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Formation of the Neurotransmitter Glycine from the Anticonvulsant Milacemide Is Mediated by Brain Monoamine Oxidase B
Author(s) -
Varebeke Philippe Janssens,
Cavalier Robert,
DavidRemacle Michèle,
Youdim Moussa B. H.
Publication year - 1988
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.1988.tb10566.x
Subject(s) - monoamine oxidase , monoamine oxidase b , neurotransmitter , glycine , neurotransmitter systems , anticonvulsant , chemistry , pharmacology , neuroscience , biochemistry , biology , amino acid , epilepsy , receptor , enzyme
Milacemide (2‐ n ‐pentylaminoacetamide) is a secondary monoamine that in the brain is converted to glycinamide and glycine. This oxidative reaction was suspected to involve the reaction of monoamine oxidase (MAO). Using mitochondrial preparations from tissues that contain MAO‐A and ‐B (rat brain and liver), MAO‐A (human placenta), and MAO‐B (human platelet and bovine adrenal chromaffin cell), it has been established that mitochondria containing MAO‐B rather than MAO‐A oxidize (H 2 O 2 production and glycinamide formation) milacemide. The apparent K m (30–90 μ M ) for milacemide oxidation by mitochondrial MAO‐B preparations is significantly lower than that for milacemide oxidation by mitochondrial MAO‐A (approximately 1.300 μM). In vitro MAO‐B (/‐deprenyl and AGN 1135) rather than MAO‐A (clorgyline) selectively inhibited the oxidation of milacemide. These in vitro data are matched by ex vivo experiments where milacemide oxidation was compared to oxidation of serotonin (MAO‐A) and β‐phenylethylamine (MAO‐B) by brain mitochondria prepared from rats pre‐treated with clorgyline (0.5–10 mg/kg) and /‐deprenyl (0.5–10 mg/kg). Furthermore in vivo experiment demonstrated that /‐deprenyl selectively increased the urinary excretion of [ 14 C]milacemide and the total radioactivity with a concomitant decrease of [ 14 C]glycinamide. Such changes were not observed after clorgyline treatment, but were evident only at doses beyond clorgyline selectivity. The present data therefore demonstrate that milacemide is a substrate for brain MAO‐B, and its conversion to glycinamide, further transformed to the inhibitory neurotransmitter, glycine, mediated by this enzyme may contribute to its pharmacological activities.