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PubMed1987

Differences in monoamine oxidase activity between cultured noradrenergic and cholinergic sympathetic neurons.

Two types of monoamine oxidase activity (MAO-A and MAO-B) help regulate the levels of biogenic amines such as catecholamines and serotonin. Although MAO-A has greater activity toward most catecholamines than MAO-B, no direct experiments have determined the types and levels of MAO activity that are normally expressed in noradrenergic neurons. Noradrenergic neurons from neonatal rat superior cervical ganglia were isolated and cultured under conditions that permit either continued expression of the noradrenergic phenotype or promote a transition to a predominantly cholinergic phenotype. After 14-21 days in vitro, neurons from both types of cultures were assayed for the type and amount of monoamine oxidase activity using tryptamine, a common substrate for both MAO-A and MAO-B. Neurons cultured under noradrenergic conditions expressed sevenfold greater MAO activity than neurons cultured under cholinergic conditions. Essentially all MAO activity in the noradrenergic cultures was inhibited by preincubation with 10(-8)-10(-9) M clorgyline, which indicated that this activity was primarily MAO-A. Cultures grown under cholinergic conditions exhibited 6- to 10-fold lower MAO-A activity and an 8- to 10-fold lower level of catecholamine synthesis from labeled precursors compared to neurons grown under noradrenergic conditions. These results directly demonstrate that high MAO-A activity is expressed in noradrenergic neurons in vitro. The corresponding decreases in both MAO-A specific activity and catecholamine synthesis as neurons become cholinergic in vitro suggest that the expression of the noradrenergic phenotype involves the coordinate regulation of degradative as well as synthetic enzymes involved in catecholamine metabolism.

Animals↗
PubMed2006

Monoamine oxidase A gene promoter polymorphism affects novelty seeking and reward dependence in healthy study participants.

It has been suggested that monoamine oxidase A plays an important role in the characterization of personality. Previous studies on the association between the polymorphism of variable number tandem repeat in the promoter region of the monoamine oxidase A gene and personality traits have, however, been unproductive. In the present study, the association between the monoamine oxidase A variable number tandem repeat polymorphism and personality traits assessed by the Temperament and Character Inventory was examined in 324 Japanese volunteers without psychiatric disorders. The low activity allele with three repeats (allele 3) and high activity allele with four repeats (allele 4) were determined by a polymerase chain reaction method. The carriers of allele 3 in males and the homozygotes of allele 3 in females were classified as the low activity group, the heterozygotes of alleles 3 and 4 in females as the medium activity group, and the carriers of allele 4 in males and the homozygotes of allele 4 in females as the high activity group. One-way analysis of variance showed that the scores of novelty seeking (P=0.006) and reward dependence (P=0.013) were significantly higher in the high activity group than in the low activity group. Multiple regression analysis demonstrated that the excess in the high activity allele was significantly associated with higher scores of novelty seeking (P=0.004) and reward dependence (P=0.003). The present study thus suggests that the monoamine oxidase A variable number tandem repeat polymorphism affects novelty seeking and reward dependence in healthy study participants.

Adult↗
PubMed1982

Validity of monoamine oxidase in serum for diagnosis of liver cirrhosis: estimation of predictive values, sensitivities and specificities.

The validity of monoamine oxidase (EC 1.4.3.4) activity in serum for the diagnosis of fibroproliferative liver disorders was assessed by measuring the specificity, sensitivity and positive and negative predictive values of the enzyme. Enzyme activity was measured in sera of 567 patients including those with biochemically and/or histologically verified non-fibrotic liver diseases (n = 64), liver fibrosis (n = 45), and liver cirrhosis (n = 51). The fraction of liver cirrhotic subjects with pathologically elevated monoamine oxidase activity (greater than 630 U/1) was 0.61, whereas only 0.16 of the cases with liver fibrosis and 0.11 of those with non-fibrotic liver diseases had abnormally high enzyme activities. Among the various categories of diseases tested, significantly increased enzyme activities were confined to liver cirrhosis and chronic active hepatitis. For liver cirrhosis, sensitivities and specificities were calculated as functions of various cut-off (critical) values of monoamine oxidase activity in serum, and with respect to a reference population of healthy men and non-cirrhotic subjects. The predictive value of the positive test result (enzyme activity higher than 720 U/1) at a prevalence of liver cirrhosis of maximum 0.033 (estimated incidence of chronic liver diseases in West Germany) is 0.68 if tested against healthy persons and less than 0.30 if tested against patients with non-liver cirrhotic diseases. It is concluded that monoamine oxidase is probably not helpful in the early diagnosis of fibroproliferative liver dysfunctions but may provide a parameter of complications of cirrhosis, e.g. portal-systemic collateral circulation (portal hypertension).

Chronic Disease↗
PubMed1994

Monoamine oxidase and catecholamine metabolism.

The enzyme which has come to be known as monoamine oxidase was discovered in liver over 60 years ago as tyramine oxidase (Hare, 1928). Almost 10 years later, Blaschko et al. (1957a,b) established that epinephrine, norepinephrine and dopamine were also substrates for this enzyme. Zeller (1938) distinguished monoamine oxidase as different from several other amine oxidases, such as diamine oxidase. Although it was generally assumed that catecholamines were metabolized by MAO, this was not established until isotopically labelled epinephrine and an MAO inhibitor became available. Schayer (1951) found that after administration of N-methyl-14C-epinephrine, only about 50% of the radioactivity appeared in the urine, whereas when the 14C label was incorporated into the beta-position on the side chain, almost all of the radioactivity could be recovered. One year later, Zeller et al. (1952) discovered that isonicotinic acid hydrazide (iproniazid) inhibited MAO. When animals pretreated with the MAO inhibitor were administered N-methyl-14C-epinephrine, almost all of the radioactivity was recovered (Schayer et al., 1955), indicating that the enzyme was responsible for the metabolism of about half of the administered catecholamine. Schayer et al. (1952, 1953) had found that five urinary metabolite products of beta-labelled-14C-norepinephrine could be separated by paper chromatography, but the chemical structures of these compounds were not known. Armstrong et al. (1957) showed that 3-methoxy-4-hydroxymandelic acid (vanillyl mandelic acid, VMA) was the major metabolite of norepinephrine and Shaw et al. (1957) demonstrated that large amounts of homovanillic acid (HVA) were excreted in urine after administration of 3,4-dihydroxy-phenylalanine (DOPA). These observations led Axelrod to examine the possibility that O-methylation might precede deamination and to his discovery of catechol-O-methyl transferase (Axelrod, 1957, 1959). At that time it became apparent that there were two possible routes for metabolism of norepinephrine to VMA--either deamination followed by O-methylation or O-methylation and subsequent deamination. The relative roles of these two pathways in terminating the physiological actions of catecholamines then became a focus of attention. Biochemical methods were used to access directly the relative importance of the two metabolic pathways. Physiological methods, based on the effects of drugs which alter metabolism of the catecholamine, were used to examine the role of MAO and COMT in terminating the actions of administered or endogenously released catecholamines.

Animals↗
PubMed1983

Cimoxatone is a reversible tight-binding inhibitor of the A form of rat brain monoamine oxidase.

Cimoxatone is a fully reversible inhibitor selective for the A form of monoamine oxidase. The inhibition is so potent against this enzyme form that it acts as a tight-binding inhibitor. Use of this inhibitor indicates that in rat brain homogenates the concentration of monoamine oxidase A is approximately 8-11 pmol . mg protein-1. Values similar to this were obtained by clorgyline titration, and both methods gave values similar to those found with a [3H]harmaline binding assay.

Animals↗
PubMed1987

Conditioned taste aversion induced in rats by intracerebral or systemic administration of monoamine oxidase inhibitors.

Conditioned taste aversion (CTA) elicited by systemic or intracerebral application of the monoamine oxidase inhibitors clorgyline (C), pargyline (P) or deprenyl (D) was studied in 402 rats. Water-deprived animals were allowed 15 min access to 0.1% sodium saccharin (CS) followed 10 min later by IP or by intracerebral injection of the drug. In the latter case, the animals were anesthetized 5 min after saccharin drinking with pentobarbital and the drug was stereotaxically injected (1 microliter/min, 1-2 microliters) into the target structure. CTA was assessed in a two-choice retention test performed 2 days later. A geometric progression of three to six dosages applied to groups of rats (n = 10) was employed to establish the effective doses of the drugs which were 4, 20 and 32 mg/kg with IP and 2.5, 10 and 80 micrograms per rat with intracerebral (n. raphé magnus) injections of C, P, and D, respectively. The ratios of intracerebral to systemic dosages eliciting comparable CTA were 1:300 for C, 1:800 for P and 1:100 for D. Injections of 2.5 micrograms C and 10 micrograms P into the mesencephalic reticular formation, medial hypothalamus and cerebral cortex were ineffective, as were injections of 10 micrograms P into the nucleus of the solitary tract and cerebellum. The results indicate that CTA is elicited more efficiently by inhibition of monoamine oxidase A (selectively inhibited by C) than of monoamine oxidase B (selectively inhibited by D).

Animals↗
PubMed1976

A routine assay procedure for monoamine oxidase and its application to human blood platelets.

In the radiometric assay procedure for monoamine oxidase separation of the reaction products by ion-exchange column chromatography was optimized. A device was constructed that allowed the separation of 48 samples at the same time. This device can be applied for a great variety of analytical methods. With a 0.1 mM substrate concentration in the incubation mixture, reaction products could be determined with a reproducibility of 2-5%, where the standard deviation depends on the substrate. Using beta-phenylethylamine as substrate 20 mug of platelet protein was sufficient for monoamine oxidase activity determinations. The dependence of human blood platelet monoamine oxidase on age and sex were studied using the method.

Adolescent↗
PubMed1984

[Monoamine oxidase activity in rabbit brain nuclei in experimental acute emotional stress].

Activity of monoamine oxidase in the neurons of catecholamine-synthesizing nuclei of hypothalamic and brainstem of rabbits with different resistance of cardiovascular functions to emotional stress was studied by the Glenner et al. method. An acute experimental emotional stress was induced by non-periodic electric stimulation of the hypothalamic ventromedial nucleus and the skin in immobilized adult chinchilla rabbits. It was found that monoamine oxidase activity in the neurons of groups A5, A6, A7 and A14 under acute experimental emotional stress increased in rabbits "resistant"to stress and remained unchanged in rabbits "predisposed" to stress. The activity of monoamine oxidase in the neurons of group A12 remained unchanged in the rabbits "resistant"to stress and decreased in the rabbit "predisposed" to stress.

Acute Disease↗
PubMed1983

Oral absorption and concentration-effect relationship of tyramine with and without cimoxatone, a type-A specific inhibitor of monoamine oxidase.

The mechanism of increased sensitivity to oral tyramine in patients taking monoamine oxidase inhibitors was investigated by measurement of plasma norepinephrine and tyramine with a reversible, monoamine oxidase form A selective inhibitor, cimoxatone. In the first open study, the pressor activity of 80 mg oral tyramine after cimoxatone was of the order of that of 800 mg without the drug. In a second double-blind study, the equivalent tyramine dose was between 400 and 800 mg. Absorption of unmetabolized tyramine increased in the presence of cimoxatone. Peak plasma concentration of tyramine after an 80-mg dose was approximately three times that of placebo when given after cimoxatone. The plasma tyramine concentration required to induce a similar pressor effect averaged 130.5 ng ml-1 without pretreatment and 17.4 ng ml-1 after cimoxatone in the open study. Another plasma concentration, 16.4 ng ml-1, elicited a lower pressor effect in the double-blind study. The increased sensitivity to oral tyramine has two components: decreased presystemic clearance in the gut wall and increased sensitivity to circulating tyramine. The tyramine dose required to induce a pressor effect after cimoxatone is relatively higher than after irreversible inhibitors such as phenelzine. This may reflect the dose of cimoxatone used, the activity of monoamine oxidase form B (MAO-B) in the gut and liver or displacement of the predominantly reversible and predominantly competitive inhibitor, cimoxatone, from the enzyme by a high local tyramine concentration.

Absorption↗
PubMed1997

I2-imidazoline binding sites and monoamine oxidase activity in human postmortem brain from patients with Parkinson's disease.

I2-imidazoline binding site (I2BS) has been identified with a regulatory site located on a sub-population of monoamine oxidase (MAO)-A and -B. Previous studies showed a modification of MAO and I2BS in the elderly and in neurodegenerative processes such as Alzheimer's disease. In the present study, we studied the potential modification of I2 binding sites and monoamine oxidases in Parkinson's disease. Putamen and cerebral cortex were collected from 17 normal subjects (79 +/- 12 yr) and 16 patients (76 +/- 9 yr) affected by Parkinson's disease. In mitochondrial preparations, radioligand binding studies with [3H]idazoxan showed that putamen and frontal cortex express equivalent amount of I2BS. The density and affinity of I2BS were similar in normal subjects (putamen: Bmax = 207 +/- 58 fmol/mg of protein, Kd = 10.1 +/- 3.4 nM; cerebral cortex: Bmax = 193 +/- 54 fmol/mg of protein, Kd = 12.8 +/- 6.8 nM) and Parkinson's disease patients (putamen: Bmax = 193 +/- 60 fmol/mg of protein, Kd = 9.8 +/- 4.6 nM; cerebral cortex: Bmax = 199 +/- 49 fmol/mg of protein, Kd = 15.9 +/- 8.1 nM). The activity of total monoamine oxidase and monoamine oxidase B, measured by [14C]tyramine and [14C]phenylethylamine oxidation, respectively, were higher in putamen than in cerebral cortex. No differences have been detected in the enzyme activity between normal and pathological subjects. These data suggest that, although MAO and I2BS may play a role in the development of Parkinson's disease, they are not altered in the chronic phase of this disease.

Aged↗
PubMed1991

Neurocatin-induced inhibition of monoamine oxidase A in rat brain synaptosomes.

Neurocatin is a small (about 2000 Da) neuroregulator isolated from mammalian brain. Earlier it was shown that addition of nanomolar concentrations of neurocatin to synaptosomes isolated from rat brain increased levels of serotonin and decreased catabolism of serotonin to 5-hydroxyindoleacetic acid (Fernandez-Novoa L and Pastuszko A. Neurosci Lett 122: 83-86, 1991). In the present study, we report that neurocatin addition resulted in a striking inhibition of monoamine oxidase A activity. This inhibition became statistically significant at a neurocatin concentration of approximately 5 nM and was significant at all higher neurocatin concentrations. Neurocatin at approximately 50 nM inhibited monoamine oxidase A activity by about 90%. The inhibitory effect of neurocatin on monoamine oxidase required its incubation with intact synaptosomes since addition after breaking the synaptosomes by hypotonic buffer or lysis by Triton X-100 almost completely blocked the inhibitory effect. Measurements of the kinetic parameters of the enzyme in lysates prepared from synaptosomes incubated with neurocatin showed a decrease in Vmax with no change in Km for the substrate (serotonin) compared to controls. Incubation of the synaptosomes with approximately 25 nM neurocatin resulted in an 80% decrease in the Vmax of monoamine oxidase A. Evidence that neurocatin is a powerful endogenous modulator of monoamine oxidase activity is particularly intriguing. This enzyme plays a major role in catabolism of the biogenic amines and is believed to contribute to several important neurological disorders.

Animals↗
PubMedDate not supplied

[Hydrazine derivative modification of the activity of brain mitochondrial monoamine oxidases].

Treatment of bovine brain stem mitochondria with hydrazine derivatives, which inhibited the monoamine oxidase activity (substrate: 5-hydroxytryptamine), was accompanied by appearance of the properties to deaminate histamine and cadaverine at a high rate. The same phenomenon was observed in vivo after treatment of mice with the hydrazine derivatives. The dramatic increase in histamine deaminating activity in brain was accompanied by a decrease in the tissue concentration of histamine. The hydrazine derivatives are considered as prooxidants stimulating via a free-radical mechanism lipid peroxidation in methyloleate solutions and in biomembranes (ref. 5) and causing qualitative alteration (transformation) in catalytic properties of monoamine oxidases of the tyre A, which acquire the histamine deaminating activity. A certain correlation was noted between the prooxidant effect of the hydrazine derivatives and the modification of catalytic properties of the membrane bound monoamine oxidases of brain mitochondria in vitro and in vivo.

Animals↗
PubMed2006

Effects of monoamine oxidase inhibitors on cocaine discrimination in rats.

This study tested the time course of the discriminative stimulus effects of inhibitors of monoamine oxidase alone or in combination with cocaine. Male Sprague-Dawley rats were trained to discriminate cocaine (10 mg/kg, intraperitoneal) from saline using a two-lever choice methodology. The nonselective monoamine oxidase inhibitors tranylcypromine (0.01-5 mg/kg) and phenelzine (1-25 mg/kg), the monoamine oxidase-A selective compound clorgyline (1-25 mg/kg), and the monoamine oxidase-B selective compounds pargyline (0.005-50 mg/kg) and selegiline (1-25 mg/kg) were tested for substitution 15 min or 24 h following administration, and in combination with 10 mg/kg of cocaine 24 and 48 h after administration. At 15 min, selegiline fully substituted for the discriminative stimulus effects of cocaine, whereas all other compounds partially substituted. At 24 h, substitution of cocaine was diminished for all compounds except phenelzine, which produced a greater amount of substitution at 24 h than at 15 min. When cocaine was administered 24 h after clorgyline, selegiline, pargyline, and phenelzine, cocaine-appropriate responding was attenuated at intermediate doses of these drugs, whereas the highest doses did not alter cocaine-lever responding. All compounds except selegiline substantially decreased response rate and produced various adverse effects. At 48 h, the effects of all compounds except phenelzine were markedly reduced. Selectivity for monoamine oxidase-A or monoamine oxidase-B did not predict the ability to substitute for or attenuate the subjective effects of cocaine. These findings suggest that monoamine oxidase inhibitors can modulate the discriminative stimulus effects of cocaine for at least 24 h, and may be useful for treatment of cocaine abuse.

Animals↗
PubMed1994

Purification, characterization, and crystallization of monoamine oxidase from Escherichia coli K-12.

The gene for monoamine oxidase (MAO) was cloned from an Escherichia coli genomic library and MAO was overproduced in the periplasmic space. The enzyme was purified to homogeneity by preparation of a periplasmic fraction, followed by ammonium sulfate fractionation and DEAE-cellulose column chromatography. Crystals were obtained by the hanging drop method using sodium citrate as a precipitant. The enzyme was found to be a dimer of identical subunits with a molecular weight of 80,000, and showed the highest activity at pH 7.5 and 45 degrees C. The enzyme was inhibited by a MAO specific inhibitor, hydroxylamine, hydrazine, phenelzine, isoniazid, and tranycpromine. The enzyme oxidized tyramine, phenethylamine, and tryptamine at higher rates, but not oxidized diamine and polyamines such as putrescine and spermine. The antibody against E. coli MAO cross-reacted with purified MAO A from Klebsiella aerogenes.

Amine Oxidase (Copper-Containing)↗
PubMed1979

Liver monoamine oxidase in the obese-hyperglycaemic (ob/ob) mouse.

1. The specific activity of monoamine oxidase was found to be greater in liver mitochondria from ob/ob mice than from lean mice. The activities of marker enzymes were similar in both tissues. 2. Experiments with various substrates (5-hydroxytryptamine, benzylamine and tyramine) and inhibitors (clorgyline and deprenyl) indicated that, unlike rat liver mitochondria, mouse liver mitochondria contain a predominance of the B-form of monoamine oxidase. 3. The Km values for lean and ob/ob mice were the same for any given substrate and were in the increasing order 5-hydroxytryptamine less than tyramine less than benzylamine. Vmax. was approximately 50% greater in obese than in lean mice. 4. Extraction of liver mitochondria with acetone/water or acetone/water/NH3 to remove lipids decreased the enzyme activity relatively more in obese- than in lean-mice preparations, but residual activity was the same in both preparations.

Animals↗
PubMed1996

Monoamine oxidase inhibitors. An update on drug interactions.

After initial enthusiasm, the use of monoamine oxidase inhibitors (MAOIs) has been limited by the wide range of MAOI-drug and MAOI-food interactions that are possible, particularly with sympathomimetic medications or tyramine-containing foods, resulting in hypertensive reactions. Despite their clinical benefits, this has led to a reduction in use of such medications. Discovery of the 2 main subgroups of monoamine oxidase, types A and B, led to the synthesis of MAOIs selective for one or other of these isoenzymes. Consequently, selegiline (deprenyl), a selective MAO-B inhibitor, was developed for the treatment of idiopathic Parkinson's disease. This drug is useful in the treatment of the early stages of the disease and later on as an adjunct to other drug therapies. Although the selective MAO-A inhibitor, clorgiline (clorgyline), was found to be effective in the treatment of depression, it still retained the potential to cause hypertensive reactions. Recently, agents that are not only selective, but reversible in their inhibition of MAO-A (RIMAs) have been synthesised (e.g. moclobemide and toloxatone), and have proven antidepressant efficacy. Whilst they are less likely to induce hypertensive reactions with the concomitant administration of sympathomimetic drugs or with tyramine-rich foodstuffs, it still seems wise to advocate care in co-prescribing potentially interacting medications and to advise a degree of caution with regard to the dietary intake of foodstuffs likely to contain a high tyramine content. Although these newer drugs represent an advance in safety, their use has, as yet, only been established in the treatment of depression. RIMAs also retain a potential for adverse interaction with other drugs. Concomitant prescription of serotonin-enhancing drugs should only be undertaken with caution for patients on moclobemide, toloxatone or selegiline. Coprescription of sympathomimetic drugs should also be avoided with these newer MAOIs and patients should be advised against purchasing over-the-counter preparations that may contain sympathomimetic drugs.

Animals↗