Characterization of the binding of N-methyl-4-phenylpyridine, the toxic metabolite of the parkinsonian neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, to neuromelanin.
N-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) selectively destroys neuronal cell bodies in the neuromelanin-containing substantia nigra of humans and primates. We show that N-methyl-4-phenylpyridine (MPP+), the active metabolite of MPTP, binds to neuromelanin with high affinity. This binding increases at higher pH and is displaced most potently by divalent cations and antimalarial drugs. MPP+ bound intracellularly to neuromelanin may be stored and released gradually, resulting in subsequent damage to neurons of the substantia nigra.
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D015655:1-Methyl-4-phenylpyridinium; D000818:Animals; D001667:Binding, Competitive; D002417:Cattle; D002738:Chloroquine / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008543:Melanins / Q000378:metabolism*; D011725:Pyridines / Q000032:analysis*; D011726:Pyridinium Compounds / Q000378:metabolism*; D011898:Ranidae; D013378:Substantia Nigra / Q000378:metabolism
D008543:Melanins; D011725:Pyridines; D011726:Pyridinium Compounds; C014121:neuromelanin; D002738:Chloroquine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D015655:1-Methyl-4-phenylpyridinium