Schwartzman, R. J., Kitt, C. A., Price, D. L., & Snyder, S. H. (1987). Evidence for neuromelanin involvement in MPTP-induced neurotoxicity. Nature, 327(6120), 324-326.