title: Inhibition of the bioactivation of the neurotoxin MPTP by antioxidants, redox agents and monoamine oxidase inhibitors.
abstract: Monoamine oxidase (MAO) enzymes located in human mitochondria oxidize neurotransmitters and bioactivate the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by oxidation to directly-acting neurotoxic pyridinium cations (MPDP⁺/MPP⁺) that produce Parkinsonism. Antioxidants and MAO inhibitors are useful as neuroprotectants. Naturally-occurring substances, antioxidants and redox agents were assessed as inhibitors of the oxidation (bioactivation) of MPTP by human mitochondria and MAO enzymes. Methylene blue, 5-nitroindazole, norharman (β-carboline), 9-methylnorharman (9-methyl-β-carboline) and menadione (vitamin-K analogue) highly inhibited the oxidation of MPTP to the neurotoxic species, MPDP⁺/MPP⁺, in human mitochondria (IC₅₀ of 0.18, 3.1, 9.9, 7.3, and 12.6 μM, respectively). Inhibition by methylene blue was similar to R-deprenyl (IC₅₀ of 0.15 μM), a known neuroprotectant. The naturally-occurring β-carbolines, harmine, harmaline and tetrahydro-β-carboline, and the antioxidants, melatonin, resveratrol, quercetin and catechin showed little or no inhibition. Oxidation of MPTP in mitochondria was performed by human MAO-B and the above active compounds were also inhibitors of this isozyme. Norharman and 5-nitroindazole were competitive inhibitors of MAO-B whereas methylene blue inhibited MPTP oxidation (IC₅₀ of 50 nM) under a mixed type and predominantly uncompetitive mechanism. Methylene blue, 5-nitroindazole, norharman, 9-methylnorharman and menadione inhibit MAO-B in mitochondria and afford protective effects, as suggested by a reduced conversion of MPTP to neurotoxic species.
authors.affiliation: Instituto de Ciencia y Tecnología de Alimentos y Nutrición (ICTAN), Spanish Council for Scientific Research (CSIC), Juan de la Cierva, Madrid, Spain. therraiz@ictan.csic.es
authors.forename: Tomás
authors.initials: T
authors.lastname: Herraiz
authors.forename: Hugo
authors.initials: H
authors.lastname: Guillén
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000037:antagonists & inhibitors*; D000975:Antioxidants / Q000494:pharmacology*; D002243:Carbolines / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D006247:Harmine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D007191:Indazoles / Q000494:pharmacology; D013058:Mass Spectrometry; D008751:Methylene Blue / Q000494:pharmacology; D008928:Mitochondria / Q000378:metabolism; D008995:Monoamine Oxidase / Q000009:adverse effects / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000037:antagonists & inhibitors*; D010084:Oxidation-Reduction; D012642:Selegiline / Q000494:pharmacology
chemical_list: C529608:9-methyl-beta-carboline; D000975:Antioxidants; D002243:Carbolines; D007191:Indazoles; D008996:Monoamine Oxidase Inhibitors; D018696:Neuroprotective Agents; D009498:Neurotoxins; C530840:5-nitroindazole; D012642:Selegiline; D006247:Harmine; C010262:norharman; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008995:Monoamine Oxidase; D008751:Methylene Blue