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Inhibition of the bioactivation of the neurotoxin MPTP by antioxidants, redox agents and monoamine oxidase inhibitors.
Herraiz, Tomás; Guillén, Hugo.
Afiliação
  • Herraiz T; 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
Food Chem Toxicol ; 49(8): 1773-81, 2011 Aug.
Article em En | MEDLINE | ID: mdl-21554916
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 (ß-carboline), 9-methylnorharman (9-methyl-ß-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 ß-carbolines, harmine, harmaline and tetrahydro-ß-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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina / Inibidores da Monoaminoxidase / Neurotoxinas / Antioxidantes Limite: Humans Idioma: En Revista: Food Chem Toxicol Ano de publicação: 2011 Tipo de documento: Article País de afiliação: Espanha

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina / Inibidores da Monoaminoxidase / Neurotoxinas / Antioxidantes Limite: Humans Idioma: En Revista: Food Chem Toxicol Ano de publicação: 2011 Tipo de documento: Article País de afiliação: Espanha