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PubMed1979

Monoamine oxidase inhibition by beta-carbolines: a quantum chemical approach.

Monoamine oxidase inhibition by beta-carboline derivatives is related to the energy change, delta E, arising from complex formation between the inhibitor and the enzyme. The energy change was expressed in terms of electronic indexes, which were estimated for a set of aromatic beta-carbolines. The electronic indexes were correlated to the experimental activity indexes by a simplified quantum chemical perturbational treatment with a multiple regression procedure. A characteristic structure for the inhibitor-enzyme complex was derived from the correlation. The molecules are linked by two kinds of bond. One involves the lone pyridine nitrogen pair of beta-carbolines; the other is due to a pi-electronic interaction between the inhibitor indole fragment and a suitable area of the enzyme. Such a model explains the competitive inhibition by beta-carbolines compared to tryptamine and other aromatic amines that are monoamine oxidase substrates.

Carbolines↗
PubMed1986

A reactive metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine is formed in rat brain in vitro by type B monoamine oxidase.

The formation of a reactive intermediate in the oxidative metabolism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) that can covalently bind to monoamine oxidase or other cellular macromolecules has been postulated by several authors. We report here direct in vitro evidence that MPTP is converted by monoamine oxidase, predominantly type B, to a reactive metabolite, which binds irreversibly to proteins in rat brain. Rat brain homogenates were incubated at 37 degrees C with 1-[methyl-3H]MPTP and the perchloric acid precipitates were washed exhaustively with organic solvents and counted for radioactivity. The amount of recovered radioactivity was enzyme-related: it was time- and temperature-dependent and did not occur with preboiled tissue. This metabolic activity required oxygen; it was concentrated in the crude mitochondrial fraction and varied in different brain regions. Pargyline and deprenyl prevented the radioactivity binding, whereas clorgyline was less potent, indicating that monoamine oxidase, predominantly of type B, is the enzyme responsible for the production of the reactive metabolite. Glutathione and, to a lesser extent, cysteine and dithiothreitol, but not ascorbic acid, inhibited the irreversible protein binding, suggesting that sulfhydryl groups may react with the metabolite possibly leading to SH-conjugates. 1-Methyl-4-phenyl-2,3-dihydropyridinium increased the irreversible protein binding, indicating that the reactive metabolite of MPTP may not be identified as the dihydropyridinium compound. This chemically reactive intermediate might play a role in MPTP neurotoxicity.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1983

Monoamines, monoamine oxidase and alcoholism.

The alcohol-addictive metabolite hypothesis of alcohol addiction is reviewed. The status of monoamine oxidase in this clinical condition is also discussed and possible reasons for low platelet activity proposed. An endogenous monoamine oxidase inhibitor, which is also a benzodiazepine receptor ligand, denominated tribulin, is produced in excess following alcohol withdrawal and may, in fact, be a predisposing factor for or the actual agent precipitating delirium tremens. Alcohol suppresses tribulin production and predisposed individuals may drink it to counter the dysphoric effects of a baseline overproduction of this compound.

Alcohol Drinking↗
PubMed1986

Monoamine oxidase activity in chick cerebral microvessels.

In chick brain microvessels, monoamine oxidase activity using catecholamines (dopamine and noradrenaline) and indoleamines (serotonin and tryptamine) as substrates was higher than that measured in synaptosomes and free mitochondria. In contrast, phenylalkyamines such as tyramine and 2-phenylethylamine were more deaminated in free mitochondria and synaptosomes than in microvessels. These results suggest that the activity of monoamine oxidase towards neurotransmitter amines in microvessels should be considered as a site of inactivation of these neurotransmitters in the chick brain parenchyma.

Animals↗
PubMed1984

Colorimetric assay for monoamine oxidase in tissues using peroxidase and 2,2'-azinodi(3-ethylbenzthiazoline-6-sulfonic acid) as chromogen.

Monoamine oxidase is assayed in tissue by a colorimetric reaction using horse radish peroxidase and 2,2'-azinodi(ethylbenzthiazoline-6-sulfonic acid to measure H2O2 formed during oxidation of amines. The method has a coefficient of variation of approximately 2.5% and provides results comparable with those of radiometric assay. Monoamine oxidase activities in rat liver mitochondria and crude mitochondrial fraction from brain and with tyramine as a substrate were 18.9 +/- 0.4 and 4.61 +/- 0.15 nmol/min/mg of protein, respectively, using this method. Kinetic parameters of liver and brain monoamine oxidase with various substrates and inhibitors appeared to be the same when determined by either colorimetric or radiometric methods.

Animals↗
PubMed1995

Effects of transient global ischemia and a monoamine oxidase inhibitor ifenprodil on rat brain monoamine metabolism.

Ifenprodil, a cerebral vasodilator and non-competitive glutamate antagonist, is also an anti-ischaemic agent; it has been shown to inhibit both forms of MAO in rat brain and lung (with slightly greater potency towards MAO-A), but it does not inhibit SSAO. The effects of ifenprodil on rat brain regional levels of monoamines and their principal metabolites following transient global ischaemia have been investigated 1 h after reperfusion. Among the three most ischaemically vulnerable brain regions (striatum, hippocampus and cortex), striatal DA, DOPAC, HVA, 5-HT and 5-HIAA levels were the most markedly increased. Simultaneous treatment with ifenprodil during reperfusion reversed the increases in the striatum, except for HVA, to the level similar to those of sham-operated controls. In contrast to the striatum, ifenprodil failed to reverse the increases seen in the cortex and hippocampus.

Animals↗
PubMed1993

Interaction of monoamine oxidase inhibitory drugs with some phospholipids.

The effect of 17 monoamine oxidase inhibitory drugs (propargylamine derivatives) on the phase transition parameters of some synthetic phospholipids has been studied by differential scanning calorimetry. The drugs modified the thermal behaviour of phospholipids proving the existence of phospholipid-drug interactions. Phosphatidylethanolamine, phosphatidylcholine and phosphatidic acid equally interact with the monoamine oxidase inhibitory drugs. Significant correlations were found between the change of the phase transition parameters of phospholipids and the hydrophilic and hydrophobic molecular parameters of drugs. Calculations suggest that both hydrophilic (between the head group of phospholipids and the polar propargylamine group of drugs) and hydrophobic (between the apolar fatty acid chains of phospholipids and the lipophilic substructures of drugs) forces are involved in the phospholipid-drug interaction. Chloro substitution in the hydrophobic moiety of drugs enhances considerably the strength of interaction.

Calorimetry, Differential Scanning↗
PubMed2005

A novel and selective monoamine oxidase B substrate.

Cyclic five- and six-membered tertiary allylamines constitute a unique class of monoamine oxidase substrates that undergo a net two-electron alpha-carbon oxidation to form the cyclic, conjugated eniminium metabolites. The corresponding saturated pyrrolidinyl and piperidinyl systems are not substrates for this flavoenzyme system. In an attempt to evaluate possible contributions that pi-orbital stabilization of the putative alpha-carbon radical intermediates may play in the catalytic pathway, we have examined the substrate properties of 3-methyl-6-phenyl-3-aza-bicyclo[4.1.0]heptane, the 3,4-cyclopropyl analog of the selective monoamine oxidase B substrate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The results, which document the first reported example of a saturated, cyclic tertiary amine with monoamine oxidase substrate properties, are consistent with alpha-carbon radical stabilization as a contributing factor in the catalytic pathway.

Animals↗
PubMed1994

Effect of moclobemide on rat brain monoamine oxidase A and B: comparison with harmaline and clorgyline.

1. Effects of moclobemide (12.5, 25 and 50 mg/kg), harmaline (10 mg/kg) and clorgyline (10 mg/kg) on monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B) were examined ex vivo by a fluorometric method with tyramine (T) and phenylethylamine (PEA) as substrates. Six rat brain areas were dissected for this purpose. 2. Moclobemide had decreased MAO-A activity in all areas examined by a dose-dependent manner; the largest decrease was observed in tuberculum olfactorium and striatum. MAO-B activity after moclobemide had presented some dose-dependently inhibition (about 30 percent at a dose of 50 mg/kg). 3. Harmaline was more potent than moclobemide as MAO-A inhibitor but had left MAO-B activity unchanged. 4. Clorgyline was the most potent of the three drug tested for MAO-A inhibition. MAO-B activity was inhibited at the dose used in these experiments. 5. MAO-A inhibitory properties on tuberculum olfactorium and striatum could be of interest according to some animal models of depression.

Animals↗
PubMedDate not supplied

Behavioral characteristics of mice with genetic knockout of monoamine oxidase type A.

Transgenic mice of line Tg8 were used to study the effects of deletion of the monoamine oxidase type A gene and the absence of the corresponding enzyme on behavior. These experiments showed that Tg8 mice with genetic knockout of monoamine oxidase type A differed from mice of the parental line C3H/HeJ by lower levels of the startle reflex in response to an acoustic signal, while there was no difference in the prestimulus inhibition of the startle response. Tg8 mice showed decreased investigative activity and decreases in the number of sector crossings in the light-dark anxiety test. There were significant increases in aggression as a motivation in male Tg8 mice, which was manifest as an increase in the number of mice demonstrating aggression and a decrease in the latent period of attack. The intensity of aggression changed to a lesser extent - the number of fights even decreased, though longer periods of keeping mice together resulted in increased numbers of deaths among intruder mice. At the same time, there were no significant differences between mice with genetic knockout of monoamine oxidase type A and control mice in terms of the expression of sexual activation: the behavioral responses of Tg8 males to presentation of females was marked and was no different from that of male C3H/HeJ mice. Knockout of the gene had no effect on movement activity on behavior in an elevated cross-shaped maze or in the test for predisposition to catalepsy.

Aggression↗
PubMed1988

In vivo relationship between monoamine oxidase type B and alcohol dehydrogenase: effects of ethanol and phenylethylamine.

The role of acute ethanol (2.5 g/kg i.p.) and phenylethylamine (100 mg/kg i.p.) on the brain and platelet monoamine oxidase activities, hepatic cytosolic alcohol dehydrogenase, redox state and motor behaviour were studied in male rats. Ethanol on its own decreased the redox couple ratio, as well as, alcohol dehydrogenase activity in the liver whilst at the same time it increased brain and platelet monoamine oxidase activity due to lower Km with no change in Vmax. The elevation in both brain and platelet MAO activity was associated with ethanol-induced hypomotility in the rats. Co-administration of phenylethylamine and ethanol to the animals, caused antagonism of the ethanol-induced effects described above. The effects of phenylethylamine alone, on the above mentioned biochemical and behavioural indices, are more complex. Phenylethylamine on its own, like ethanol, caused reduction of the cytosolic redox ratio and elevation of monoamine oxidase activity in the brain and platelets. However, in contrast to ethanol, this monoamine produced hypermotility and activation of the hepatic cytosolic alcohol dehydrogenase activity in the animals. The results suggest that some of the toxic actions of ethanol in rats may be mediated through the activation of monoamine oxidase type B, with the consequent depletion of the endogenous levels of phenylethylamine. The data appear to support the concept of phenylethylamine involvement in affective disorders.

Alcohol Dehydrogenase↗
PubMed1998

First partial three-dimensional model of human monoamine oxidase A.

A survey of the major known structural aspects of monoamine oxidase (MAO) is given and a first partial model of human MAO A is presented. This 3D model has been established using secondary structure predictions and fold recognition methods. It shows two alpha/beta domains (the FAD-binding N-terminal and central domains) and an alpha+beta domain. The C-terminal region is predicted to be responsible for anchoring the protein into the mitochondrial membrane and was not modeled. The covalent binding of the flavin cofactor to a cysteine residue is well predicted. The model is validated with experimental data from the literature and should be useful in designing new experimental studies (site-directed mutagenesis, chemical modification, specific antibodies). This first step towards the 3D structure of monoamine oxidase should contribute to a better understanding of the mechanisms of action and inhibition of this drug target in the treatment of clinical depression.

Amino Acid Sequence↗
PubMed1979

Effect of cadmium and copper on monoamine oxidase type A and B in brain and liver mitochondria.

The effect of cadmium and copper on monoamine oxidase type A and B in mitochondrial preparations from brain and liver was determined in vitro. The results showed a dose-related inhibition of the enzyme. Both the A and B forms of the enzyme were similarly inhibited by the presence of either cadmium or copper. Copper has been shown to be a 7-8 times more potent inhibitor of monoamine oxidase than cadmium. The data suggest that the intracellular concentration of unbound copper (13 mumol/l) or cadmium (100 mumol/l) may inhibit monoamine oxidase in brain and liver by 50%.

Animals↗
PubMed1984

Platelet monoamine oxidase and phenolsulphotransferase M and P in cancer.

Phenolsulphotransferase and monoamine oxidase inactivate a wide range of dietary and endogenous phenols/monoamines by sulphoconjugation and oxidative deamination respectively. In this study, both enzymes were measured in platelets from cancer patients and controls. Of the two variants of phenolsulphotransferase, activity of the P form was normal in all groups. Activity of the M form was, however, significantly less than control values in patients with cancer of the rectum and bowel but not in other cancer patient groups. If this finding reflects enzyme activity elsewhere in the body and is not merely a manifestation of an abnormal platelet population, the deficit could expose affected subjects to the action of potentially carcinogenic dietary phenols. Platelet monoamine oxidase activity was significantly raised in the cancer group as a whole, and in all sub-types investigated apart from breast cancer. The increase in the cancer group as a whole was independent of sex, age, drugs, radiotherapy, smoking or platelet count. Its mechanism and significance are unknown but there may be links with the patients' psychiatric state.

Adult↗