title: N-methyltetrahydropyridines and pyridinium cations as toxins and comparison with naturally-occurring alkaloids.
abstract: 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.
authors: Instituto de Ciencia y Tecnología de Alimentos y Nutrición (ICTAN), Spanish National Research Council (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain. Electronic address: tomas.herraiz@csic.es.
authors: Tomás
authors: T
authors: Herraiz
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects*; D002412:Cations; D006801:Humans; D009498:Neurotoxins / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011726:Pyridinium Compounds / Q000494:pharmacology*
chemical_list: D000470:Alkaloids; D002412:Cations; D009498:Neurotoxins; D011725:Pyridines; D011726:Pyridinium Compounds
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