Nitroindazole compounds inhibit the oxidative activation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin to neurotoxic pyridinium cations by human monoamine oxidase (MAO) |
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Authors: | Tomás Herraiz Vicente J. Arán Hugo Guillén |
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Affiliation: | 1. Instituto de Fermentaciones Industrialestherraiz@ifi.csic.es;3. Instituto de Química Médica, Spanish Council for Scientific Research, CSIC, Juan de la Cierva, 3, 28006, Madrid, Spain;4. Instituto de Fermentaciones Industriales |
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Abstract: | Monoamine oxidase (MAO) B is a mitochondrial enzyme selectively involved in the oxidative activation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin to toxic pyridinium cations producing Parkinsonism in animal models. Various synthesized 5-nitroindazoles, 6-nitroindazole and the neuroprotectant 7-nitroindazole were examined as inhibitors of MAO and as antioxidants and radical scavengers. The oxidation of MPTP by human MAO-B and mitochondria was assessed by HPLC. Simple nitroindazoles inhibited MPTP oxidation to 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP+) and 1-methyl-4-phenylpyridinium (MPP+) in a competitive and reversible manner. 5-Nitroindazole (IC50=0.99 µM, Ki=0.102 µM) and 6-nitroindazole (IC50=2.5 µM) were better inhibitors of human MAO-B than 7-nitroindazole (IC50=27.8 µM). 6-Nitroindazole also inhibited MAO-A. Nitroindazole isomers were good hydroxyl radical (OH?) scavengers, with 5-nitro-, 6-nitro- and 7-nitroindazole showing similar activity (k ~1010 M?1 s?1). Neuroprotective actions of nitroindazoles (7-nitroindazole) could be linked to their MAO-inhibitory and antiradical properties besides inhibition on nitric oxide synthase (NOS). 5-Nitro- and 6-nitroindazole, previously reported as weak NOS inhibitors, were better inhibitors of human MAO-B and more active against MPTP neurotoxin oxidation (lower MPDP+ and MPP+ levels) than 7-nitroindazole and acted as good radical scavengers and could be potential neuroprotective agents in addition to MAO-B inhibitors. |
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Keywords: | Monoamine oxidase inhibition MPTP neurotoxin nitroindazoles antioxidants hydroxyl radical scavengers neuroprotection Parkinson's disease |
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