N-methyltetrahydropyridines and pyridinium cations as toxins and comparison with naturally-occurring alkaloids

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 beta-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-beta-carbolines (TH beta Cs), beta-carbolines (beta Cs) 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, beta-carbolinium (beta C(+)s) and isoquinolinium cations (IQ(+) s) are neurotoxicants resembling MPP+ although they are less potent and selective. beta C(+)s and IQ(+)s have been detected in the human brain but their toxicological significance remains unknown. TH beta Cs/beta Cs 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 beta Cs and TIQs are neuroprotectants and neurorestorative, raising the interest of these molecules. (C) 2016 Elsevier Ltd. All rights reserved.