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PubMed2002

Monoamine oxidase inhibitors: a new generation.

Monoamine oxidase inhibitors (MAOIs), which ushered in the modern era of psychopharmacology in the 1950s, have remained useful in the treatment of depression despite important safety concerns, such as acute hypertensive episodes brought on by ingestion of foods with high-tyramine content. Experience has shown that MAOIs are broadly effective in the treatment of depressive disorders, including atypical, chronic, and double depressions. Newer selective and reversible inhibitors of the two forms of mitochondrial monoamine oxidase (MAO) enzymes, MAO-A and MAO-B, have been developed in an effort to improve the safety and tolerability of MAOIs. Selegiline, a selective inhibitor of MAO-B has been shown to be effective in the treatment of depression at higher oral doses where selectivity for MAO-B is lost. Transdermal delivery of selegiline bypasses first-pass metabolism and avoids impairment of the gastrointestinal barrier provided by MAO-A of the gastrointestinal mucosa. Studies have shown that the selegiline transdermal system (STS) does not significantly affect sensitivity to ingested tyramine, unlike tranylcypromine, which markedly increases sensitivity. STS has been found to be efficacious in the treatment of patients with major depression in placebo-controlled trials, without the need for dietary precautions. The favorable safety profile of STS should allow this MAOI to be a broadly used antidepressant drug.

Administration, Cutaneous↗

PubMed1979

Occurrence of mitochondrial monoamine oxidase in human semen.

Mitochondrial monoamine oxidase (MAO) was found in human semen, showing its Km and Vmax values of 91.7 microM and 290 pmoles/mg of protein/60 min, respectively, with kynuramine as substrate. A major part of the activity was due to type A MAO.

Humans↗

PubMed2004

Crystallization and preliminary crystallographic analysis of rat monoamine oxidase A complexed with clorgyline.

Monoamine oxidase (MAO) is an FAD-containing mitochondrial outer-membrane protein which catalyzes the degradation of several neurotransmitters in the central nervous system. The two subtypes of MAO, MAOA and MAOB, have similar primary sequences but different substrate and inhibitor specificities. The structure of human MAOB has recently been determined, but the structure of MAOA remains unknown. To clarify the mechanisms underlying their unique substrate and inhibitor recognition and thereby facilitate the development of new specific inhibitors to treat MAO-related neurological disorders, rat MAOA was crystallized in a complex with the specific inhibitor clorgyline. Diffraction data were collected to 3.2 A resolution. The crystal belongs to the space group P4(3)2(1)2, with unit-cell parameters a = b = 158.2, c = 258.4 A.

Animals↗

PubMed2003

1-methyl-2-undecyl-4(1H)-quinolone as an irreversible and selective inhibitor of type B monoamine oxidase.

The inhibitory compound of monoamine oxidase (MAO) activity was isolated from the CH(2)Cl(2) fraction of the fructus of Evodia rutaecarpa and identified as 1-methyl-2-undecyl-4(1H)-quinolone (1). Compound 1 showed a selective inhibition of type B MAO (MAO-B) activity with the IC(50) value of 15.3 microM using a substrate kynuramine, but did not inhibit type A MAO (MAO-A) activity. The kinetic analysis using Lineweaver-Burk plots indicated that compound 1 competitively inhibited MAO-B activity with the K(i) value of 9.91 microM. The inhibition of MAO-B by compound 1 was found to be irreversible by dialysis of the incubation mixture. These results suggest that compound 1 is a potent irreversible inhibitor of MAO-B, and may regulate catecholamine content in the neurons.

Animals↗

PubMed1986

Modulation by phospholipids of the activity of monoamine oxidase purified from pig liver.

Monoamine oxidase was purified from pig liver mitochondria to homogeneity. The enzyme sample contained a large amount of phospholipids. Depletion of lipids from the enzyme sample resulted in a decrease in its activity, while activity was restored by the binding of the lipid-depleted enzyme to phosphatidylcholine, phosphatidylethanolamine, or mitochondrial lipids. Upon binding the lipid-depleted enzyme to the mixture of phosphatidylcholine and phosphatidylethanolamine (molar ratio, 1 : 1), the enzymatic activity toward serotonin was elevated over that of the purified enzyme, but not toward benzylamine, suggesting a change in substrate specificity. Upon lipid depletion, inhibition by deprenyl became weaker, while that by clorgyline became stronger. This alteration was reversed by the binding to lipids. By the binding of the lipid-depleted enzyme to some lipids such as the mixture of phosphatidylcholine and phosphatidylethanolamine (molar ratio, 1 : 1), inhibition by clorgyline became even weaker than for the original enzyme sample.

Animals↗

PubMed1984

Effect of alpha-methylation on inactivation of monoamine oxidase by N-cyclopropylbenzylamine.

Monoamine oxidase (MAO) was shown previously [Silverman, R. B., & Hoffman, S. J. (1980) J. Am. Chem. Soc. 102, 7126-7128] to catalyze the oxidation of N-cyclopropylbenzylamine (N-CBA) at two sites on the molecule. Oxidation at the benzyl methylene gave benzaldehyde and cyclopropylamine; oxidation of the cyclopropyl group, which involved cyclopropyl ring cleavage, led to inactivation of the enzyme. In this paper it is shown that methylation of the benzyl methylene dramatically alters this partition ratio in favor of enzyme inactivation. Contrary to a previous report [Alles, G., & Heegaard, E. V. (1943) J. Biol. Chem. 147, 487-503], it is shown here that alpha-methylbenzylamine is a substrate for MAO; consequently, N-cyclopropyl-alpha-methylbenzylamine (N-C alpha MBA) is a good candidate for mechanism-based inactivation. N-Cyclopropyl[7-14C]benzylamine, N-cyclopropyl-alpha-methyl[phenyl-14C]benzylamine, N-[1-3H]-cyclopropylbenzylamine, and N-[1-3H]cyclopropyl-alpha-methylbenzylamine are synthesized, and product formation following MAO inactivation is quantified. The results obtained with these compounds indicate that with N-C alpha MBA, alpha-methylbenzyl oxidation (which produces acetophenone and cyclopropylamine) is only 1% that of cyclopropyl oxidation (which gives enzyme inactivation), whereas with N-CBA the amount of oxidation at the corresponding sites is equal. It also is shown that the Ki values for (R)-(+)- and (S)-(-)-alpha-methylbenzylamine are similar, suggesting that dimethylation of N-CBA should not interfere with binding to MAO.(ABSTRACT TRUNCATED AT 250 WORDS)

Amines↗

PubMed2005

Molecular characterization of monoamine oxidase in zebrafish (Danio rerio).

Monoamine oxidase (MAO) is responsible for the degradation of a number of neurotransmitters and other biogenic amines. In terrestrial vertebrates, two forms of the enzyme, named MAO A and B, were found in which mammals are coded by two similar but distinct genes. In teleosts, the biochemical data obtained so far indicate that enzyme activity is due to a single form, whose sequence, obtained for trout, displays 70% identity with mammal MAO A and B. In this paper, we carried out an investigation of zebrafish MAO (Z-MAO) to shed further light on the nature of the MAO form present in aquatic vertebrates. Sequencing studies have revealed an open reading frame 522-amino-acids long with MW 58.7 kDa, displaying 84% identity with trout MAO and about 70% identity with mammal MAO A and MAO B. Analysis of the sequence and of the predicted secondary structure shows that also in Z-MAO principal domains characterizing the MAOs are present. The domain linking the FAD is very well conserved, while the transmembrane domain sequence linking the enzyme to the external mitochondrial membrane does not appear to be conserved even with respect to trout MAO. Comparison with the amino acids which, according to the human MAO B and rat MAO A models, line the substrate-binding site shows that in Z-MAO, several residues (V172, N173, F200, L327) differ from MAO B but are similar or identical to the corresponding ones present in rat MAO A, as well as in trout MAO. A three-dimensional model is reported of the substrate-binding site of Z-MAO obtained by comparative modeling. Our observations support the hypothesis that the MAO form present in aquatic vertebrates is a MAO A-like form. Experiments performed to test the effect of selective MAO A (clorgyline) and MAO B (deprenyl) inhibitors on the enzyme's activity in liver and brain confirm the presence of a single form of MAO in zebrafish.

Amino Acid Sequence↗

PubMed1972

Inhibition of monoamine oxidase by substituted hydrazines.

1. The initial rate of inhibition of monoamine oxidase by phenethylhydrazine was shown to be similar, in pH-dependence and kinetic properties, to the oxidation of that compound by monoamine oxidase. 2. The time-course of irreversible inhibition of monoamine oxidase by phenethylhydrazine lags behind that of reversible inhibition. 3. Hydralzine was shown to be a reversible competitive inhibitor of monoamine oxidase, but phenylhydrazine is an irreversible inhibitor. Inhibition by the latter compound is not affected by the absence of oxygen, and the presence of substrate exerts no protective action. 4. Hydrazine does not inhibit monoamine oxidase unless a substrate and oxygen are present. 5. Phenethylidenehydrazine was found to be a time-dependent inhibitor of monoamine oxidase and the rate of inhibition was hindered by increasing oxygen concentration. 6. A mechanism for the inhibition of the enzyme by phenethylhydrazine is proposed in which the product of oxidation of this compound is a potent reversible inhibitor and an irreversible inhibitor of the enzyme. A computer simulation of such a mechanism predicts time-courses of inhibition that are in reasonable agreement with those observed experimentally.

Animals↗

PubMed1996

Molecular neuroanatomy of human monoamine oxidases A and B revealed by quantitative enzyme radioautography and in situ hybridization histochemistry.

Monoamine oxidases are key enzymes in the metabolism of amine neurotransmitters and neuromodulators and are targets for drug therapy in depression, Parkinson's and Alzheimer's diseases. Knowledge of their distribution in the brain is essential to understand their physiological role. To study the regional distribution and abundance of monoamine oxidases A and B in human brain, pituitary and superior cervical ganglion, we used quantitative enzyme radioautography with radioligands [3H]Ro41-1049 and [3H]lazabemide, respectively. Furthermore, 35S-labelled oligonucleotides complementary to isoenzyme messengerRNAs were used to map the cellular location of the respective transcripts in adjacent sections by in situ hybridization histochemistry. A markedly different pattern of distribution of the isoenzymes was observed. Highest levels of monoamine oxidase A were measured in the superior cervical ganglion, locus coeruleus, interpeduncular nucleus and ventromedial hypothalamic nucleus. The corresponding messengerRNA was detected only in the noradrenergic neurons of the superior cervical ganglion and locus coeruleus. In contrast to rat brain, monoamine oxidase B was much more abundant in most human brain regions investigated. Highest levels were measured in the ependyma of ventricles, stria terminalis and in individual hypothalamic neurons. Monoamine oxidase B transcripts were detected in serotoninergic raphe neurons, histaminergic hypothalamic neurons and in dentate gyrus granule cells of the hippocampal formation. We conclude that [3H]Ro41-1049 and [3H]azabemide are extremely useful radioligands for high-resolution analyses of the abundance and distribution of catalytic sites of monoamine oxidases A and B, respectively, in human brain sections. From levels of messenger RNA detected, the cellular sites of synthesis of the isoenzymes are the noradrenergic neurons of the locus coeruleus (for monoamine oxidase A) and the serotoninergic and histaminergic neurons of the raphe and posterior hypothalamus, respectively (for monoamine oxidase B). The combination of quantitative enzyme radioautography with in situ hybridization histochemistry is a useful approach to study, with high resolution, both the physiology and pathophysiology of monoamine oxidases in human brain.

Aged↗

PubMed1981

Early change in mitochondrial monoamine oxidase activity of rat liver during 2-acetylaminofluorene feeding.

The activities of mitochondrial type A and B monoamine oxidase were determined in the liver of rats fed a diet containing 2-acetylaminofluorene (AAF). Three days after the initiation of AAF-feeding, there was a significant decrease of type B monoamine oxidase activity without affect on type A enzyme. The decreased activity of type B monoamine oxidase, which reached a minimum after three weeks, was sustained for as long as AAF-feeding was continued. Sex-related difference in response to AAF was seen in the rat with respect to the onset and the intensity of the decreased type B monoamine oxidase activity, male rats being more sensitive to the carcinogen than female rats. In contrast to the in vivo effect, AAF showed a potent inhibitory effect on type A monoamine oxidase, rather than on type B enzyme, when added in vitro. The pI50 values were estimated to be 7.5 against type A monoamine oxidase and 4.1 against type B enzyme, respectively. The in vitro inhibition of both types of monoamine oxidase by AAF was competitive. The Ki values for AAF were calculated to be 9.51 x 10(-9)M for type A monoamine oxidase and 1.30 x 10(-5)M for type B enzyme, respectively. In accordance with the potent inhibitory effect of AAF on type A monoamine oxidase in vitro, a single administration of the carcinogen, at a dose of 50 mg/kg, resulted in a marked and temporal decrease of the enzyme activity in the mitochondria of male rat liver. Recovery of the decreased type B monoamine oxidase activity was slow, and the enzyme activity did not return to control levels, even if rats were fed the basal diet for 2 or 4 weeks after the cessation of AAF-feeding

2-Acetylaminofluorene↗

PubMed1998

Studies on the behaviour of semicarbazide-sensitive amine oxidase in Sprague-Dawley rats treated with the monoamine oxidase inhibitor tranylcypromine.

The possibility that increased levels of the activity of the semicarbazide-sensitive amine oxidase (SSAO) might, to some extent, compensate for the loss of monoamine oxidase (MAO) activity in the atypical form of Norrie Disease, was examined using the rat as a model. Long-term treatment with the MAO inhibitor tranylcypromine (1 mg/kg/day) resulted in sustained inhibition of MAO-A and MAO-B activities in liver and brain. After one week, the SSAO activity in heart had increased by 79% above the control levels. This increase was maintained for 3 weeks. Since such alterations might result from enzyme induction, the turnover of the enzyme was studied in cultured cells from rat aortic smooth muscle. The time-course of recovery of enzyme activity following irreversible inhibition by MDL 72145 corresponded to a half-life of approximately 6 days for this process.

Allylamine↗

PubMed1990

Participation of type A monoamine oxidase in the activated deamination of brain monoamines shortly after reperfusion in rats.

Changes in monoamine levels during and after ischemia and effects of RS-8359, a type A monoamine oxidase (MAO-A) inhibitor, were studied in the cerebral cortex, hippocampus, and striatum of rats killed by microwave irradiation. The patterns of the changes in norepinephrine (NE), dopamine (DA), and serotonin (5HT) levels were similar during ischemia: All these monoamines decreased in all three regions. After reperfusion, however, the three monoamines showed different patterns of changes: NE, except in the striatum, decreased further; DA increased over the controls; 5HT remained suppressed in all three regions. With regard to the metabolites of the monoamines, the changes during and after reperfusion were almost similar in all regions: O-methylated metabolites, normetanephrine and 3-methoxytyramine, markedly increased during ischemia; After reperfusion, the elevated levels of normetanephrine and 3-methoxytyramine returned to normal, while deaminated metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid, homovanillic acid (HVA), and 3-methoxy-4-hydroxy-phenylethyleneglycol clearly increased. RS-8359 pretreatment (30 mg/kg, p.o.) at an hour prior to ischemia elevated the levels of NE in the cortex and hippocampus during ischemia and inhibited the increases in DOPAC and HVA levels and the decrease in 3MT levels at 30 min after reperfusion. These results suggest that deamination of NE, DA, and 5HT is activated by the increases in the substrates for MAO in all three regions, except the noradrenergic system in the striatum, and that MAO-A participates in the activated deamination after reperfusion.

Animals↗

PubMed1995

Secondary structure of monoamine oxidase by FTIR spectroscopy.

The secondary structure of human monoamine oxidase A and bovine monoamine oxidase B has been investigated by Fourier Transform Attenuated Total Reflection Spectroscopy (FTIR ATR). The experimental results are compared for both isoenzymes and the data are incorporated in a statistical attribution of secondary structure of the enzyme describing the distinct folding and molecular specificity of the two types of monoamine oxidase.

Amino Acid Sequence↗

PubMed1990

Enhancement of rat brain cytosolic monoamine oxidase activity by clorgyline. Comparison with (-)-deprenyl and MDL 72145.

The presence of unsedimentable forms of monoamine oxidase (EC 1.4.3.4) in liver and brain homogenates has prompted fresh studies on the effects of inhibitors on this cytosolic monoamine oxidase. Clorglycine is a specific monoamine oxidase A inhibitor and (-)-deprenyl and MDL 72145 are specific monoamine oxidase B inhibitors. We investigated the effects of (-)-deprenyl, MDL 72145 and clorgyline on the purified enzyme from mitochondria and cytosolic monoamine oxidase along with high speed cytosol and 1% Triton X-100 treated mitochondrial preparations. Clorgyline enhanced the activity of the purified enzyme several-fold. (-)-Deprenyl and MDL 72145 also enhanced and inhibited the activity of cytosolic monoamine oxidase in a concentration-dependent manner.

Allylamine↗

PubMed2000

Time-dependent changes in brain monoamine oxidase activity and in brain levels of monoamines and amino acids following acute administration of the antidepressant/antipanic drug phenelzine.

Phenelzine (PLZ) is a non-selective monoamine oxidase (MAO) inhibitor commonly used to treat depression and panic disorder. Acute administration of PLZ produces several neurochemical changes, including an increase in brain levels of the catecholamines norepinephrine (NE) and dopamine (DA), of 5-hydroxytryptamine (5-HT), and of the amino acids alanine and gamma-aminobutyric acid (GABA). The goal of the present series of experiments was to characterize the time course of these PLZ-induced changes. Male Sprague-Dawley rats were sacrificed 6, 24, 48, 96, 168, or 336 hr after acute PLZ administration (15 or 30 mg/kg, i.p., based on free base weight). Whole brain levels of monoamines and amino acids were determined using HPLC, and MAO A and B activities were determined using a radiochemical procedure. The results indicated that PLZ changed amino acid levels 6 and 24 hr after injection, but not 48 hr later. In contrast, the effects of PLZ on MAO activity and monoamines were longer-lasting. For example, PLZ-induced increases in dopamine and 5-HT were observed 1 week after injection, and PLZ-induced inhibition of MAO activity persisted for 2 weeks. Thus, in addition to demonstrating that the effects of PLZ on MAO activity and monoamines were long-lasting, these results indicate that the effects of PLZ on MAO activity and on brain levels of monoamines and amino acids are temporally dissociated. These findings regarding the long-term effects of PLZ on neurochemistry will have considerable critical implications for the design and interpretation of behavioral studies of the acute effects of PLZ.

Amino Acids↗

PubMed1993

Monoamine oxidase inhibitors increase preferentially extracellular 5-hydroxytryptamine in the midbrain raphe nuclei. A brain microdialysis study in the awake rat.

We have examined the local and systemic effects of clorgyline, tranylcypromine and deprenyl on extracellular serotonin (5-HT) and 5-hydroxyindoleacetic acid in the raphe nuclei and in frontal cortex of awake, freely-moving rats using microdialysis. When administered through the dialysis probe, monoamine oxidase (monoamine: oxygen oxidoreductase (deaminating), E.C. 1.4.3.4., MAO) inhibitors increased 5-HT output in a dose-dependent manner in both brain areas. The effects were more pronounced in the raphe nuclei for the three MAO inhibitors at all doses assayed. When the monoamine oxidase inhibitors were given i.p., dialysate 5-HT increased dramatically, after tranylcypromine (15 mg/kg), in raphe nuclei and frontal cortex (area under the curve (AUC) to 4 h post-treatment: 63-fold and 11-fold, respectively) whereas the effects of clorgyline (10 mg/kg) were much less pronounced (+47% increase in the AUC for raphe nuclei, P < 0.09; +18% increase in the AUC for frontal cortex, n.s.). Deprenyl (2.5 mg/kg, i.p.) induced a moderate (+22%) increase of dialysate 5-HT from the raphe nuclei but did not cause a change in dialysate 5-HT from the frontal cortex (+4%). However, clorgyline, or deprenyl, dramatically increased dialysate 5-HT in animals which had been pre-treated with the above dose of deprenyl, or clorgyline, respectively, showing that the blockade of both forms of MAO results in much larger increases of extracellular 5-HT than does the blockade of either form alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1999

Ketanserin and tetrabenazine abolish aggression in mice lacking monoamine oxidase A.

Mice deficient in monoamine oxidase A (MAO A) have elevated brain levels of 5-HT and manifest enhanced aggression. We used these mice as a model to study the role of 5-HT in aggression. Our results show that ketanserin and tetrabenazine (TBZ) strikingly abolished the aggressive behavior of MAO A-deficient mice. The anti-aggressive effect of ketanserin may be primarily mediated by 5-HT(2A) receptors. Another specific 5-HT(2A) antagonist, [R-(+)-a-(2, 3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methan ol (MDL 100907), also blocks the aggression of mutant mice but was less dramatic. Ketanserin and TBZ are both antagonists of the vesicular monoamine transporter (VMAT2). The anti-aggressive effect of TBZ and part of the effect of ketanserin may be mediated by the VMAT2. Using radioligand binding and autoradiography, we also showed that the numbers of VMAT2, 5-HT(1A), 5-HT(2A) and 5-HT(2C) sites are decreased in brains of mutant mice, which may reflect down-regulation by excess 5-HT. This study suggests that ketanserin and TBZ may be developed as novel anti-aggressive agents.

Adrenergic Uptake Inhibitors↗

PubMed1976

Heterogeneity of pig liver and pig brain mitochondrial monoamine oxidase.

Pig liver and pig brain mitochondrial monoamine oxidase were inhibited by increasing concentrations of clorgyline (selective inhibitor for the "A" form of monoamine oxidase) and deprenil (selective inhibitor for the "B" form of the enzyme) and the activities were then estimated with serotonin, tyramine and beta-phenylethylamine as substrates. The results indicate that both the "A" and the "B" forms are present in these tissues. Serotonin and tyramine are shown to be oxidized by both the "A" and the "B" forms of the enzyme, whereas beta-phenylethylamine appears to be oxidized almost exclusively by the "B" form. Lipid-depletion of the mitochondrial preparation from these tissues by extraction with aqueous methyl ethyl ketone eliminated almost all of the "A" form activity while most of the "B" form activity remained.

Animals↗