HUMANGGP:001709 - FACTA Search

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Query: HUMANGGP:001709 (MAO-A)
2,432 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The present study investigates the effects of selective and a non-selective monoamine oxidase (MAO) inhibitors combined with L-tryptophan on MAO-A and -B activity, hypothalamic extracellular 5-hydroxytryptamine (5-HT) in vivo and the occurrence of the 5-HT behavioural syndrome. 2. Selective inhibition of intraneuronal MAO-A with MDL 72394 (0.5 mg kg-1, i.p.) had no effect on extracellular 5-HT and following administration of L-tryptophan (50 mg kg-1, i.p.) the 5-HT behavioural syndrome was not induced. 3. Selective inhibition of MAO-A at all sites with clorgyline (5 mg kg-1, i.p.) increased extracellular 5-HT but did not induce the 5-HT behavioural syndrome when combined with L-tryptophan administration. 4. Selective inhibition of MAO-B with selegiline (10 mg kg-1, i.p.) had no effect on extracellular 5-HT and the 5-HT behavioural syndrome was not observed after L-tryptophan administration. 5. Inhibition of MAO-A and -B with a higher and therefore non-selective, dose of MDL 72394 (2 mg kg-1) markedly increased extracellular 5-HT but failed to induce the 5-HT behavioural syndrome after L-tryptophan administration. 6. Inhibition of MAO-A and -B at all sites in the brain (tranylcypromine 20 mg kg-1, i.p. or clorgyline 5 mg kg-1 plus selegiline 10 mg kg-1) increased extracellular 5-HT and induced the behavioural syndrome on administration of L-tryptophan. 7. The results demonstrate that inhibition of MAO-A and -B both within amine neurones and elsewhere in the brain is essential for the development of the 5-HT behavioural syndrome. Whilst the syndrome is associated with increased extracellular 5-HT this does not appear necessarily to result in the syndrome and may indicate that increased extracellular 5-HT is not solely involved in the induction of the '5-HT behavioural syndrome'. Whilst the syndrome is associated with increased extracellular 5-HT this does not appear necessarily to result in the syndrome and may indicate that increased extracellular 5-HT is not solely involved in the induction of the '5-HT behavioural syndrome'.
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PMID:Relationship between extracellular 5-hydroxytryptamine and behaviour following monoamine oxidase inhibition and L-tryptophan. 245 63

After pretreatment with either clorgyline, a monoamine oxidase (MAO)-A-selective inhibitor, or pargyline, an MAO-B-selective inhibitor with less selectivity than l-deprenyl, i.c.v. administration of para-hydroxyamphetamine (p-OHA) significantly increased both the frequency and total number of head-twitches in mice. A typical MAO-B-selective inhibitor, l-deprenyl, however, did not change the total count of the p-OHA-induced head-twitch response (HTR). These effects were also found with fixed doses of the selective MAO inhibitors when p-OHA was varied. Administration of clorgyline (1 mg/kg) or pargyline (5 mg/kg) almost inhibited completely MAO-A in the mouse forebrain, and pargyline also almost inhibited completely MAO-B. l-Deprenyl, in contrast, almost inhibited completely MAO-B without affecting MAO-A activity. Systemic administration of l-5-hydroxytryptophan also induced HTR and the total number of twitches was enhanced by clorgyline, but not by pargyline or l-deprenyl. Chlorimipramine or cocaine significantly reduced p-OHA-induced HTR, suggesting an intraneuronal site of action. Together with the presence of considerable MAO-A in 5-hydroxytryptamine (5-HT) neurons of various animal species, and possible accumulation and subsequent monoamine-releasing properties of p-OHA, the present results indicate that p-OHA might induce the HTR by interaction with intraneuronally increased 5-HT. This mechanism probably results in 5-HT release onto the postsynaptic 5-HT2 receptors. Taken together, different roles of MAO-B in "the hyperactivity syndrome" and the HTR are discussed.
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PMID:Potentiation of para-hydroxyamphetamine-induced head-twitch response by inhibition of monoamine oxidase type A in the brain. 250 77

Subcutaneous injection of 1 mg/kg 5-hydroxytryptamine (5-HT) reduced the intake of a 10% sucrose solution in rats. A single injection of the monoamine oxidase inhibitor (MAOI) clorgyline enhanced the anorectic effect of 5-HT. Such an effect persists 2, 24, 48, 72 and 96 h after injection. The clorgyline treatment almost completely inhibited type A MAO activity in the liver at 2 h post-injection. By 120 h, the time at which potentiation of 5-HT induced anorexia disappeared, MAO-A activity had returned to 80% of control values. These results demonstrate that the clorgyline effect is long-lasting and irreversible. Brofaromine (5 mg/kg) and cimoxatone (20 mg/kg) also enhanced the anorectic effect of 5-HT injected 2 h later. The potentiating effects of brofaromine and cimoxatone were not observed when 5-HT was administered 24 h later. These results indicate that brofaromine and cimoxatone are short-acting, reversible inhibitors of MAO-A activity in vivo. Moclobemide (30 mg/kg) failed to enhance the anorectic action of 5-HT injected 2 and 24 h later. The potentiation of 5-HT induced anorexia may be a useful behavioural test for investigating the degree of reversibility, and time course of action of MAOIs.
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PMID:Enhancement of 5-HT-induced anorexia: a test of the reversibility of monoamine oxidase inhibitors. 250 97

The effect of RS-8359, pyrimidine on monoamine oxidase (MAO) has been compared with a hydrazinic MAO inhibitor, safrazine (beta-piperonylisopropylhydrazine hydrochloride,) which is a MAO inhibitor used clinically. In-vitro radiochemical determination of MAO activity showed that the IC50 of RS-8359 was 0.52 microM for the deamination of 5-hydroxytryptamine (5-HT) in the mouse brain mitochondrial preparation, while beta-phenylethylamine (PEA) deamination was inhibited by only 20% at 100 microM of the drug. 5-HT deamination in the brain homogenate prepared from mice killed 60 min after administration of RS-8359 was inhibited significantly by 14 and 48%, at 30 and 100 mg kg-1 (p.o.), respectively, while deamination of PEA was little affected at the same doses. On the other hand, safrazine strongly inhibited both 5-HT and PEA deaminations, but showed no selectivity toward the substrate used. The extent of MAO inhibition by RS-8359, measured fluorometrically with kynuramine as a substrate in the brain homogenate, was independent of preincubation up to 80 min. In contrast, the inhibitory potency of safrazine was strengthened by preincubation in a time-dependent manner. Oral administration of RS-8359 (3-30 mg kg-1) caused a dose-dependent increase in endogenous monoamines in mouse brain, which disappeared a few hours after its administration. Increase in monoamine content caused by safrazine lasted for at least 24 h. These results indicate that RS-8359 is a reversible and specific inhibitor of MAO-A, while safrazine is an irreversible and non-specific MAO inhibitor, in-vivo and in-vitro in mouse brain.
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PMID:Comparative studies of the effects of RS-8359 and safrazine on monoamine oxidase in-vitro and in-vivo in mouse brain. 256 61

Acceptance into clinical practice of monoamine oxidase (MAO) antidepressants requires unequivocal evidence that novel, non-hepatotoxic and reversible MAO-A inhibitors carry little or no risk of inducing severe hypertensive crises (cheese effect). This study summarizes the most relevant preclinical aspects which differentiate the novel reversible MAO-A inhibitors moclobemide and brofaromine, from previous irreversible MAO inhibitors of the old generation, particularly phenelzine and tranylcypromine. Moclobemide and brofaromine bear no chemical relation to irreversible inhibitors such as hydrazine derivatives (phenelzine) or aminocyclopropyl derivatives (tranylcypromine). Experiments in rats show that moclobemide and brofaromine increase the level of serotonin (5-hydroxytryptamine) and decrease that of 3,4-dihydroxyphenylacetic acid for only 16-24 hours. In vitro, moclobemide and brofaromine behave as mechanism-based, enzyme-activated inhibitors since their intrinsic inhibitory activity increases with the duration of their interaction with the enzyme in tissue homogenates. In contrast to irreversible monoamine oxidase inhibitors, which are much more potent in vitro than in vivo, moclobemide has the characteristic to be virtually equipotent in vitro and in vivo. MAO-A inhibition induced by moclobemide in the rat in vivo was rapidly reversed by simply incubating liver homogenates at 37 degrees C in the absence of the inhibitor, indicating a rapid metabolic inactivation of moclobemide in vitro. This reversibility is a distinctive feature of moclobemide, when compared with brofaromine or irreversible MAO inhibitors. Hepatotoxicity is not an inherent property of MAO inhibitors indeed, moclobemide or brofaromine, due to their chemical structures, cannot be converted into isopropyl hydrazine, the hepatotoxic metabolite of iproniazid suspected to induce liver necrosis. Results from preclinical and clinical investigations demonstrate that moclobemide and brofaromine, in contrast to tranylcypromine and phenelzine, very weakly potentiate the pressor effects of orally administered tyramine. In conclusion, the reversible MAO-A inhibitors moclobemide and brofaromine, due to their well-documented safety characteristics, to their lack of anticholinergic-effects and to their good tolerability, will provide innovative tools for clarifying the role of MAO-A inhibitors in the treatment of endogenous and atypical depressive states.
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PMID:Preclinical profiles of the novel reversible MAO-A inhibitors, moclobemide and brofaromine, in comparison with irreversible MAO inhibitors. 267 42

Moclobemide belongs to a new generation of short-acting, reversible, monoamine oxidase (MAO) inhibitors. In vitro (rat brain homogenates) moclobemide inhibits MAO-A selectively with lower potency than many of the reference MAO inhibitors. However, when measured ex vivo in the rat, the potency of moclobemide is similar to that of reference compounds. In vivo the drug induces a dose-dependent, short-lasting (8-16 hr) and preferential inhibition of MAO-A in the brain and both MAO-A and MAO-B inhibition in extracerebral organs (liver, small intestine and kidney). In the extracerebral tissues of the rat moclobemide induces marked peripheral MAO-B inhibition due to rapid and extensive biotransformation of its morpholine ring. The active molecular species is probably the metabolite Ro 16-6491. The moderate MAO-B inhibition measured after moclobemide intake in human platelets indicates that only minor amounts of Ro 16-6491 are formed in humans. Virtually all metabolites of moclobemide so far identified have been tested in vitro and ex vivo in the rat and proved to be either equipotent or, mostly, less effective than moclobemide as MAO-A inhibitors. In liver homogenates of moclobemide-treated rats MAO-A activity recovers during dialysis or simple incubation at 37 degrees C, suggesting a biodegradation of moclobemide and/or the moclobemide-derived active metabolite(s) by MAO itself or a slow dissociation of the active inhibitory species from the enzyme. Similar to other MAO-A inhibitors, moclobemide induces an increase in the rat brain levels of 5-hydroxytryptamine, norepinephrine and dopamine and a concomitant decrease of their deaminated metabolites. These effects are of short duration (8-16 hr) and parallel the time course of MAO-A inhibition. Moclobemide administered subchronically down-regulates beta adrenoceptors as shown by binding experiments with brain cortical membranes using dihydroalprenolol as ligand. In vitro MAO inhibition by moclobemide is specific in that the compound does not affect other amine oxidases or monoamine uptake mechanisms; furthermore, it does not interact with various neurotransmitter or drug receptor sites. In conclusion, a large body of preclinical evidence characterizes moclobemide as a short-acting and reversible MAO-inhibitor. The neurochemical profile of moclobemide indicates clearly that this nonhydrazine nonhepatotoxic MAO-A inhibitor represents a novel and safe drug for treatment of affective disorders.
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PMID:Neurochemical profile of moclobemide, a short-acting and reversible inhibitor of monoamine oxidase type A. 278 11

Oil/water partition coefficients of various substrates of monoamine oxidase (MAO) and kinetic parameters of MAO-A and -B of rat liver at two pH values, pH 7 and pH 9, were investigated. Octanol, heptane or benzene were chosen for the oil phases. The deamination of the biogenic amines 5-hydroxytryptamine (5-HT), tyramine, 2-phenethylamine (PEA) and benzylamine was studied at pH 7 and pH 9. Results indicated all four substrates were very hydrophilic, and the oil/water partition coefficients of benzylamine and PEA were higher than those of 5-HT and tyramine. The changes in Km and Vmax values at pH 7 and pH 9 indicated that the affinities of MAO-A towards 5-HT and tyramine slightly increased at pH 9 and those of MAO-B towards tyramine and benzylamine also increased at pH 9, while uncharged amines at pH 9 amounted to about a hundred times of those at pH 7. It is concluded that the mitochondrial MAO bound to the membrane may metabolize charged molecules as well as uncharged counterparts.
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PMID:Comparative lipophilicities of substrates of monoamine oxidase. 287 16

Amethocaine (tetracaine) (1-10 microM) produces a concentration-dependent in-vitro inhibition of mitochondrial membrane-bound MAO activity towards tyramine (18-84% in brain and 19-84% in liver) and 5-hydroxytryptamine (5-HT) (23-94% in brain and 20-100% in liver). At relatively higher concentrations (25-300 microM) of amethocaine, benzylamine oxidation is inhibited in brain (24-91%) and liver (29-100%). The extent of MAO inhibition is appreciably reduced when preincubation time of the enzyme with a low concentration (7.5 microM) of amethocaine is increased from zero to 45 min. This inhibition is reversible. The Km of MAO for tyramine is increased in brain (106-473%) and liver (121-352%) in the presence of amethocaine (2-7.5 microM) accompanied by a decrease in Vmax (21-51% in brain and 18-57% in liver). Similarly the Km of MAO for 5-HT is increased to the extent of 79-336% in brain and 51-225% in liver and the corresponding Vmax is decreased by 35-55% and 39-74%, respectively, in the presence of 2-5 microM amethocaine. At relatively higher concentrations (25-100 microM), amethocaine increases the Km of MAO for benzylamine in brain (25-101%) and liver (26-85%) and decreases the Vmax by 28-64% and 32-63% in the respective tissues. Thus these results suggest that amethocaine preferentially inhibits MAO-A and the nature of inhibition is reversible and of mixed type.
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PMID:Amethocaine-induced inhibition of mitochondrial monoamine oxidase activity. 287 23

In a homogenate of epithelium isolated from the small intestine of male Wistar rats, the amine oxidase activity with 10(-3)M tyramine was 9200 +/- 200 nmol (g tissue)-1 h-1 of which 91% was due to the A form of monoamine oxidase (MAO) and 9% to the B form. Semicarbazide-sensitive amine oxidase activity was not detected with either 10(-3)M tyramine or 10(-4)M benzylamine as substrate. However, it was detectable in the homogenate of the gut residue where the activity with 10(-4)M benzylamine was 3600 +/- 200 nmol (g tissue)-1 h-1. The MAO activity, in homogenates of epithelium prepared with 0.1 M sodium phosphate pH 7.4, was stable at 4 degrees C for at least 6 h whilst at minus 20 degrees C it decreased by 70% within 24 h. Incorporation of 10% (v/v) glycerol into the homogenization medium stabilized the enzymes. The total activity and proportions due to MAO-A and MAO-B and kinetic constants for tyramine and 5-hydroxytryptamine, did not alter during 5 weeks storage at -20 degrees C. The ability to store tissue homogenates should facilitate studies of intestinal amine oxidases.
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PMID:A method for stabilization of monoamine oxidases in homogenates of rat intestine epithelium. 289 57

The metabolism of some aromatic amines by amine oxidase activities in human umbilical artery homogenates has been studied. The inhibitory effects of clorgyline showed that 5-hydroxytryptamine (5-HT) and tryptamine, 1 mM, were predominantly substrates for monoamine oxidase (MAO) type A, whereas MAO-A and B were both involved in the metabolism of beta-phenylethylamine (PEA), 100 microM, and tyramine, 1 mM. About 20-30% of tyramine and PEA metabolism was resistant to 1 mM clorgyline, but sensitive to inhibition by semicarbazide, 1 mM, indicating the presence of a semicarbazide-sensitive amine oxidase (SSAO). Benzylamine, 1 mM, appeared to be metabolized exclusively by SSAO with a Km (161 microM) at pH 7.8 similar to that found for SSAO in other human tissues. Tyramine and PEA were relatively poor substrates for SSAO, with very high apparent Km values of 17.6 and 13.3 mM, respectively, when determined in the presence of clorgyline, 10(-3) M, added to inhibit any metabolism of those amines by MAO activities. However, kinetic studies with benzylamine indicated that clorgyline, 10(-3) M, also appears to inhibit SSAO competitively such that the true Km values for tyramine and PEA may be about 60% of those apparent values given above. No evidence for the metabolism of 5-HT or tryptamine by SSAO was obtained. The aliphatic amine methylamine was recently shown to be a specific substrate for SSAO in umbilical artery homogenates. We have used benzylamine and methylamine as SSAO substrates in histochemical studies to localize SSAO in tissue sections.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Properties of a semicarbazide-sensitive amine oxidase in human umbilical artery. 290 29

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