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PubMed1996

In vivo hydroxylation of the neurotoxin, 1-methyl-4-phenylpyridinium, and the effect of monoamine oxidase inhibitors: electrospray-MS analysis of intra-striatal microdialysates.

The neurotoxin 1-methyl-4-phenylpyridinium (MPP+) has been shown to increase hydroxyl radical formation in the striatum. The production of hydroxyl radicals correlates with the MPP(+)-driven dopamine release which presumably leads to increased metabolism via monoamine oxidase or increased dopamine autoxidation. Both processes result in enhanced production of hydrogen peroxide, which in the presence of iron(II) ions decomposes to the hydroxyl radical. Monoamine oxidase inhibitors decrease the production of hydroxyl radicals as measured by salicylate and 4-hydroxybenzoate trapping. As both MPP+ and monoamine oxidase inhibitors, such as deprenyl and MDL-72,974A, possess aromatic rings, hydroxyl radical adduct formation was investigated in vitro in defined Fenton systems and also in vivo using intra-striatal microdialysis to infuse MPP+ to rats pretreated systemically with either deprenyl or MDL-72,974A. Electrospray mass spectrometric analysis, using full-scan, fragment ion and constant neutral loss spectra, demonstrated ring hydroxylation of all three compounds in the Fenton systems. Spectral comparison of microdialysis samples with spectra from the Fenton reactions indicated the in vivo hydroxyl radical adduct attachment to MPP+, deprenyl and possibly MDL-72,974A.

1-Methyl-4-phenylpyridinium↗
PubMed1998

Monoamine oxidase activities in catfish (Parasilurus asotus) tissues.

The substrate- and inhibitor-related characteristics of monoamine oxidase (MAO) were studied for catfish brain and liver. The kinetic constants for MAO in both tissues were determined using 5-hydroxytryptamine (5-HT), tyramine and beta-phenylethylamine (PEA) as substrates. For both tissues, the Vmax values were highest with 5-HT and lowest with PEA. The Km value for the brain was highest with 5-HT, followed by tyramine and PEA; but for the liver its value was highest with PEA, followed by 5-HT and tyramine, although all values were in the same order of magnitude. The inhibition of MAO by clorgyline and deprenyl by use of 5-HT, tyramine and PEA as substrates showed that the MAO-A inhibitor clorgyline was more effective than the MAO-B inhibitor deprenyl for both catfish tissues; a single form was present since inhibition by clorgyline or deprenyl with 1000 microM PEA showed single phase sigmoid curves. It is concluded that catfish brain and liver contain a single form of MAO, relatively similar to mammalian MAO-A.

Animals↗
PubMed2002

Comparative effects of dehydropirlindole and other compounds on rat brain monoamine oxidase type A.

Dehydropirlindole (DHP) is the dehydroderivative of pirlindole, a short-acting inhibitor of monoamine oxidase type A (MAO-A). DHP would be formed in vivo from oxidation of pirlindole by MAO-A. The aim of this work is to compare the inhibitory potency of DHP with three reference compounds: harmaline, befloxatone and clorgyline; the two former are reversible inhibitors and the later is an irreversible inhibitor of MAO-A. Both in vitro and ex vivo assays were performed on rat brain homogenates, and IC50 and ID50 were calculated by a fluorometric method with octopamine as selective MAO-A substrate. In vitro clorgyline and befloxatone were more potent inhibitors than DHP and harmaline with IC50 values of 1.6 and 7.7 nM vs. 40 and 55 nM; ex vivo ID50 values were 1.5 and 32 micromol/kg vs. 41 and 49 micromol/kg. Befloxatone had an ID50/IC50 ratio four to five times higher than DHP and harmaline. Preincubation time experiments did not distinguish befloxatone from DHP and harmaline. In conclusion, this study shows that DHP behaves as a reversible MAO-A inhibitor whose potency is situated between that of befloxatone and harmaline.

Animals↗
PubMed1988

Carcinogenic tryptophan pyrolysis products potent inhibitors of type A monoamine oxidase and the platelet response to 5-hydroxytryptamine.

The effects of carcinogenic heterocyclic amines and beta-carbolines on 5-hydroxytryptamine-induced human platelet aggregation, on the uptake of 5-hydroxytryptamine by platelets, and on human monoamine oxidase activity were investigated. Of the dietary carcinogens and beta-carbolines studied, carcinogenic tryptophan pyrolysis products had greater pharmacological activities than other heterocyclic amines. The carcinogenic tryptophan pyrolysis products, 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole and 3-amino-1-methyl-5H-pyrido[4,3-b]indole, which have been identified in the dialysis fluid of uraemic patients, were the most potent inhibitors of the aggregation response to 5-hydroxytryptamine, with IC50 (the concentrations causing 50% inhibition) values of 10 mumol/l and 50 mumol/l, respectively. 3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole and 3-amino-1-methyl-5H-pyrido[4,3-b]indole by themselves did not induce platelet aggregation, although these dietary carcinogens structurally resemble 5-hydroxytryptamine. Kinetic analyses showed that 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole and 3-amino-1-methyl-5H-pyrido[4,3-b]indole were potent competitive inhibitors of 5-hydroxytryptamine uptake by platelets with Ki 18 mumol/l and 42 mumol/l, respectively. Furthermore, carcinogenic tryptophan pyrolysates as well as beta-carbolines were found to be competitive selective inhibitors of monoamine oxidase 'type A'.

Blood Platelets↗
PubMedDate not supplied

[Age alterations of monoamine oxidase activity in structures of visual analyzer as affected by light stimulation].

Light stimulation affected the monoamine oxidase activity in mitochondria of dog visual analyzer structures. The enzymatic activity was elevated as the mitochondrial fraction was increased in brain visual cortex (area 17) and in lateral geniculate body at the period from the 1 to the 21 day after birth. Light stimulation led to maximal increase in monoamine oxidase activity in the anterior colliculus of dog brain visual cortex (area 17) within 21 day after birth and in the lateral geniculate body--within the 45 day.

Aging↗
PubMed1982

Relationship between tyramine potentiation and selective inhibition of monoamine oxidase types A and B in the rat vas deferens.

1 The degree of selective monoamine oxidase (MAO) inhibition produced by (-)-deprenyl, clorgyline, LY51641 and tranylcypromine was examined in relation to modification of tyramine and noradrenaline contractile responses of the rat isolated vas deferens. 2 All inhibitors possessed reversible alpha-adrenoceptor blocking activity, determined against noradrenaline on the denervated vas deferens. For LY51641 and tranylcypromine, antagonism was competitive, with pA2 values of 6.17 and 5.16. 3 Clorgyline, LY51641 and (-)-deprenyl (10(-5) M) inhibited the tyramine response while present in the organ bath: LY51641, which was the most potent as an alpha-adrenoceptor blocker, produced this effect at 10(-6) M. Responses to tyramine and noradrenaline were potentiated on wishing out the inhibitors, but noradrenaline potentiation was seen only when tyramine had been present in the system. 4 Tranylcypromine (10(-6) M) potentiated responses to noradrenaline and tyramine while present in the organ bath. 5 Potentiation of tyramine responses by clorgyline and LY51641 occurred at 91% and 64% inhibition of MAO type A respectively, although full potentiation of the tyramine response was elicited only when substantial inhibition of both enzyme types occurred. Selective inhibition of MAO type B by 67% (with deprenyl) was not associated with tyramine potentiation.

Adrenergic alpha-Antagonists↗
PubMed2005

Mutation of surface cysteine 374 to alanine in monoamine oxidase A alters substrate turnover and inactivation by cyclopropylamines.

Modification of cysteine (Cys) residues inactivates monoamine oxidases (MAO) yet the crystal structure shows no conserved cysteines in the active site of MAO A (Ma, J. et al. J. Mol. Biol.2004, 338, 103-114). MAO A cysteine 374 was mutated to alanine and the purified enzyme characterized kinetically. The mutant was active but had decreased k(cat)/K(m) values compared to the wild-type enzyme. Cyclopropylamine-containing mechanism-based inactivators similarly showed lower turnover rates. Spectral studies and measurement of free thiols established that 1-phenylcyclopropylamine (1-PCPA) formed an irreversible flavin adduct whereas 2-phenylcyclopropylamine (2-PCPA) and N-cyclo-alpha-methylbenzylamine (N-CalphaMBA) formed adducts that allowed reoxidation of the flavin on denaturation and decreased cysteine in both wild-type and mutant MAO A. In the 1-PCPA and N-CalphaMBA inactivations, the partition ratio was decreased by more than 50% in the mutant. The data suggest that mutation of Cys374 influences MAO A catalysis, which has implications for MAO susceptibility to redox damage. These results are compared with previous work on the equivalent residue in MAO B, namely, cysteine 365.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1985

4-Fluoro-3-nitrophenyl azide, a selective photoaffinity label for type B monoamine oxidase.

The effects of 4-fluoro-3-nitrophenyl azide (FNPA) on types A and B monoamine oxidase in rat brain cortex were studied using serotonin and phenylethylamine as substrates respectively. FNPA competitively inhibited the oxidative deamination of both serotonin (Ki = 3 microM) and phenylethylamine (Ki = 0.78 microM) in the dark. Upon photoirradiation in the presence of FNPA, a photodependent inhibition of type B MAO activity resulted. This photodependent inhibition was apparently irreversible since there was no recovery of activity upon washing of the photolyzed FNPA-enzyme mixture. Additional evidence for the photoinduced covalent binding of FNPA to type B MAO is that non-competitive inhibition kinetics resulted after photolysis. The specificity of the photodependent incorporation of FNPA to type B MAO was shown by the protective effect of phenylethylamine and by decreased [3H]pargyline labeling after the enzyme was photolyzed with FNPA. Under the same experimental conditions, only minimal photodependent inhibition of type A MAO by FNPA was found. The observed difference in the efficiencies of the photodependent inactivation of the two types of MAO by FNPA suggests that there is a conformational or a structural difference in the active sites of the two types of MAO. The active site of type B MAO could be characterized by utilizing FNPA as a photoaffinity labeling probe.

Affinity Labels↗
PubMedDate not supplied

[Effect of new 2-propinylamine derivatives on mitochondrial monoamine oxidase activity].

New derivatives of 2-propinyl amine were studied as possible inhibitors of mitochondrial monoamine oxidases (MAO) from rat liver and brain tissues. Kinetics of inhibition of the MAO activity (A and B types) is described for one of the substances studied -- N-(8-quinolyl methyl)-N-methyl-2-propinyl amine. Interaction of N-(8-quinolylmethyl)-N-methyl-2-propinyl amine with MAO of the A type (serotonin as a substrate) and of the B type (beta-phenylethylamine as a substrate) was studied by the kinetic method, which enabled to determine and quantitatively estimate the steps of enzyme-inhibitor complexes formation. The inhibition of the mitochondrial MAO A and B types by the substance was shown to include the steps of formation of dissociating enzyme-inhibitor intermediates with the subsequent irreversible modification of them. The data on K1 values, estimated in experiments with serotonin and beta-phenylethylamine as substrates, show that the affinity of N-(8-quinolyl methyl)-N-methyl-2-propinyl amine towards MAO of the A type was 10-fold higher than the affinity towards MAO of the B type. The rates of these complexes conversion into irreversibly blocked forms of the MAO A and B types was found to be similar.

Alkynes↗
PubMed1992

Potent in vivo but not in vitro inhibition of monoamine oxidase by 3-chloro-alpha-phenylpyrazinemethanol.

3-Chloro-alpha-phenylpyrazinemethanol (3-CPM) inhibited monoamine oxidase (MAO) types A and B in vivo in mouse brain, heart and liver. The inhibition was dose-dependent at doses of 0.3-32 mg/kg i.p. and occurred within 1 h after the compound was injected. 3-CPM was a very weak inhibitor of mouse brain mitochondrial MAO activity in vitro, even when preincubated with the enzyme; MAO-A was inhibited only about 50% at a high concentration of 3-CPM (1 mM), and MAO-B was inhibited even less. After a 10 mg/kg i.p. dose of 3-CPM in mice, both MAO-A and MAO-B were inhibited at day 1, but activity had largely recovered within a few days in brain, liver and heart. 3-CPM at doses of 1, 3, 10 and 32 mg/kg i.p. caused dose-dependent antagonism of the depletion of striatal dopamine and of cortical norepinephrine by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. 3-CPM is therefore a potent inhibitor of MAO-A and of MAO-B in mice in vivo despite its weak effect on the enzyme in vitro. A metabolite of the drug may be involved in the in vivo effects.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2005

Human monoamine oxidase enzyme inhibition by coffee and beta-carbolines norharman and harman isolated from coffee.

Monoamine oxidase (MAO) is a mitochondrial outer-membrane flavoenzyme involved in brain and peripheral oxidative catabolism of neurotransmitters and xenobiotic amines, including neurotoxic amines, and a well-known target for antidepressant and neuroprotective drugs. Recent epidemiological studies have consistently shown that coffee drinkers have an apparently lower incidence of Parkinson's disease (PD), suggesting that coffee might somehow act as a purported neuroprotectant. In this paper, "ready to drink" coffee brews exhibited inhibitory properties on recombinant human MAO A and B isozymes catalyzing the oxidative deamination of kynuramine, suggesting that coffee contains compounds acting as MAO inhibitors. MAO inhibition was reversible and competitive for MAO A and MAO B. Subsequently, the pyrido-indole (beta-carboline) alkaloids, norharman and harman, were identified and isolated from MAO-inhibiting coffee, and were good inhibitors on MAO A (harman and norharman) and MAO B (norharman) isozymes. beta-carbolines isolated from ready-to-drink coffee were competitive and reversible inhibitors and appeared up to 210 microg/L, confirming that coffee is the most important exogenous source of these alkaloids in addition to cigarette smoking. Inhibition of MAO enzymes by coffee and the presence of MAO inhibitors that are also neuroactive, such as beta-carbolines and eventually others, might play a role in the neuroactive actions including a purported neuroprotection associated with coffee consumption.

Carbolines↗
PubMed1982

Comparison of biochemical properties of platelet monoamine oxidase in mentally disordered and healthy individuals.

We have investigated some biochemical properties of platelet monoamine oxidase (MAO) isolated from chronic schizophrenic and agoraphobic patients, nonschizophrenic institutional controls, and healthy volunteers. The enzyme activity level in the healthy population was reasonably constant over at least a 6-week period. High correlations were found between MAO activity assessed for different substrates (p-tyramine, beta-phenylethylamine, and tryptamine). Some heterogeneity of the platelet MAO may exist, however, at least in some of the chronic schizophrenics, since the substrate specificities were changed and the Km values reduced. The half-life of the enzyme at 58 degrees C was 2-3 minutes and the transition temperature derived from Arrhenius plots was 16-17 degrees C with respect to beta-phenylethylamine. Platelet MAO from chronic schizophrenics was not significantly different from control values with respect to temperature effects. SDS-polyacrylamide gel electrophoresis of the 3H-pargyline-MAO adduct revealed that the subunit of platelet MAO is a single band protein with a molar individuals. The adjacent structure of the flavine site of the platelet MAO was chromatographically identical to the penta-peptide isolated from MAOs from other tissues. The response of platelet MAO to thimerosal, a new differential type A MAO inhibitor, could be distinguished not only from type A MAO isolated from human placenta, but also from type B MAO isolated from bovine liver.

Agoraphobia↗
PubMed2004

Inactivation of purified human recombinant monoamine oxidases A and B by rasagiline and its analogues.

The inactivation of purified human recombinant monoamine oxidases (MAO) A and B by rasagiline [N-propargyl-1(R)-aminoindan] and four of its analogues [N-propargyl-1(S)-aminoindan (S-PAI), 6-hydroxy-N-propargyl-1(R)-aminoindan (R-HPAI), N-methyl-N-propargyl-1(R)-aminoindan (R-MPAI), and 6-(N-methyl-N-ethyl carbamoyloxy)-N-propargyl-1(R)-aminoindan (R-CPAI)] has been investigated. All compounds tested, with the exception of R-CPAI, form stoichiometric N(5) flavocyanine adducts with the FAD moiety of either enzyme. No H(2)O(2) is produced during either MAO A or MAO B inactivation, which demonstrates that covalent addition occurs in a single turnover. Rasagiline has the highest specificity for MAO B, as demonstrated by a 100-fold higher inhibition potency (k(inact)/K(i)) compared to MAO A, with the remaining compounds exhibiting lower isozyme specificities. MAO B and MAO A are more selective for the R-enantiomer (rasagiline) compared to the S-enantiomer (S-PAI) by 2500-fold and 17-fold, respectively. Differences in UV/vis and CD spectral data of the complexes of the studied compounds with both MAO A and MAO B are interpreted in light of crystallographic data of complexes of MAO B with rasagiline and its analogues (Binda, C.; et al. J. Med. Chem. 2004, 47, 1767-1774.

Alkynes↗
PubMed1966

Monoamine oxidase activity in various parts of the rat brain during the estrous cycle.

The activity of monoamine oxidase was estimated in the hypothalamus, amygdala, and frontal cortex of adult female rats during the estrous cycle. Enzymatic activity in all three areas of brain was at its lowest during the diestrus phase of the estrous cycle and progressively increased to its highest during estrus. Throughout the estrous cycle the greatest activity of monoamine oxidase was found in the hypothalamus, as compared with the other brain areas. The significance of the activity is discussed.

Amygdala↗
PubMed1975

Ontogenesis of monoamine oxidase and catechol-O-methyl transferase in various tissues of domestic swine.

Activities of monoamine oxidase (MAO) and catechol-o-methyl transferase (COMT) in liver, kidney, heart, spleen, hindbrain, and adrenal glands were compared in adult dogs, cats, guinea-pigs, rabbits, rats, sheep, and 150-day-old swine. Swine had the highest COMT activity and dogs or cats, the lowest in most tissues. MAO was more tissue and species variable. The ontogenesis of MAO or COMT was evaluated in the same six tissues of swine from 10 days before birth through 150 days of age. COMT and MAO generally increased in swine kidney and liver with age, but the developmental patterns were more variable in other tissues. COMT increased in heart, spleen, and adrenals through 14 days of age, decreased in spleen and adrenals to 150 days, but remained elevated in heart. Brain MAO activities were near or above 150-day-old levels at birth and changed little with age. Cardiac MAO fell from birth to 70 days of age, while splenic and adrenal activities increased with age. MAO substrate specificity to tyramine, benzylamine, and serotinin along with selective inhibition by harmine, pargyline, and clorgyline were used as indices of multiple enzymic forms. Type B MAO may dominate in all swine tussues except spleen, although the biochemical characteristics of this enzyme form do not seem to fit all of the patterns described for other species. Thermal stability of MAO in swine resembles that in the guinea-pig.

Age Factors↗
PubMed1992

Treatment of imipramine-resistant recurrent depression, III: Efficacy of monoamine oxidase inhibitors.

BACKGROUND: The effectiveness of monoamine oxidase inhibitors (MAOIs) in tricyclic resistant depression has received surprisingly little systematic study. METHOD: Patients who failed to respond to sustained, adequate treatment with the tricyclic imipramine (mean maximum dosage = 260 mg/day) and interpersonal psychotherapy were withdrawn from imipramine and treated in a standardized, but open-label 6-week trial with either phenelzine (N = 4; 60 mg/day) or tranylcypromine (N = 36; mean = 38.5 mg/day) and continued interpersonal psychotherapy. RESULTS: Forty of 42 patients (95%) completed the trial, of whom 23 (58%) responded to treatment. Highly significant improvement was documented on measures of depression, reversed neurovegetative symptoms, and somatic symptoms. Response was significantly correlated with severity of depression (pre-MAOI score on the Hamilton Rating Scale for Depression), severity of a composite score of anergic and reversed neurovegetative features, and low levels of improvement during initial imipramine/interpersonal psychotherapy. Of patients who met criteria for proposed subforms of anergic or atypical depression, 67% (18/27) responded (p less than .05); 77% (17/22) of patients who scored above the mean on the composite measure of anergic and reversed neurovegetative features responded (p less than .01). CONCLUSION: These findings provide strong evidence of the utility of MAOIs in tricyclic-resistant depression, especially in patients with features such as fatigue, volitional inhibition, motoric retardation, hypersomnia, and/or weight gain.

Adult↗
PubMed1993

Molecular size and flexibility as determinants of selectivity in the oxidation of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine analogs by monoamine oxidase A and B.

The introduction of a methylene bridge between the phenyl and tetrahydropyridyl moieties of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) results in increased selectivity for monoamine oxidase B (MAO B) over monoamine oxidase A (MAO A). However, lengthening of this bridge results in a total loss of selectivity. In the present study, a number of isomeric 4-naphthyl-, 4-(naphthylalkyl)-, 4-thienyl-, and 4-(thienylalkyl)tetrahydropyridines, conformationally restrained and flexible analogs of MPTP, were synthesized and evaluated as potential selective substrates of MAO A and B. In terms of the parameter (turnover number)/Km, the bulky naphthyl analogs were invariably better substrates of MAO A than kynuramine, the reference substrate for this enzyme. In addition, all naphthyl analogs, regardless of conformational mobility, were more effective substrates of MAO A than MAO B. Similarly, all thienyl analogs were found to be more effective substrates of MAO B. In contrast to the naphthalenes, the conformationally restrained thiophenes 9a and 10a were found to be poor substrates of MAO B, relative to benzylamine, the reference substrate. These results suggest that the selectivity of these compounds for either MAO A or B is determined by the complex interplay of molecular size and flexibility. In this interplay, either one of these two factors may predominate.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2004

Childhood adversity, monoamine oxidase a genotype, and risk for conduct disorder.

BACKGROUND: Very little is known about how different sets of risk factors interact to influence risk for psychiatric disorder. OBJECTIVE: To replicate a recent report of a genotype-environment interaction that predicts risk for antisocial behavior in boys. DESIGN: Characterizing risk for conduct disorder in boys in association with monoamine oxidase A genotype and exposure to familial adversity, defined by interparental violence, parental neglect, and inconsistent discipline. SETTING: A community-based sample of twin boys. PARTICIPANTS: Five hundred fourteen male twins aged 8 to 17 years. MAIN OUTCOME MEASURE: Conduct disorder. RESULTS: There was a main effect of adversity but not of monoamine oxidase A on risk for conduct disorder. Low monoamine oxidase A activity increased risk for conduct disorder only in the presence of an adverse childhood environment. Neither a passive nor an evocative genotype-environment correlation accounted for the interaction. CONCLUSION: This study replicates a recent report of a genotype-environment interaction that predicts individual variation in risk for antisocial behavior in boys.

Adolescent↗