1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium cation (MPP+) are selective dopaminergic neurotoxins producing Parkinsonism. MPTP is activated by monoamine oxidase-B (MAO-B) to MPP+ that inhibits mitochondrial function. Molecules resembling MPTP which afford pyridinium cations are also neurotoxins. The herbicide paraquat (a bipyridinium dication) and the naturally-occurring β-carboline and isoquinoline alkaloids are structural analogues of MPTP/MPP+. Paraquat generates reactive oxygen species (ROS) producing neurotoxicity by a mechanism that differs from MPTP/MPP+. Human exposure to PQ is increasingly associated with neurodegeneration. Tetrahydro-β-carbolines (THβCs), β-carbolines (βCs) and tetrahydroisoquinolines (TIQs) are bioactive compounds occurring in foods and the human body. They are not MPTP-like toxins and do not appear to induce neurotoxicity at normal levels of exposure. Among TIQs, endogenous dopamine-derived TIQs (i.e. salsolinol) and 1-benzyl-TIQ are toxic through ROS generation. In contrast, β-carbolinium (βC+s) and isoquinolinium cations (IQ+s) are neurotoxicants resembling MPP+ although they are less potent and selective. βC+s and IQ+s have been detected in the human brain but their toxicological significance remains unknown. THβCs/βCs and TIQs are activated to toxic cations by N-methyltransferases (NMT) and/or heme peroxidases and are metabolized by cytochrome P450 enzymes. Remarkably, recent findings suggest, instead, that βCs and TIQs are neuroprotectants and neurorestorative, raising the interest of these molecules.
Keywords: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP); 1-methyl-4-phenylpyridinium cation (MPP(+)); Neuroprotectants; Neurotoxins; Paraquat; Parkinson's disease; Tetrahydroisoquinoline; β-carboline.
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