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PubMed1990

Effect of Monoamine Oxidase Inhibition, Thiopental Anesthesia, and Electroconvulsive Shock (ECS).

A series of experiments were conducted to investigate the effect of the monoamine oxidase inhibitor (MAOI), phenelzine, on thiopental anesthesia, electroshock, and blood pressure. After demonstrating that phenelzine (1 mg/kg/day orally) produced the same decrease in pig platelet monoamine oxidase as seen in humans, we compared MAOI-treated vs. non-MAOI-treated groups of pigs following anesthesia and electroconvulsive shock (ECS). In the majority of pigs, the increase in blood pressure associated with general anesthesia and ECS is no greater after MAOI treatment than after no MAOI treatment. One phenelzine-treated pig demonstrated an excessive catecholamine surge and elevated blood pressure.

Journal Article↗
PubMed1984

A new method for in vivo measurement of brain monoamine oxidase activity.

The radiotracers, C-14-N-methylphenylethylamine (MPEA) and N-methylphenylethanolamine (MPEOA) both rapidly entered mouse brain after their intravenous injection and were metabolized by brain monoamine oxidase (MAO) to C-14-methylamine and corresponding aldehydes. The labelled metabolite was trapped in the brain. Measurement of radioactivity showed that the amount of the metabolite produced in the brain from C-14-MPEA was proportional to the MAO activity remaining after combined treatment with a specific MAO-A inhibitor, clorgyline and a MAO-B inhibitor, 1-deprenyl, but not by treatment with either inhibitor alone. The rate of production of the labelled metabolite produced from C-14-MPEOA was highly sensitive to the extent of inhibition of MAO-B activity (with phenylethylamine as substrate) by pretreatment with 1-deprenyl, but was relatively insensitive to inhibitor clorgyline. This selectivity suggests that MPEOA is a specific substrate of MAO-B in mouse brain in vivo. The above results indicate that C-14-labelled N-methylphenylethylamine and N-methylphenylethanolamine derivatives can be used for measurement of brain MAO activity and that C-14-MPEOA is a specific substrate for mouse brain MAO-B. The value and possible applications of this method for measurement of MAO-B in brain under different physiological conditions are discussed.

2-Hydroxyphenethylamine↗
PubMed2000

Phe(208) and Ile(199) in human monoamine oxidase A and B do not determine substrate and inhibitor specificities as in rat.

It has been reported previously that reciprocally switching Phe(208) and Ile(199) in rat monoamine oxidase (MAO) A and B, respectively, was sufficient to switch their substrate and inhibitor preferences. In this study, the same mutants were made in the human forms of MAO. When compared with MAO A, MAO A-F208I showed a sixfold decrease in the specificity constant k(cat)/K(m) for both the MAO A- and the MAO B-preferring substrates 5-hydroxytryptamine and beta-phenylethylamine, respectively. The reciprocal point mutant MAO B-I199F had no effect on substrate affinity. To investigate if the region neighboring these two residues is responsible for conferring preferences, we have also made chimeric constructs by reciprocally switching the corresponding amino acid segments 159-214 in MAO A and 150-205 in MAO B. Chimerics MAO AB(159-214)A and MAO BA(150-205)B had small changes in K(m) and IC(50) values when compared with MAO A and B, respectively, but did not exhibit a preference switch. The results suggest that Phe(208) in MAO A and amino acid segments 159-214 and 150-205 in MAO A and B, respectively, influence the enzyme active site. However, substrate and inhibitor preferences of human MAO A and B are not determined by the respective residues Phe(108) and Ile(199) as in rat MAO nor by their neighboring regions.

Animals↗
PubMed1985

Inhibition of types A and B monoamine oxidase by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was studied as an inhibitor of type A monoamine oxidase (MAO) acting on [14C]serotonin as substrate and of type B MAO acting on [14C]phenylethylamine as substrate. MPTP was a reasonably potent (Ki = 9 microM), competitive, reversible inhibitor of MAO-A from rat brain in vitro. MPTP given at a 30-mg/kg i.p. dose antagonized the irreversible inactivation of MAO-A in rat brain by pargyline, indicating that it inhibited MAO-A in vivo. At that same dose, MPTP prevented the conversion of dopamine released by Ro 4-1284 to 3,4-dihydroxyphenylacetic acid and attenuated its conversion to homovanillic acid. Because dopamine is mainly deaminated by MAO-A, at least in rodent brain, inhibition of MAO-A by MPTP might play some part in its production of persistent effects on striatal dopamine neurons such as protection of intraneuronal, extragranular dopamine from deamination. MPTP was less potent as an inhibitor of MAO-B from rat brain in vitro (Ki = 106 microM). In contrast to the inhibition of MAO-A, the inhibition of MAO-B by MPTP showed noncompetitive kinetics, was not fully reversible by dialysis and was time dependent. The characteristics of MAO-B inhibition are like those of a kcat inhibitor, which is acted upon by an enzyme to produce a reactive product that can covalently attach to the enzyme or other macromolecules.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1993

The serotonin receptor agonist 5-methoxy-N,N-dimethyltryptamine facilitates noradrenaline release from rat spinal cord slices and inhibits monoamine oxidase activity.

1. The influences of the purported serotonergic agonist 5-methoxy-N,N-dimethyltryptamine (MeODMT) on noradrenaline release and metabolism were investigated in a rat spinal cord release model and a monoamine oxidase (MAO) assay. 2. MeODMT inhibited the basal outflow of tritium from rat spinal cord slices preincubated with [3H]noradrenaline and enhanced the electrically-evoked overflow. 3. Effects on basal outflow were not observed, when monoamine oxidase (MAO) was inhibited by pargyline. Effects on the evoked overflow were not observed in the presence of metitepine or phentolamine. 4. Preferential inhibition by MeODMT of MAO A-type enzyme activity was found in a direct assay. 5. The results provide evidence for two different effects by which MeODMT reinforces noradrenergic neurotransmission in the rat spinal cord: facilitation of stimulation-evoked noradrenaline release and inhibition of noradrenaline metabolism by MAO inhibition.

Animals↗
PubMed1979

Anticonvulsant, analgesic and monoamine oxidase inhibitory properties of newer 4-hydroxy-4-phenylpiperidinocarbamides.

Fourteen 1-[N-acetyl(4-hydroxy-4-phenyl-piperidino)]-3-aryl carbamides were synthesized, characterized and evaluated for their anticonvulsant, analgesic and monoamine oxidase inhibitory properties. All carbamides (100 mg/kg, i.p.) provided 20--60% protection against pentylenetetrazol-induced seizures in mice. The analgesic activity possessed by these carbamides, with the exception of two compounds, was reflected by their ability to provide 17--67% protection against tail pinch response in mice. All carbamides (1 mM) inhibited (5--90%) in vitro activity of rat brain monoamine oxidase. The low toxicity of these carbamides was reflected by their higher approximate LD50 values which ranged from 500 - greater than 1000 mg/kg.

Analgesics↗
PubMed1988

A method for stabilization of monoamine oxidases in homogenates of rat intestine epithelium.

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.

Animals↗
PubMed1995

The role of monoamine oxidase and catechol O-methyltransferase in dopaminergic neurotransmission.

The action of dopamine (DA) released in the synaptic cleft is mainly terminated by its reuptake and catabolism by the enzymes monoamine oxidase (MAO) and catechol O-methyltransferase (COMT). Preclinical data show that the reduction of the catabolism of DA elicited by MAO and COMT inhibitors leads to an enhancement of DA neurotransmission. Moreover, there is evidence suggesting that MAO-B inhibition might protect DA neurons from oxidative stress. Nevertheless, due to differences in enzyme localization and activity between man and rodents, results obtained in experimental animals might not reflect the actual situation in humans. Today the availability of potent and selective MAO and COMT inhibitors makes it feasible for the clinician to test whether the blockade of catabolic enzymes would result in a symptomatic improvement in Parkinsonian patients, and whether MAO-B inhibition might additionally exert a neuroprotective effect.

Catechol O-Methyltransferase↗
PubMed1993

Dopamine metabolism and neurotransmission in primate brain in relationship to monoamine oxidase A and B inhibition.

The "cheese effect", potentiation of sympathomimetic action of indirectly acting amines such as tyramine, the main side effect of irreversible non-selective and selective monoamine oxidase (MAO) A inhibitors, has largely been eliminated in the new generation of reversible selective MAO-A and B and irreversible MAO-B inhibitors. These selective inhibitors are demonstrating unique pharmacology and initial controlled clinical studies are providing evidence to support their action as anti-depressants and anti-Parkinson's disease drugs and possibly as neuroprotectors. Thirty years of experience with non-selective MAO inhibitors has resulted in a better understanding and management of the new generation of MAO inhibitors. Because of their selective action on the specific forms of MAO, which results in selective elevation of brain noradrenaline and serotonin on the one hand and dopamine and phenylethylamine on the other, it is hoped that these drugs will be able to elucidate the functional roles of MAO-A and B subtypes with regards to dopamine metabolism in the human brain.

Animals↗
PubMed1999

Stereoselective pharmacokinetics of RS-8359, a selective and reversible inhibitor of A-type monoamine oxidase, in rats, mice, dogs, and monkeys.

RS-8359, (+/-)-4-(4-cyanoanilino)-5,6-dihydro-7-hydroxy-7H-cyclopenta[d]-py rimidine, inhibits, selectively and reversely, A-type monoamine oxidase (MAO-A). In order to clarify the stereoselective metabolism of this drug, plasma concentrations of the [R] and [S]-enantiomers of RS-8359 were determined by chiral column HPLC after oral administration of each enantiomer to rats, mice, dogs, and monkeys. After administration of the [R]-enantiomer, high levels were retained in all animal species studied. On the other hand, when the [S]-enantiomer was administered, plasma concentrations decreased rapidly in rats and mice, and extremely rapidly in dogs, while in monkeys, only a trace amount was detected immediately after dosing. Thus, it was found, as a common phenomenon in rats, mice, dogs, and monkeys, that plasma concentrations of the [S]-enantiomer were markedly lower than those of the [R]-enantiomer. Secondly, the [R]-enantiomer was observed in plasma after administration of the [S]-enantiomer, and the [S] to [R] chiral inversion rate was estimated from AUC([R] after [S])/AUC([R] after [R]). The percentage was 45.8% in rats, 3.8% in mice, 0.8% in dogs, and 4.2% in monkeys. Further, the [S]-enantiomer was detected in plasma of SD rats dosed with the [R]-enantiomer, suggesting [R] to [S] chiral inversion in rats. These results show marked species differences in the chiral inversion of the cyclopentanol group of RS-8359. A mechanism of chiral inversion is discussed based on experiments using isolated rat hepatocytes.

Animals↗
PubMed2000

TV3326, a novel neuroprotective drug with cholinesterase and monoamine oxidase inhibitory activities for the treatment of Alzheimer's disease.

TV3326, [(N-propargyl-(3R) aminoindan-5-yl)-ethyl methyl carbamate] is a novel aminoindan derivative of the selective irreversible monoamine oxidase (MAO)-B inhibitor, rasagiline (N-propargyl-(1R)-aminoindan), possessing both cholinesterase (ChE) and MAO-inhibitory activity. In doses of 35-100 micromoles/kg administered orally to rats, it inhibits ChE by 25-40% and antagonises scopolamine-induced impairments in spatial memory. After daily administration of 75 micromoles/kg for 2 weeks, TV3326 does not show any motor stimulant effects but significantly reduces immobility in the forced swim test, an action consistent with that of known antidepressants. This could result from more than 70% inhibition of both MAO-A and B in the brain that occurs under these conditions, since it is not shared by the S-isomer, TV3279, which does not block MAO. TV3326 also shows selectivity for brain MAO, even after 2 months of daily administration, with little or no effect on the enzyme in the intestinal tract and liver. This reduces the likelihood of it producing the "cheese effect" if administered with tyramine-containing foods or beverages. TV3326 and TV3279 protect against ischemia-induced cytotoxicity in PC12 cells and reduce the oedema, deficits in motor function and memory after closed head injury in mice. These neuroprotective effects do not result from MAO inhibition. The pharmacological actions of TV3326 could be of clinical importance for the treatment of AD, and the drug is currently in development for this purpose.

Acetylcholinesterase↗
PubMed2003

Increased tryptophan decarboxylase and monoamine oxidase activities induce Sekiguchi lesion formation in rice infected with Magnaporthe grisea.

Sekiguchi lesion (sl)-mutant rice infected with Magnaporthe grisea showed increased light-dependent tryptophan decarboxylase (TDC) and monoamine oxidase (MAO) activities. TDC and MAO activities were observed before the penetration of M. grisea to rice cells and maintained high levels even after Sekiguchi lesion formation. Light-dependent expression of TDC gene was observed in leaves inoculated with M. grisea before Sekiguchi lesion formation. Spore germination fluid (SGF) of M. grisea also induced Sekiguchi lesion formation accompanied by increased enzymes activities and tryptamine accumulation. Sekiguchi lesion was also induced by treatments with tryptamine and beta-phenylethylamine, which are substrates for MAO, but was not induced by non-substrates such as indole-3-propionic acid, (+/-)-phenylethylamine and tryptophan under light. Light-dependent induction of Sekiguchi lesion by tryptamine was significantly inhibited in the presence of MAO inhibitors, metalaxyl and semicarbazide, and H2O2-scavengers, ascorbic acid and catalase. H2O2 in M. grisea-infected leaves with and without Sekiguchi lesions was demonstrated directly in situ by strong 3,3'-diaminobenzidine (DAB) staining. On the other hand, H2O2 induced Sekiguchi lesions on leaves of cv. Sekiguchi-asahi under light, but not in darkness. This difference was associated with the decrease of catalase activity in infected leaves under light and the absence of decrease in darkness. We hypothesize that the H2O2-induced breakdown of cellular organelles such as chloroplasts and mitochondria in mesophyll cells may cause high TDC and MAO activities and the development of Sekiguchi lesion, and that the sl gene products in wild-type rice may function as a suppressor of organelle breakdown caused by chemical or environmental stress.

Aromatic-L-Amino-Acid Decarboxylases↗
PubMed1968

Effect of oral contraceptives on depressive mood changes and on endometrial monoamine oxidase and phosphatases.

Significant variations in the incidence of depression and loss of libido were found with the various types of oral contraceptives. The highest incidence occurred with strongly progestogenic compounds (especially with those containing a small amount of oestrogen) which have high monoamine oxidase activity for most of the cycle. The lowest incidence was found with the strongly oestrogenic sequential regimens which have weak monoamine oxidase activity for most of the cycle.

Acid Phosphatase↗
PubMedDate not supplied

[Comparative study of the mechanism of action of biologically active substances on the membrane-bound mitochondrial monoamine oxidase and Ca2+, Mg2+-dependent ATPase of the sarcoplasmic reticulum].

Mechanism of interaction between biologically active substances and membranes as well as and membrane-bound enzymes of two types: mitochondrial monoamine oxidase (MAO) from rat liver tissue and Ca2+, Mg+2-dependent ATPase from sarcoplasmic reticulum (SR) were studied. All the substances studied inhibited most distinctly the SR ATPase as compared with mitochondrial MAO. EPR technique enabled to detect that BeSO4, aminazine, Pt- and Pd-5-sulpho-8-mercaptoquinolinate affected the membranes of both types decreasing the microviscosity in its hydrophobic part. K2PtCl4 and K2PdCl4 altered the conformation of membrane proteins. All the substances studied were bound by the same amino acid residues of proteins and affected similarly the structure lability of these membranes. As distinct from MAO, interaction of the substances with active sites of ATPase was responsible for pronounced differences in the inhibitory effect of the same substances on various membrane enzymes. Transformation of MAO, accompanied by a decrease in viscosity of hydrophobic part of mitochondrial membrane, contributed to appearance of new enzymatic properties, which appear to occur due to alteration in the protein conformation and to redistribution of the enzyme reactive sites situated relatively close to the membrane surface.

Animals↗
PubMed1984

Benzylamine metabolism at low O2 concentrations. Relative sensitivities of monoamine oxidase, aldehyde dehydrogenase and hippurate synthesis to hypoxia.

The O2 dependence of the metabolism of benzylamine to benzaldehyde, benzoate and hippurate was studied in isolated rat hepatocytes. The initial oxidation to benzaldehyde, catalyzed by monoamine oxidase, had an apparent Kmo2 value of 34 microM in cells and 40 microM in isolated rat liver mitochondria. The conversion of benzaldehyde to benzoate was essentially independent of O2 concentration in spite of the dependence of the reaction upon cytosolic NAD+. The conversion of benzoate to hippurate was half-maximal at 2.4 microM O2 in hepatocytes and at about 0.5 microM O2 in rat liver mitochondria. These values are consistent with the O2 dependence of bioenergetic changes in these preparations and indicate that the O2 dependence of hippurate formation is due to ATP availability for synthesis of benzoyl-CoA. These studies show that the three metabolic processes involved in benzylamine metabolism have markedly different dependences upon O2 and that metabolism of benzylamine by monoamine oxidase is O2 dependent over a physiologically important range.

Aldehyde Oxidoreductases↗
PubMed1992

Inhibition and inactivation of monoamine oxidase by 3-amino-1-phenyl-prop-1-enes.

We have previously shown that E-3-amino-1-phenyl-prop-1-ene (E-cinnamylamine) is readily oxidised by monoamine oxidase (MAO) type B from either rat or bovine liver (Williams et al. (1988), Biochem. J. 256, 411-415) in each case producing a non-linear progress curve which was attributed to inhibition by the reaction product E-cinnamaldehyde. We have now found that although this aldehyde inhibits MAO B competitively (Ki 0.017 mM) this cannot account for the inhibitory process, since during a 60 min incubation with the substrate (0.5 mM; Km, 0.074 mM) more than 95% inhibition of MAO B was observed and the concentration of aldehyde had reached approx. 0.025 mM. Inhibition was relieved either by dialysis or dilution of inhibited samples. The activity of MAO A from rat liver was largely unaffected by E-cinnamylamine. Oxidation of N-methyl-E-cinnamylamine and its Z-isomer by MAO B produced progress curves similar to that obtained with the primary amine, but in these cases inhibition was not reversed either by dilution or dialysis. Partition ratios for the pair of N-methyl isomers with bovine MAO B were calculated to be 1640 (E-isomer) and 1430 (Z-isomer). The time-dependent inhibition process for all three amines obeyed pseudo-first-order kinetics. A tritiated form of N-methyl-E-cinnamylamine, incubated with MAO B from bovine liver, resulted in incorporation of radioactivity into the enzyme. This labelling was stable to dialysis and to SDS-PAGE.

Acrolein↗