Evidence for neuromelanin involvement in MPTP-induced neurotoxicity.
Exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) reproduces certain clinical, pathological, and neurochemical features of Parkinson's disease. MPTP is metabolized by monoamine oxidase Type B to 1-methyl-4-phenylpyridine (MPP+), which is selectively accumulated by high-affinity uptake mechanisms into dopaminergic neurons. Lyden et al. described low-affinity binding of MPTP to synthetic and retinal melanin. We showed that MPP+ binds to neuromelanin with high affinity, 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. 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 chloroquine, which has a high affinity for melanins. 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.
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D002421:Caudate Nucleus / Q000378:metabolism; D002738:Chloroquine / Q000627:therapeutic use; D004298:Dopamine / Q000378:metabolism; D006719:Homovanillic Acid / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D008543:Melanins / Q000378:metabolism*; D008995:Monoamine Oxidase / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010302:Parkinson Disease, Secondary / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control; D011699:Putamen / Q000378:metabolism; D011725:Pyridines / Q000378:metabolism / Q000633:toxicity*; D013378:Substantia Nigra / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D008543:Melanins; D011725:Pyridines; C014121:neuromelanin; D002738:Chloroquine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D008995:Monoamine Oxidase; D004298:Dopamine; D006719:Homovanillic Acid