Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: HUMANGGP:001709 (MAO-A)
 2,432 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Befloxatone, a novel oxazolidinone derivative, inhibited selectively and competitively monoamine oxidase (MAO)-A in human and rat brain, heart, liver and duodenum homogenates with Ki values ranging from 1.9 to 3.6 nM for MAO-A and from 270 to 900 nM for MAO-B. In vitro, befloxatone was more potent at inhibiting MAO-A activity than reference compounds (befloxatone > harmaline > brofaromine > BW 137OU87 > RS 8359 > toloxatone > moclobemide). The inhibition of MAO-A by befloxatone was time-dependent and fully reversible after dilution. After p.o. administration, befloxatone induced a dose-dependent and selective inhibition of rat brain and duodenum MAO-A activities ex vivo with ED50 values of 0.06 and 0.025 mg/kg, respectively. Befloxatone (0.5 mg/kg p.o.) decreased MAO-B activity by only 20% in both tissues. In the brain, liver and duodenum, the inhibition of MAO-A activity by befloxatone was short lasting. Twenty-four hours after administration of befloxatone (0.75 mg/kg p.o.), a full recovery of MAO-A activity was observed in the brain, but the enzyme activity was still decreased by 38 and 56% in the duodenum and liver, respectively. In the rat brain, befloxatone (0.75 mg/kg p.o.) increased levels of norepinephrine, dopamine and 5-hydroxytryptamine and decreased levels of their respective deaminated metabolites. These variations were dose-dependent and reversed 24 hr after administration. In addition, befloxatone (0.75 mg/kg p.o.) decreased free 3,4-dihydroxyphenylethylene glycol levels in the brain and plasma. Befloxatone (10 microM) did not modify the activities of diamine or benzylamine oxidase and did not interact with monoamine uptake mechanisms or with a variety of neurotransmitter or drug receptor sites. In conclusion, the neurochemical profile of befloxatone demonstrates that this compound is a selective, competitive, potent and reversible MAO-A inhibitor.
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PMID:Befloxatone, a new reversible and selective monoamine oxidase-A inhibitor. I. Biochemical profile. 861 28

Human keratinocytes under in vitro conditions synthesize norepinephrine and epinephrine, whereas melanocytes lack this capacity. Keratinocytes established from lesional and nonlesional skin of patients with vitiligo synthesized four and two times more norepinephrine, respectively, than controls. Epinephrine synthesis was similar in keratinocytes from uninvolved epidermis and controls, but cells from involved skin had 6.5-fold less epinephrine than controls, indicative of low phenylehtanolamine-N-methyl transferase (PNMT) activity. Similar results were obtained in five patients with vitiligo who showed low epinephrine levels in involved epidermis. Both human keratinocytes and melanocytes expressed significant levels of monoamine oxidase A (MAO-A) activities as shown using 14C-labelled 5-hydroxytryptamine as substrate and immunohistochemical staining with mouse monoclonal antibody. MAO-A activities in the total epidermis of patients with vitiligo were increased five- to ten-fold compared with skin of type-matched controls. Similar increases in MAO-A activities were also found in both keratinocytes and melanocytes established in vitro from vitiliginous epidermis. Based on these results, it can be concluded that defective catecholamine synthesis in the epidermis of patients with vitiligo leads to increased levels of norepinephrine with a concomitant increase in MAO-A activity.
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PMID:Increased monoamine oxidase A activity in the epidermis of patients with vitiligo. 875 Sep 29

Fluoxetine and its primary metabolite, norfluoxetine, are inhibitors of neuronal uptake of 5-hydroxytryptamine. While fluoxetine has also been reported to inhibit monoamine oxidase (MAO) in vitro at concentrations much lower than those measured in brain following chronic fluoxetine treatment, neurochemical profiles are not consistent with substantial MAO inhibition in vivo. In an attempt to explain this inconsistency, we have examined the interactions of fluoxetine and norfluoxetine with rat brain MAO-A and -B by a radiochemical assay method. Fluoxetine and norfluoxetine were competitive inhibitors of MAO-A in vitro, with Ki values of 76.3 microM and 90.5 microM, respectively. Both compounds were non-competitive or uncompetitive inhibitors of MAO-B in vitro. Inhibition of MAO-B was time-dependent and was very slowly reversible by dialysis. IC50 values versus metabolism of 50 microM beta-phenylethylamine were 17.8 microM (fluoxetine) and 18.5 microM (norfluoxetine). Analysis of the time-dependence of MAO-B inhibition by fluoxetine revealed that an initial competitive interaction between the enzyme and the inhibitor (Ki 245 microM) was followed by tight-binding enzyme inactivation (K(inact) 0.071 min-1). Following administration of fluoxetine (20 mg kg-1 day-1) for 7 days, the cortical concentration of fluoxetine + norfluoxetine was estimated by gas-liquid chromatography to be 700 microM. Such drug treatment reduced MAO-A activity by 23% in 1:8 (w/v) cortical homogenates, but not in 1:80 homogenates. Inhibition of MAO-B in 1:8 homogenates was modest (12%) and was not significantly reduced by homogenate dilution. The concentration of 5-hydroxyindole-3-acetic acid, measured by high pressure liquid chromatography, was reduced by 47% in cortices from drug-treated rats, while concentrations of 5-hydroxytryptamine, noradrenaline, dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid were unchanged. These results suggest that, following chronic drug administration leading to relatively high tissue concentrations of fluoxetine and norfluoxetine, inhibition of either form of MAO would be restricted by competition for the enzyme with intraneuronal amine substrates.
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PMID:Inhibition of rat brain monoamine oxidase enzymes by fluoxetine and norfluoxetine. 883 83

We have recently described an association between abnormal behaviour and monoamine oxidase A (MAOA) deficiency in several males from a single large Dutch kindred. Affected males differed from unaffected males by borderline mental retardation and increased impulsive behaviour (aggressive behaviour, abnormal sexual behaviour and arson). Nevertheless, a specific psychiatric diagnosis was not made in four affected males who had psychiatric examination. Since MAOA deficiency raises 5-hydroxytryptamine (5-HT) levels, it provides an interesting exception to the low 5-HT paradigm of impulsive aggression. Even if the possible relationship between MAOA deficiency and abnormal behaviour is confirmed in other kindreds, the data do not support the hypothesis that MAOA constitutes an "aggression gene'. In fact, because genes are essentially simple and behaviour is by definition complex, a direct causal relationship between a single gene and a specific behaviour is highly unlikely. In the case of MAOA deficiency, some of the complexities are illustrated by the variability in the behavioural phenotype, as well as by the highly complex effects of MAOA deficiency on neurotransmitter function. Thus, the concept of a gene that directly encodes behaviour is unrealistic.
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PMID:MAOA deficiency and abnormal behaviour: perspectives on an association. 886 75

The effect of 5-morpholinemethyl-3-(4-chlorobenzylideneamino)-2-oxazolidin one (AS-8), a potential antidepressant drug, was tested on 5-hydroxytryptamine (5-HT) metabolism in the brains of rat, mouse and chick. The ip administration of AS-8 (25-500 mg/kg) did not modify the cerebral 5-HT level, but significantly increased the level of 5-hydroxyindoleacetic acid (5-HIAA) the main 5-HT metabolite. In animals receiving pargyline (a MAO-A inhibitor which blocks 5-HT catabolism), AS-8 markedly enhanced 5-HT accumulation in the brains of rats and mice, but not chicks. It is concluded that AS-8 is capable of stimulating of 5-HT synthesis at least in the mammalian brain.
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PMID:Effects of a new oxazolidinone derivative AS-8 on serotonin metabolism in the brains of mouse, rat and chick. 886 38

We have previously shown that subordination causes a reduction in the levels of 5-hydroxytryptamine and dopamine selectively in the frontal cortex [6]. These monoamines are catabolised mainly by the enzyme monoamine oxidase (MAO) which exists in two isoforms; MAO-A and MAO-B. The present study was carried out to determine whether there is any change in the activity of these two iso-enzymes induced by subordination and if any such alteration is confined to the frontal cortex. The animal model of dominance-subordination used was a worker-parasite paradigm in male Wistar rats. The enzyme activities were measured in five brain regions, the frontal cortex, entorhinal cortex, hippocampus, hypothalamus and striatum, using kynuramine as the substrate. Clorgyline and L-deprenyl were used in vitro to block the activities of MAO-A and MAO-B, respectively. There was a significant (P < 0.001) reduction in the activity of MAO-A as well as MAO-B selectively in the frontal cortex of the subordinate animals. This finding may suggest a reduced neurotransmitter turnover in the serotonergic and dopaminergic neurons terminating in the frontal cortex.
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PMID:Selective reduction of monoamine oxidase A and B in the frontal cortex of subordinate rats. 920 54

We assessed the role of glial cells in the uptake of serotonin (5-hydroxytryptamine, 5-HT). Primary cultures of rat and mouse cortical astrocytes took up and deaminated 5-HT. The antidepressants citalopram, clomipramine, fluoxetine, fluvoxamine, paroxetine and sertraline inhibited this process. The presence of the mRNAs for the 5-HT transporter and monoamine oxidase-A (MOA-A) was established in cultured astrocytes and in adult rat brain areas with (midbrain and brainstem) and without (frontal cortex) serotonergic cell bodies after reverse transcription-polymerase chain reaction and hybridization with probes complementary to the cloned neuronal 5-HT transporter and MAO-A. To examine in vivo the role of astrocytes in the elimination of 5-HT from the extracellular brain space, 5-HT was perfused through dialysis probes implanted in the frontal cortex of conscious rats and its concentration was measured at the probe outlet. Tissue 5-HT recovery was dose-dependently inhibited by the concurrent perfusion of citalopram, fluoxetine and paroxetine, showing that it essentially measured uptake through the high-affinity 5-HT transporter. Rats lesioned with 5,7-dihydroxytryptamine (5,7-DHT; 88% reduction of tissue 5-HT) displayed tissue 5-HT recovery slightly higher than sham-operated rats (55 +/- 2 vs. 46 +/- 3%, P < 0.001), a finding perhaps attributable to the astrogliosis induced by 5,7-DHT denervation. Rats lesioned with 6-hydroxydopamine showed tissue 5-HT uptake similar to controls, suggesting negligible reuptake of 5-HT by catecholaminergic terminals. These results are consistent with the presence of a glial component of 5-HT uptake in the rodent brain, sensitive to antidepressants, which takes place through a 5-HT transporter very similar or identical to that present in neurons.
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PMID:Antidepressant drugs inhibit a glial 5-hydroxytryptamine transporter in rat brain. 928 27

To explore further the usefulness of opossum kidney (OK) cells in the study of renal dopaminergic physiology, we have undertaken the study of aromatic L-amino acid decarboxylase (AAAD), catechol-O-methyltransferase (COMT) and type A and B monoamine oxidase (MAO-A and MAO-B), the main enzymes involved in the synthesis and degradation of dopamine. The Vmax values for AAAD, using L-DOPA as the substrate, in rat renal tubular cells were found to be significantly (P < 0.01) higher (120-fold) than in OK cells. However, K(m) values in OK cells (1.1 mM [0.3, 1.9]) were similar to those observed in rat renal tubular cells (K(m) = 1.0 mM [0.8, 1.2]). The Vmax values for COMT (in nmol/mg protein/30 min) in OK cells (2.1 +/- 0.2) were similar to those in the rat renal tubular cells (1.6 +/- 0.1), whereas K(m) values in OK cells (2.3 microM [0.1, 4.5]) differ considerably (4.8-fold, P < 0.01) from those in rat renal tubular cells (11.2 microM [9.2, 13.1]). The Vmax values (in nmol/mg protein/20 min) for deamination of [3H]-5-hydroxytryptamine, the specific MAO-A substrate, was similar in rat renal tubular cells (12.4 +/- 1.0) and OK cells (12.9 +/- 1.1); K(m) values also did not differ between these two preparations. In contrast to rat renal tubular cells, deamination of [14C]-beta-phenylethylamine, the substrate for MAO-B, in OK cells was found to be non-saturable and to represent less than 10% of that observed in homogenates of rat tubular cells. In conclusion, OK cells in culture are endowed with the synthetic and metabolic machinery needed to form and degrade dopamine. The amounts of the enzymes AAAD, COMT and MAO-A found in this cell line are likely to be sufficient to reproduce, under in vitro conditions, the environment in which the renal dopaminergic system normally operates.
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PMID:Opossum kidney (OK) cells in culture synthesize and degrade the natriuretic hormone dopamine: a comparison with rat renal tubular cells. 936 46

Pirlindole is a tetracyclic compound that has been characterized as a potential antidepressant drug. It has pharmacological characteristics in common with both tricyclic antidepressants and classical irreversible monoamine oxidase inhibitors. Its main mechanism of action consists of a selective and reversible inhibition of monoamine oxidase A. Secondarily, it exerts an inhibitory effect on noradrenaline and 5-hydroxytryptamine reuptakes. It has no effect on the dopaminergic and cholinergic systems. It has only a low potential for amplifying tyramine and noradrenaline pressor effect, which makes one expect that it will not be at the basis of a 'cheese effect'. Pirlindole has an absolute bioavailability of between 20 and 30% due to an extensive first-pass effect. Orally, the Tmax varies between 2.5 and 6 h in the rat and 0.8 and 2 h in the dog. Two phases of elimination (7.5 and 34-70 h) are measured in the rat and three phases in the dog (1.3, 10.8 and 185 h); it is extensively metabolized. The rat eliminates mainly unconjugated products while the dog eliminates mostly conjugated products. Acute and chronic toxicological studies have not revealed potentially dangerous effects of the drug at the usual doses. It does not present measurable mutagenic, clastogenic or carcinogenic properties. Thus, pirlindole shows pharmacological, pharmacokinetic and toxicological properties which make it suitable for the management of depression.
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PMID:Pirlindole: a selective reversible inhibitor of monoamine oxidase A. A review of its preclinical properties. 936 11

RS-8359 is a new reversible inhibitor of monoamine oxidase A (RIMA). With a selectivity ratio of about 2200 for the A:B enzyme types, it is one of the most specific of this class of compounds. As a result, it shows relatively little effect upon blood pressure when administered together with tyramine, thus effectively eliminating the 'cheese' effect which has contributed to the limited clinical use of the classical monoamine oxidase inhibitors (MAOIs). RS-8359 shows little affinity for the common central nervous system receptors and little anticholinergic effect. These characteristics suggest a relatively benign adverse event profile, which may be particularly advantageous in the elderly and may generally contribute to patient acceptance and compliance. In terms of its effects upon serotonin (5-hydroxytryptamine), RS-8359 gives increases similar to those of other MAOIs with activity sustained for about 9 h. In behavioural investigations, the compound gives results similar to those found with several antidepressants widely used in the clinic. Overall, the pharmacology of RS-8359 indicates that it should have antidepressant activity in man.
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PMID:Pharmacology of the new reversible inhibitor of monoamine oxidase A, RS-8359. 946 63


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