Inhibition of brain monoamine oxidase in the rat by multiple pyrazidol administration

Pyrazidol, which is chemically 2,3, 3a, 4, 5, 6-hexahydro-8-methyl-1H-pyrazino[3,2,1-j,k] carbazole hydrochloride (international name pirlindole) administered repeatedly (21 days) to rats at a dose of 25 mg/kg per os maintained the selectivity of its inhibitory effect toward type A MAO. When administered repeatedly the inhibitory effect of pyrazidol was 1.5-2-fold higher than after a single administration. The effect of pyrazidol on rat brain MAO was reversible whatever the route of administration. The enzymatic activity returned to normal within 24 h after the last administration. The data obtained suggest that the capacity of selective inhibiting the deamination of the neurotransmitters such as serotonin and noradrenaline in human brain is of paramount importance for therapeutic effect of pyrazidol.     

Imipramine inhibits monoamine oxidase activity in hyperglycemic rat brain

The effect of the chronic treatment of tricyclic antidepressants like Imipramine on the catecholamine metabolism of rat brain, in normal and hyperglycemic conditions was investigated. Imipramine was found to elevate the catecholamine levels in controls, while chronic treatment of hyperglycemic animals with the drug, failed to cause any change other than seen as a result of hyperglycemia. The activities of Monoamine oxidase on the other hand, decreases significantly as a result of the treatment, both in controls and in the hyperglycemic state. The results suggest that the drug apart from acting as an antidepressant, assumes the role of a monoamine oxidase inhibitor under pathological conditions.     

Multiple catalytic sites of rat brain mitochondrial monoamine oxidase

We compared the inhibitory and catalytic effects of various monoamines on forms A and B of monoamine oxidase (MAO) on mitochondrial preparations from rat brain in mixed substrate experiments. MAO activity was determined by a radioisotopic assay. MAO showed lower K_m values for tryptamine and β-phenylethylamine than for tyramine and serotonin. The K_m values of the untreated preparation for tyramine, tryptamine, and β-phenylethylamine obtained were the same as those of the form B enzyme and the K_m value for serotonin was the same as that of the form A enzyme. Tyramine and tryptamine were competitive inhibitors of serotonin oxidation and β-phenylethylamine did not bind with form A enzyme or inhibit the oxidation of serotonin, while tyramine and tryptamine were competitive inhibitors of β-phenylethylamine oxidation. Although serotonin was not oxidized by form B enzyme, serotonin was a competitive inhibitor of β-phenylethylamine oxidation. It is suggested that rat brain mitochondrial MAO is characterized by two kinds of binding sites.     

Effect of prolonged cold exposure on monoamine oxidase activity and kinetics and on serotonin metabolism in the rat brain

Effects of long-term cold exposure on the content of serotonin and its metabolite 5-hydroxyindolacetic acid (5-HIAA) and monoamine oxidase (MAO) activity and kinetic parameters (Km and Vmax) of oxidative deamination of serotonin in rat brain stem. The increase of 5-HIAA level in the initial period of chronic cold exposure was determined by the blockade of active metabolite transport from the brain. The level of serotonin and the rate of its catalytic deamination by MAO were found to be decreased in cold-adapted rats. The magnitude of the Km of serotonin deamination was unchanged.     

Influence of prolonged fasting on monoamine oxidase and semicarbazide-sensitive amine oxidase activities in rat white adipose tissue

Monoamine oxidase (MAO) and semicarbazide-sensitive amine oxidase (SSAO) activities are very high in white adipose tissue (WAT). SSAO, also known as Vascular Adhesion Protein-1 in vessels, is present at the surface of fat cells and independent approaches have evidenced its impressive increase during adipogenesis. However, the factors that might regulate the expression SSAO and MAO in adipose tissue are still poorly defined. Here, we report the influence of fasting on MAO and SSAO activities in adipose depots. A decrease of MAO activity occurred after three days of starvation in the intra-abdominal adipose tissue (INWAT) of male Wistar rats, regardless of their initial adiposity or fat loss. The reduced fat stores of seven-week old rats, loosing 59% of INWAT mass during fasting, contained only one half of the MAO activity found in fed control. The same reduction of MAO was observed after prolonged fasting in older rats which lose only 26% of their INWAT during the same starvation duration, leading to a fat mass comparable to that of younger fed control rats. It was therefore the endocrine and metabolic changes occurring during fasting that were responsible for the reduced MAO activity and not the amount of INWAT. Surprisingly, SSAO activity remained unchanged during starvation. In subcutaneous WAT, the changes in MAO and SSAO activities exhibited the same tendencies than those found in INWAT. Taken together, these data show that both MAO and SSAO activities increase in INWAT with age-dependent fattening, and indicate that only MAO diminishes during fasting.     

Activation of platelet monoamine oxidase by plasma in the human.

A pronounced activation of platelet monoamine oxidase (MAO) by human plasma has been observed. The activation was substrate selective, since serotonin, $\text{p}$-tyramine, dopamine and benzylamine were much more effective than β-phenylethylamine or tryptamine. The activator(s) in the plasma was heat stable but labile to acid hydrolysis and treatment with lipase and protease. The plasma was also found to be capable of activating partially purified MAO obtained from rat liver mitochondria. Phospholipids such as phosphatidylethanolamine were shown to activate MAO.     

Effect of benzamide derivatives on rat brain monoamine oxidase activity in vitro

The ability of moclobamide and other benzamide derivatives to inhibit the activity of monoamine oxidase in the rat brain was studied. Distinct effects of these compounds on the deamination of serotonin and norepinephrine (MAO-A substrates); 2-phenylethylamine (selective MAO-B substrate); tyramine and dopamine (MAO-A and MAO-B substrates) are shown. It was demonstrated that among all the compounds studied moclobamide appeared to be the most active and selective inhibitor of MAO-A: at a concentration of 100 microM it caused a 100% inhibition of serotonin and norepinephrine deamination, which might be explained by the presence of C1 atom in the para-position of benzene ring in moclobamide molecule. Other benzamide derivatives were less active in inhibiting MAO-A and had but a negligible effect on dopamine- and 2-phenylethylamine deamination.     

Effect of adafenoxate on different rat brain structures monoamine oxidase activity in vitro

1. The effect of the nootropic drug adafenoxate on monoamine oxidase (MAO) activity in rat brain cortex, striatum, hypothalamus and hippocampus has been studied using the following substrates: tyramine (total MAO), serotonin (MAO A) and beta-phenylethylamine (MAO B). 2. In a series of increased concentrations (from 5 x 10(-4) up to 1 x 10(-5) M) adafenoxate inhibits total MAO, MAO A and MAO B in the brain structures studied. 3. The adafenoxate IC50 values obtained illustrate its inhibitory properties and its lack of selectivity toward MAO in the brain structures isolated. 4. The results of our research prove the participation of MAO in the mechanisms through which adafenoxate affects the brain monoaminergic systems and realises its central effects.     

Multiple substrate determination of monoamine oxidase distribution and iproniazid inhibition in rat brain

Abstract— —A variety of monoamine oxidase substrates (tyramine, dopamine, serotonin, tryptamine) have been used with and without Iproniazid inhibition to evaluate further the extent to which enzyme multiplicity may exist in various regions of rat brain. Levels of monoamine oxidase activity, as measured by ammonia production, were found to vary as a function of both brain area and kind of substrate used, in the absence as well as in the presence of Iproniazid, in vivo and in vitro. Similarity of substrate metabolizing patterns among the different brain areas, however, strongly suggests that only one kind of monoamine oxidase exists in rat brain.     

Mitochondrial monoamine oxidase activity and serotonin content of rat brain following gamma-irradiation

It is shown that gamma-irradiation of albino rats with a dose of 30 Gy leads to pronounced phase changes in monoaminoxidase activity and serotonin content in rat brain at early times after whole-body exposure. There is a similar direction of changes in the activity of the enzyme and in the content of the substrate adequate to the latter.     

Serum prolactin and brain and pituitary monoamine responses to chronic monoamine oxidase inhibition in the rat.

The acute administration of the monoamine oxidase inhibitor iproniazid to rats causes a highly significant suppression of serum prolactin levels at 2 h. At the same time there is a significant rise in the hypothalamic-median eminence concentrations of the biogenic monoamines dopamine, noradrenaline and serotonin. When iproniazid is administered daily to rats for 4 days and the animals are examined on the fifth day brain noradrenaline and serotonin levels are elevated similarly to those seen after acute administration but dopamine concentration is near normal while serum prolactin is significantly elevated. This study thus demonstrates that a quite specific and unexpected change occurs in the regulation of hypothalamic-median eminence dopamine when iproniazid is administered chronically and provides an explanation of previous observations in human subjects where raised serum prolactin levels are observed after chronic therapy with monoamine oxidase inhibitors.     

Inhibition of type A monoamine oxidase by coptisine in mouse brain

The inhibitory effects of coptisine, a protoberberine isoquinoline alkaloid, on type A and type B monoamine oxidase (MAO-A and MAO-B) activities in mouse brain were investigated. Coptisine showed an inhibitory effect on MAO-A activity in a concentration-dependent manner using a substrate kynuramine, but coptisine did not inhibit MAO-B activity. Coptisine exhibited 54.3% inhibition of MAO-A activity at 2 microM. The values of Km and Vmax of MAO-A were 151.9 +/- 0.6 microM and 0.40 +/- 0.03 nmol/min/mg protein, respectively (n=5). Coptisine competitively inhibited MAO-A activity with kynuramine. The Ki value of coptisine was 3.3 microM. The inhibition of MAO-A by coptisine was found to be reversible by dialysis of the incubation mixture. These results suggest that coptisine is a potent reversible inhibitor of MAO-A, and that coptisine functions to regulate the catecholamine content.     

Titration of human brain type-B monoamine oxidase

The interaction of the substrate-selective irreversible inhibitor J-508 [N-methyl-N-propargyl-(1-indanyl)-ammonium hydrochloride] with the B form of human brain monoamine oxidase has been investigated, and the conditions necessary for this inhibitor to titrate the concentration of this enzyme form determined. It was found that the concentration of monoamine oxidase-B determined in this way was the same when either benzylamine or -phenethylamine was used to assay for activity, which would indicate that this enzyme form is not heterogeneous. Furthermore, the variation in activity from sample to sample was found to be due to a variation in the concentration of available monoamine oxidase-B active centers, rather than due to a variation in the molecular turnover numbers of this enzyme form towards its amine substrates.     

Effect of neurocatin on the activity of monoamine oxidase B in rat brain synaptosomes

Neurocatin, a small (about 2,000 Dalton) neuroregulator isolated from mammalian brain, is a powerful effector of monoamine oxidase B in rat brain synaptosomes. Incubation of intact synaptosomes with neurocatin caused an inhibition of the enzyme dependent on the concentration of neurocatin. This inhibition became statistically significant at a neurocatin concentration of 10 ng/200 l and was significant at all higher neurocatin concentrations. At 40 ng/200 l, neurocatin inhibited monoamine oxidase B activity by about 60%. This inhibitory effect was almost completely abolished by breaking the synaptosomal membrane by hypotonic buffer prior to incubation with neurocatin. In addition, incubation of the synaptosomes in calcium free medium almost completely abolished the inhibitory effect of neurocatin on monoamine oxidase B. The inhibition appeared to involve covalent modification of the enzyme mediated by a neurocatin receptor(s). Measurements of the kinetic parameters of the enzyme showed that 20 ng of neurocatin caused a statistically significant decrease in V_max (by 20%) with no significant change in K_M, compared to controls. Inhibition of monoamine oxidase by neurocatin is potentially of great clinical importance because this enzyme plays a major role in catabolism of the biogenic amines and alterations in its activity is believed to contribute to several neurological disorders.     

Influence of age on brain vascular and cardiovascular monoamine oxidase activity in the rat

Monoamine oxidase (MAO) activity in brain microvessels and cardiovascular tissues was examined in rats of different age. MAO activity continued to increase with age in the heart, but in contrast, reached maximum activity in three weeks in the aorta, mesenteric artery and mesenteric vein. Between 7 and 60 weeks, there was a small decline in the MAO activity in the testicular artery. The highest MAO activity was found in the cerebral microvessels and increased with age. The half-life of MAO was estimated in the heart and peripheral blood vessels in young and old animals. The half-life of cardiac MAO was increased with age whereas that of the mesenteric vein, mesenteric artery and aorta remained constant between 7 and 112 weeks. Thus an explanation for this increased cardiac MAO activity in old rats was a reduced rate of degredation of this enzyme. The high activity of the enzyme in the brain microvessels suggests that it may participate in regulating the influx and efflux of monoamines in the central nervous system.     

Characterization of rat pulmonary monoamine oxidase.

The substrate specificities and kinetics of rat lung monoamine oxidase (MAO) have been studied. Utilizing the irreversible MAO inhibitors, clorgyline and deprenyl, rat lung was shown to possess at least two types of MAO, A and B. Tyramine was a substrate for both forms of the enzyme, whereas 5-hydroxytryptamine (5-HT) was a preferred substrate for the A-form. In contrast to most other tissues, 2-phenylethylamine was not solely a B-type substrate for the rat lung MAO and some metabolism by the A-type was apparent $\text{(}\text{B}\text{A}\text{=}\text{80}\text{20}\text{)}$. Using tyramine as substrate the ratio A/B was shown to be $\text{55}\text{45}$. Rat pulmonary MAO-B was inhibited by deprenyl and the kinetics of MAO-A studied. The Km values for the A-form for tyramine, phenylethylamine and 5-HT were relatively similar and were 270, 244 and 170 μM respectively. Whereas, when the A-form was inhibited by clorgyline, the Km values for the B-form were found to differ considerably: 330, 42 and 850 μM for tyramine, phenylethylamine and 5-HT respectively.