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

Abstract

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.