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PubMed1998

Monoamine oxidase B single-photon emission tomography with [123I]Ro 43-0463: imaging in volunteers and patients with temporal lobe epilepsy.

Imaging of monoamine oxidase of subtype B (MAO B) is of interest in various neurological diseases. In the past non-invasive assessment of MAO B has only been possible with positron emission tomography (PET) ligands. Given the limited availability of PET, a single-photon emission tomography (SPET) ligand would be desirable. In this study SPET imaging with the new MAO B inhibitor [123I]Ro 43-0463 was performed in five volunteers and nine patients with temporal lobe epilepsy (TLE). In two volunteers a second study was performed 12 h following blockade with deprenyl. In the TLE patients the tracer was administered as bolus (n = 4) or as prolonged infusion (n = 5). The regional uptake pattern correlated well with the known distribution of MAO B. In the two blocking studies ligand uptake was substantially reduced compared with baseline. In the TLE patients increased uptake was found in the ipsilateral mesial temporal lobe and, surprisingly, in the ipsilateral putamen. This study indicates the potential of the new SPET ligand [123I]Ro 43-0463 to map MAO B concentration in the human brain. The new finding of increased MAO B in the putamen of TLE patients needs further studies to elucidate its exact pathophysiology.

Adult↗
PubMed1988

Circulating monoamine oxidase B and phenolsulfotransferase activities in essential hypertensive patients.

Circulating monoamine oxidase (MAO) and phenolsulfotransferase M and P (PST M, PST P) activities were determined in 24 untreated essential hypertensive patients and in 35 age-matched normotensive healthy controls. These enzymes are involved in the inactivation of monoamines and their metabolites. After lysis of blood, enzymatic activities were determined by radioenzymatic techniques using as substrates [14C]-beta-phenylethylamine for MAO, 3-methoxy-4-hydroxyphenylglycol for PST M and phenol for PST P. MAO activity measured by this method is fully accounted for by platelet MAO B activity. Women presented higher MAO activity than men. Significantly lower MAO-B activities were observed in hypertensive patients, both in men and in women, when compared to normotensive controls. Circulating PST activities, of which more than 80% is platelet-derived, were similar in hypertensive and normotensive subjects. These data suggest that the intracellular serotonin inactivation processes, through MAO and PST, cannot account for the reduction of platelet 5-HT content observed in essential hypertension.

Adult↗
PubMed2005

Type A monoamine oxidase is the target of an endogenous dopaminergic neurotoxin, N-methyl(R)salsolinol, leading to apoptosis in SH-SY5Y cells.

Mitochondrial monoamine oxidase (MAO) has been considered to be involved in neuronal degeneration either by increased oxidative stress or protection with the inhibitors of type B MAO (MAO-B). In this paper, the role of type A MAO (MAO-A) in apoptosis was studied using human neuroblastoma SH-SY5Y cells, where only MAO-A is expressed. An endogenous dopaminergic neurotoxin, N-methyl(R)salsolinol, an MAO-A inhibitor, reduced membrane potential, DeltaPsim, in isolated mitochondria, and induced apoptosis in the cells, which 5-hydroxytryptamine, an MAO-A substrate, prevented. In contrast, beta-phenylethylamine, an MAO-B substrate, did not suppress the DeltaPsim decline by N-methyl(R)salsolinol. The binding of N-methyl(R)salsolinol to mitochondria was inhibited by clorgyline, a MOA-A inhibitor, but not by (-)deprenyl, an MAO-B inhibitor. RNA interference targeting MAO-A significantly reduced the binding of N-methyl(R)salsolinol with simultaneous reduction in the MAO activity. To examine the intervention of MAO-B in the apoptotic process, human MAO-B was transfected to SH-SY5Y cells, but the sensitivity to N-methyl(R)salsolinol was not affected, even although the activity and protein of MAO increased markedly. These results demonstrate a novel function of MAO-A in the binding of neurotoxins and the induction of apoptosis, which may account for neuronal cell death in neurodegenerative disorders, including Parkinson's disease.

Apoptosis↗
PubMed2002

Neuroprotective effect of the monoamine oxidase inhibitor PF 9601N [N-(2-propynyl)-2-(5-benzyloxy-indolyl) methylamine] on rat nigral neurons after 6-hydroxydopamine-striatal lesion.

Monoamine oxidase B (MAO-B) inhibitors are potentially useful in the therapeutic treatment of Parkinson's disease. L-Deprenyl has been shown to slow nigrostriatal tract degeneration in human idiopathic Parkinsonism and to be an effective neuroprotector in experimental 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity models. However, L-amphetamine and (-)methamphetamine, the metabolites generated by L-deprenyl, can have adverse and severe side-effects. Therefore, the search for new MAO-B inhibitors without potential amphetamine-like properties is a matter of great therapeutic interest. The present report is the first to describe the neuroprotective effect--following chronic intraperitoneal (i.p.) treatment--of a novel and non-amphetaminic MAO-B inhibitor, [N-(2-propynyl)-2-(5-benzyloxy-indolyl) methylamine] (PF 9601N), on the neurodegeneration of nigral dopaminergic neurons caused by administration of intrastriatal 6-hydroxydopamine (6-OHDA). Two groups of six animals were unilaterally injected with 6-OHDA in the right striatum. One group was treated daily with 60 mg/kg PF 9601N i.p., starting before stereotaxic lesion and continuing for 18 days thereafter. The other group was treated with vehicle solution. Coronal slabs including the substantia nigra pars compacta (SNpc) were processed for tyrosine hydroxylase immunohistochemistry (TH). The number of TH positive (TH+) neurons in the SNpc was 60% lower in 6-OHDA lesioned rats. However, the loss of TH+ neurons in the SNpc was only 30% in PF 9601N i.p.-treated animals. Therefore, treatment with the specific MAO-B inhibitor significantly reduced the 6-OHDA-induced degeneration to about 50%.

Animals↗
PubMed1993

Types A and B monoamine oxidase contribute to the metabolism of norepinephrine in perfused lungs of rats.

The aim of the study was to determine the activity of monoamine oxidase (MAO) and the contributions of the A and B forms of MAO to the metabolism of norepinephrine (NE) in isolated perfused lungs of the rat. Preliminary experiments to investigate the MAO-A and MAO-B selective inhibitors, Ro41-1049 and Ro19-6327, respectively, were carried out in isolated preparations of rat vas deferens incubated in 10 nM [3H]NE (Uptake2 and catechol-O-methyltransferase inhibited) to measure rates of deamination of NE and the rate constant for deamination (kMAO) by MAO-A. These experiments showed that 1) the IC50 of Ro41-1049 for inhibition of MAO-A was 9.62 nM with 97% inhibition by 300 nM and 2) 100 or 300 nM Ro19-6327 did not affect deamination of NE by MAO-A. Hence, 300 nM Ro41-1049 and 100 nM Ro19-6327 were used to inhibit selectively MAO-A and MAO-B, respectively, in rat lungs perfused in vitro with 10 nM [3H]NE. Catechol-O-methyltransferase was inhibited and kMAO values for metabolism of NE were determined. The kMAO value for deamination of NE in the absence of Ro41-1049 or Ro19-6327 was 0.186 min-1. Ro41-1049 and Ro19-6327 decreased this kMAO value by 79 and 33%, respectively. Thus, it was concluded that both MAO-A and MAO-B contribute to the deamination of NE in the pulmonary circulation of the rat, with MAO-A responsible for 67-79% of the total deamination and MAO-B for 21-33%.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2005

Analysis of monoamine oxidase enzymatic activity by reversed-phase high performance liquid chromatography and inhibition by beta-carboline alkaloids occurring in foods and plants.

Monoamine oxidase (MAO) is a flavin adenine dinucleotide (FAD)-containing enzyme located at the outer membranes of mitochondria that catalyzes the oxidative deamination of biogenic and xenobiotic amines. We have used a chromatographic method to measure MAO-enzymatic activity by using kynuramine as a non-selective substrate with its MAO-oxidation product subsequently analyzed by RP-HPLC-DAD and HPLC-mass spectrometry (MS). This method was applied to study the kinetic parameters, inhibition and reaction products of MAO recombinant enzymes in presence of tetrahydro-beta-carboline and beta-carboline alkaloids occurring in foods, plants and mammals. Analysis by HPLC showed that tetrahydro-beta-carbolines or beta-carbolines were not modified by MAO. Several beta-carbolines such as tryptoline (1,2,3,4-tetrahydro-beta-carboline) and 1-methyltryptoline (1-methyl-1,2,3,4-tetrahydro-beta-carboline) were inhibitors of MAO-A; instead their corresponding 6-hydroxy-derivatives (6-hydroxytryptoline and 6-hydroxy-1-methyltryptoline) lacked this activity. Tetrahydro-beta-carboline-3-carboxylic acids were unable to inhibit MAO enzymes. In contrast, their oxidation products, i.e. the fully aromatic beta-carbolines (norharman and harman), acted as good inhibitors of MAO. Two tetrahydro-beta-carbolines (i.e. tryptoline and 1-methyltryptoline) occurring in foods were isolated by solid-phase extraction (SPE) and RP-HPLC from selected samples of sausages and the corresponding extracts exhibited good inhibition properties over MAO-A. These results suggest that beta-carbolines from foods, plants, and mammals may exert inhibitory actions on MAO enzymes.

Alkaloids↗
PubMed1984

Enzymic and molecular characteristics of a new form of monoamine oxidase, distinct from form-A and form-B.

The present study was undertaken to clarify the enzymic and molecular properties of monoamine oxidase (MAO) in carp brain. In particular, its sensitivities to selective MAO inhibitors, kinetic properties and molecular weight were compared with those of the enzyme in carp liver. The selective and potent MAO-A and MAO-B inhibitors FLA 788(+), FLA 336(+), MD 780236 and benzylcyanide caused dose-dependent inhibitions of MAO activity in both carp brain and liver; the inhibition curves were all single-sigmoidal, and the degrees of inhibition of the activities towards 5-hydroxytryptamine (5-HT, selective MAO-A substrate), tyramine (substrate for both forms of MAO) and beta-phenylethylamine (PEA, selective MAO-B substrate) were similar. This was also the case for inhibition of activity in carp brain by the irreversible and selective MAO-A and MAO-B inhibitors clorgyline and I-deprenyl, indicating the presence in both preparations of a single MAO which differs from either form of MAO. Studies on the substrate specificities and Km values for these three substrates and the inhibitory effects of some compounds suggested that the enzymic characters of MAO in carp preparations were similar and that these enzymes might be FAD-containing enzymes, like MAO in various mammals. By labelling the preparations with radioactive pargyline and then subjecting them to sodium dodecyl sulfate electrophoresis, the apparent molecular weights of carp brain and liver MAO were estimated as 60,000 daltons. The same value was also obtained for rat brain and liver mitochondrial MAO-B. These results indicate that by the present definitions of MAO-A and MAO-B, MAO in carp brain and liver is similar to, but distinct from, both these forms of MAO.

Animals↗
PubMed1978

The influence of respiratory state on monoamine oxidase activity in rat liver mitochondria.

Changes in the respiratory state of rat liver mitochondria caused significant changes (up to 10-fold) in the rates of oxidative deamination of tyramine, indicating interactions between the inner coupling membrane and the monoamine oxidase sites in the outer membrane, and suggesting the possibility that monoamine oxidase is regulated by the thermodynamic state of the mitochondria.

Animals↗
PubMed1997

Parkinson disease: a new link between monoamine oxidase and mitochondrial electron flow.

Two factors that contribute to the progression of Parkinson disease are a brain defect in mitochondrial respiration and the generation of hydrogen peroxide (H2O2) by monoamine oxidase (MAO). Here we show that the two are linked. Metabolism of the neurotransmitter dopamine, or other monoamines (benzylamine, tyramine), by intact rat brain mitochondria suppresses pyruvate- and succinate-dependent electron transport. MAO inhibitors prevent this action. Mitochondrial damage is also reversed during electron flow. A probable explanation is that MAO-generated H2O2 oxidizes glutathione to glutathione disulfide (GSSG), which undergoes thiol-disulfide interchange to form protein mixed disulfides, thereby interfering reversibly with thiol-dependent enzymatic function. In agreement with this premise, direct addition of GSSG to mitochondria resulted in similar reversible inhibition of electron transport. In addition, the monoamines induced an elevation in protein mixed disulfides within mitochondria. These observations imply that (i) heightened activity and metabolism of neurotransmitter by monoamine neurons may affect neuronal function, and (ii) apparent defects in mitochondrial respiration associated with Parkinson disease may reflect, in part, an established increase in dopamine turnover. The experimental results also target mitochondrial repair mechanisms for further investigation and may, in time, lead to newer forms of therapy.

Animals↗
PubMed1987

Cardiac myonecrosis in hypertensive crisis associated with monoamine oxidase inhibitor therapy.

A young woman taking tranylcypromine for depression was hospitalized with severe chest pain and hypertension after eating cheese. Electrocardiography initially showed arrhythmias and precordial ST segment depression. Myocardial creatine kinase values were elevated, and echocardiography showed regional ventricular dysfunction, suggestive of focal cardiac myonecrosis. The cardiovascular pathophysiology of tyramine hypertensive crisis and related catecholamine excess states, including pheochromocytoma and clonidine withdrawal, is reviewed. Cardiac myonecrosis is a potential adverse effect of the hypertensive crisis associated with monoamine oxidase inhibitor use. Psychiatric indications for monoamine oxidase inhibitors may be expanding, but clinicians should continue to exercise caution in the use of these agents.

Adult↗
PubMedDate not supplied

Studies on 1,2,3,6-tetrahydropyridine derivatives as potential monoamine oxidase inactivators.

The Parkinsonian-inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and close structural analogs are the only known cyclic tertiary amines with good monoamine oxidase substrate properties. In addition to its excellent substrate properties, MPTP is a mechanism-based inactivator of monoamine oxidase B (MAO-B). In an attempt to exploit the special interactions between this cyclic tertiary allylamine and MAO-B, we have initiated studies to evaluate the enzymatic and biological properties of MPTP analogs bearing functional groups which are known to mediate the metabolism-dependent inactivation of this enzyme. This paper describes the synthesis, enzyme substrate/inhibitor properties, and neurotoxic/neuroprotective properties of 1-cyclopropyl-4-phenyl-1,2,3,6-tetrahydropyridine, the corresponding acyclic secondary amine (E)-4-cyclopropyl-2-phenyl-2-butene, and 4-cyclopropyl-1-methyl-1,2,3,6-tetrahydropyridine.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1976

Effects of imipramine, nomifensine and d-amphetamine on type B monoamine oxidase, cyclic AMP phosphodiesterase and dopamine-beta-hydroxylase.

The three dissimilar structural antidepressant drugs, imipramine, nomifensine and d-amphetamine, were compared for their effects on type B monoamine oxidase, cyclic AMP phosphodiesterase and dopamine-beta-hydroxylase. Three antidepressant drugs caused a dose-dependent inhibition on type B monoamine oxidase. Of the three drugs, imipramine had a most potent effect. Unlike d-amphetamine, both imipramine and nomifensine inhibited the cyclic AMP phosphodiesterase activity at concentrations more than 10(-4)M. No effect was observed below this concentration. All drugs seemed to have little or no effects on the partially purified dopamine-beta-hydroxylase activity. The weak inhibitory effects of nomifensine on these three enzymes may not be attributable to its antidepressant properties. Morphine had no effect on the three enzyme activities.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1980

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 beta-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, raher than due to a variation in the molecular turnover numbers of this enzyme form towards its amine substrates.

Alkynes↗
PubMed1999

Monoamine oxidase inhibitor properties of some benzazoles: structure-activity relationships.

Benzazoles containing two or three nitrogen atoms were screened for their inhibitory activity toward monoamine oxidases MAO-A and MAO-B. In order to clarify the mechanism of interaction of these compounds with the enzyme, their electronic structure was calculated at the ab initio level and the influence of lipophilicity on activity was investigated. The mode of binding of benzazoles to MAO-B appears different from that of previously investigated heterocycles.

Animals↗
PubMed1984

Influence of age, sex and osteogenesis imperfecta on count, protein content, and monoamine oxidase activity of human thrombocytes.

We determined the effect of count, age (2 to 24 year), sex, and osteogenesis imperfecta (OI) on the protein content and monoamine oxidase activity in human platelets. The reaction rate in presence of paramethoxybenzylamine was assessed in a sensitive and continuously recording spectrophotometric system. Platelets harvested from control subjects and OI patients displayed significant inverse linear correlations between count and protein content; there was near-constancy of the products of the two variables. The effects of age, sex, and osteogenesis imperfecta on protein content, count, and MAO activity were assessed by multivariate analysis of variance. It was found that, with increasing age, the count increased linearly and the protein content decreased. In patients with OI the protein content was depressed and monoamine oxidase activity elevated regardless of whether the latter was calculated on the basis of pellet protein or of count. The data suggest that, in osteogenesis imperfecta, thrombocytic monoamine and protein metabolism deviate from that of controls.

Adolescent↗
PubMed1990

Monoamine oxidase B inhibition reduces gastric mucosal blood flow, basal acid secretion, and cold water restraint-induced gastric mucosal injury in rats.

Inhibition of monoamine oxidase B (MAO B) by selective inhibitors pargyline and L-deprenyl increases dopamine (DA) and norepinephrine (NE) concentrations in nucleus accumbens (NACB) and is associated with reduction in cold water restraint-induced gastric mucosal injury, inhibition of basal gastric acid output, and regional gastric mucosal blood flow. Similar effects were not observed with administration of MAO A inhibitors. These observations suggest that activation of central dopamine and norepinephrine receptors, particularly in NACB, are involved in the control of gastric mucosal function.

Animals↗
PubMed1987

Monoamine oxidase B inhibition and the "cheese effect".

The absence of initiation of "cheese effect" (potentiation of sympathomimetic action of tyramine) by 1-deprenyl (selective monoamine oxidase, MAO-B inhibitor) was regarded to be an intrinsic property of this inhibitor. However, availability of other selective MAO-B inhibitors have clearly shown that this is not the case, since the "cheese effect" is associated with the selective inhibition of MAO-A, the enzyme responsible for intraneuronal oxidation of noradrenaline. Following inhibition of neuronal MAO-A, noradrenaline in the cytoplasmic intraneuronal pool can increase to high levels. Since tyramine releases noradrenaline into the cytoplasm and not by exocytosis, its action is potentiated by inhibition of neuronal MAO-A.

Animals↗