Evidence for neuromelanin involvement in MPTP-induced neurotoxicity

Exposuretol-methyl-4-phenyl-l,293,6-tetrahydropyridine(MPTP) reproduces certain clinical, pathological, and neurochemical features of Parkinson's disease^1,7. 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 affinity^11,12, 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.