title: Evaluation of the oxidation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to toxic pyridinium cations by monoamine oxidase (MAO) enzymes and its use to search for new MAO inhibitors and protective agents.
abstract: Monoamine oxidase (MAO) enzymes catalyze the oxidative deamination of amines and neurotransmitters and inhibitors of MAO are useful as neuroprotectants. This work evaluates the human MAO-catalyzed oxidation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a dopaminergic neurotoxin, to the directly-acting neurotoxic metabolites, 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP(+)) and 1-methyl-4-phenylpyridinium (MPP(+)) measured by High-Performance Liquid Chromatography (HPLC), and this approach is subsequently used as a new method for screening of MAO inhibitors and protective agents. Oxidation of MPTP by human MAO-B was more efficient than by MAO-A. R-Deprenyl, a known neuroprotectant, norharman (β-carboline), 5-nitroindazole and menadione (vitamin K3) inhibited MAO-B and reduced the formation of toxic pyridinium cations. Clorgyline and the β-carbolines, harman and norharman, inhibited the oxidation of MPTP by MAO-A. Cigarette smoke, as well as the naturally occurring β-carbolines (norharman and harman) isolated from smoke and coffee inhibited the oxidation of MPTP by MAO-B and/or MAO-A, suggesting protective effects against MPTP. The results show the suitability of the approach used to search for new MAO inhibitors with eventual neuroprotective activity.
authors: Spanish National Research Council, (CSIC), Instituto de Ciencia y Tecnología de Alimentos y Nutrición (ICTAN), Madrid, Spain. therraiz@ictan.csic.es
authors: Tomás
authors: T
authors: Herraiz
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000037:antagonists & inhibitors / Q000737:chemistry*; D015655:1-Methyl-4-phenylpyridinium / Q000737:chemistry*; D002243:Carbolines; D002851:Chromatography, High Pressure Liquid; D003010:Clorgyline / Q000737:chemistry; D057075:Enzyme Assays; D006247:Harmine / Q000031:analogs & derivatives / Q000737:chemistry; D006801:Humans; D007191:Indazoles / Q000737:chemistry; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008995:Monoamine Oxidase / Q000737:chemistry*; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry*; D018696:Neuroprotective Agents / Q000737:chemistry*; D010084:Oxidation-Reduction; D011726:Pyridinium Compounds / Q000737:chemistry*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D012642:Selegiline / Q000737:chemistry; D012906:Smoke; D014026:Nicotiana / Q000737:chemistry; D024483:Vitamin K 3 / Q000737:chemistry
chemical_list: D002243:Carbolines; D007191:Indazoles; D007527:Isoenzymes; D008996:Monoamine Oxidase Inhibitors; D018696:Neuroprotective Agents; D011726:Pyridinium Compounds; D011994:Recombinant Proteins; D012906:Smoke; C530840:5-nitroindazole; D012642:Selegiline; D006247:Harmine; D024483:Vitamin K 3; C044755:1-methyl-4-phenyl-2,3-dihydropyridinium; C010262:norharman; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008995:Monoamine Oxidase; D003010:Clorgyline; D015655:1-Methyl-4-phenylpyridinium