کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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5854123 | 1130881 | 2011 | 9 صفحه PDF | دانلود رایگان |
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.
Highlights⺠Human mitochondria and MAO-B oxidized MPTP to neurotoxic pyridinium species (bioactivation process). ⺠Antioxidants, alkaloids and redox agents were assessed as inhibitors and protective substances. ⺠MAO-B inhibitors and redox agents inhibited the oxidation of MPTP to toxic species. ⺠Methylene blue, 5-nitroindazole, norharman, 9-methylnorharman and menadione inhibited MAO-B and decreased the toxic species. ⺠Several naturally-occurring antioxidants (resveratrol, catechin, melatonin) did not inhibit the oxidation of MPTP.
Journal: Food and Chemical Toxicology - Volume 49, Issue 8, August 2011, Pages 1773-1781