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.     

Biochemistry and physiology of monoamine oxidase (MAO) activity in the ring dove (Streptopelia risoria). II. Distribution of MAO in different tissues

Monoamine oxidase (MAO) activity was measured fluorometrically in liver, kidney, intestine and brain of adult male and female ring doves. Liver MAO was inhibited in a concentration-related fashion by clorgyline and harmaline (MAO type A inhibitors) where a plateau in the inhibition curve occurred with about 15% activity remaining, and also by the type B inhibitor deprenyl, which produced a plateau when about 85% activity remained. Kidney, intestine and brain MAO were inhibited in a biphasic manner by harmaline. Results with inhibitors suggest that 85% of liver MAO, 86% of kidney MAO, 88% of intestine and 75% of brain MAO is type A. Using 10(-6) M harmaline to differentiate between MAO-A and MAO-B type activities, the apparent maximal velocities (Vmax) and Michaelis constants (Km) were determined in different tissues. Most activity occurred in the intestine, with proportionally lesser amounts of kidney, liver and brain. The majority of MAO present was in the A form. Except for kidney, Km of MAO-B was higher than that of MAO-A. Both MAO-A and -B activities were higher in the intestines of male birds, although sex differences in content and type of MAO activity were not observed in other tissues of the ring dove.     

Characterization of monoamine oxidase isoforms in human islets of Langerhans.

In this paper, we describe the characterization of the expression of monoamine oxidase (MAO) in whole pancreas and in isolated islets of Langerhans from human. Classical monamine oxidase activity assays reveal that both isoforms A & B are present in human pancreas. Two complementary approaches indicated that both MAO A and B are expressed in isolated islet: RT-PCR using specific primers revealed amplification products with the expected size for MAO-A and MAO-B: two peptides corresponding to MAO A (approximately 61 kDa) and B (approximately 55 kDa) were detected using a polyclonal anti MAO-A/MAO-B antiserum. Western blotting and subsequent densitometric analysis indicate that whole and endocrine pancreas express the two isoforms with different relative proportions. Islets appear to express almost twice as much MAO protein as whole pancreas, in near equal proportions of the two isoforms, whereas whole pancreas expresses more MAO-A than the B isoform. The expression of MAO A and B in islets could be the first step toward the characterization of the functional properties of these enzymes in the endocrine pancreas.     

Modification of substrate-inhibitor affinities of human platelet monoamine oxidase B in vitro

The rate of benzylamine utilization by monoamine oxidase (MAO)-B from human blood platelets was 2-4 times higher than that for octopamine. Both activities were inhibited 100% by 10(-7) M deprenyl (a specific MAO-B inhibitor) and were not affected by clorgyline (a specific MAO-A inhibitor) or by polyclonal antibodies to MAO-A. The preincubation of platelet MAO-B with purified MAO-A from mitochondrial membranes of human placenta resulted in appearance of excess octopamine activity. This additional activity was not precipitated by antibodies to MAO-A or inhibited by deprenyl but was inhibited by clorgyline. Incubation of the MAO-A preparation from placenta at 45 degrees C for 15 min before its preincubation with MAO-B caused 50% loss of both activities. Protease inhibitors had no effect on the modification of MAO. These data indicate that MAO-A or a factor tightly bound to it can modify MAO-B yielding a form of the enzyme with both MAO-A and MAO-B substrate and inhibitor affinities and MAO-B immunospecificity.     

Human monoamine oxidase is inhibited by tobacco smoke: beta-carboline alkaloids act as potent and reversible inhibitors

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. Recently, positron emission tomography imaging has shown that smokers have a much lower activity of peripheral and brain MAO-A (30%) and -B (40%) isozymes compared to non-smokers. This MAO inhibition results from a pharmacological effect of smoke, but little is known about its mechanism. Working with mainstream smoke collected from commercial cigarettes we confirmed that cigarette smoke is a potent inhibitor of human MAO-A and -B isozymes. MAO inhibition was partly reversible, competitive for MAO-A, and a mixed-type inhibition for MAO-B. Two beta-carboline alkaloids, norharman (beta-carboline) and harman (1-methyl-beta-carboline), were identified by GC-MS, quantified, and isolated from the mainstream smoke by solid phase extraction and HPLC. Kinetics analysis revealed that beta-carbolines from cigarette smoke were competitive, reversible, and potent inhibitors of MAO enzymes. Norharman was an inhibitor of MAO-A (K(i)=1.2+/-0.18 microM) and MAO-B (K(i)=1.12+/-0.19 microM), and harman of MAO-A (K(i)=55.54+/-5.3nM). Beta-carboline alkaloids are psychopharmacologically active compounds that may occur endogenously in human tissues, including the brain. These results suggest that beta-carboline alkaloids from cigarette smoke acting as potent reversible inhibitors of MAO enzymes may contribute to the MAO-reduced activity produced by tobacco smoke in smokers. The presence of MAO inhibitors in smoke like beta-carbolines and others may help us to understand some of the purported neuropharmacological effects associated with smoking.     

Can Carnosine Prevent the Aging-Induced Changes of Blood Platelet and Brain Regional Monoamine Oxidase-A mRNA in Relation to its Activity?

It is well known that the monoamine oxidase (MAO) activity deregulates during aging along with anti-oxidant activity. Carnosine (β-Ala-l-His) is an endogenous dipeptide biomolecule, having both anti-oxidant and anti-glycating properties. The present study deals with the effect of carnosine on aging-induced changes in MAO-A mRNA expression of brain regions and blood platelets in relation to their MAO-A activity. Results showed that aging significantly and characteristically increased the brain regional MAO-A mRNA whereas, in blood platelets it was significantly reduced with an increase in blood platelet counts. Carnosine attenuated both aging-induced (i) increase in brain regional MAO-A mRNA expression and blood platelet count, (ii) decrease in blood platelet MAO-A mRNA expression and its (platelet MAO-A) activity without affecting the young rats’ brain regions and platelet. The present results thus suggest that carnosine attenuated and restored the aging-induced (a) increase of platelet count and (b) changes in brain regional and blood platelet MAO-A mRNA expression and (c) decrease in platelet MAO-A activity, towards their respective basal level that were observed in young rats.     

Inhibition of brain monoamine oxidase activity by the generation of hydroxyl radicals: potential implications in relation to oxidative stress

Monoamine oxidase (MAO) is an enzyme involved in brain catabolism of monoamine neurotransmitters whose oxidative deamination results in the production of hydrogen peroxide. It has been documented that hydrogen peroxide derived from MAO activity represents a special source of oxidative stress in the brain. In this study we investigated the potential effects of the production of hydroxyl radicals (*OH) on MAO-A and MAO-B activities using mitochondrial preparations obtained from rat brain. Ascorbic acid (100 microM) and Fe2+ (0.2, 0.4, 0.8, and 1.6 microM) were used to induce the production of *OH. Results showed that the generation of *OH significantly reduced both MAO-A (85-53%) and MAO-B (77-39%) activities, exhibiting a linear correlation between both MAO-A and MAO-B activities and the amount of *OH produced. The reported inhibition was found to be irreversible for both MAO-A and MAO-B. Assuming the proven contribution of MAO activity to brain oxidative stress, this inhibition appears to reduce this contribution when an overproduction of *OH occurs.     

Effect of perchlorate treatment on mitochondrial MAO-A and -B activities

Rat liver mitochondrial monoamine oxidase-A (MAO-A) and -B (MAO-B) were solubilized and isolated by procedures that included two cycles of treatment with a non-ionic detergent, Triton X-100, and then treatment with sodium perchlorate. After the treatment cycles with Triton X-100 about 23 and 36% of the original mitochondrial MAO-A and MAO-B activity, respectively, towards 0.1 mM serotonin and benzylamine remained in the residue. Of those activities, virtually no (2%) MAO-A activity, but appreciable (28%) MAO-B activity survived in the soluble state after the subsequent perchlorate treatment. The Km value and molecular turnover number of the soluble MAO-B, for benzylamine, were similar to those of the original activity in mitochondria, suggesting that this form of MAO has not undergone any qualitative change. After selective labelling of either form of MAO in mitochondria with 3H-pargyline and application of the isolation procedures, similar amounts of labelled MAO-A and -B were found in a soluble state, indicating that both forms of the enzyme were solubilized by the perchlorate treatment but that MAO-A was present in an inactivated state.     

A comparative study of the expression of monoamine oxidase-A and -B mRNA and protein in non-CNS human tissues

The distributions of monoamine oxidase (MAO)-A and -B proteins and mRNAs in human heart, lung, liver, duodenum, kidney and vasculature were compared using immunohistochemistry and cRNA in situ hybridisation. MAO-A and -B mRNA were detected in all tissues, to differing extents, but particularly in glomeruli, hepatocytes, and the crypts, muscularis mucosa and muscularis externa of duodenum. Renal proximal and distal tubules and loops of Henle had more intense labelling for mRNA of MAO-B than MAO-A; this was reflected in MAO protein expression. Little immunoreactivity was detected in glomeruli. Hepatocytes expressed MAO-A moderately, but MAO-B strongly. In lungs, similar moderately intense labelling for both MAO mRNAs and immunoreactivities was evident in pneumocytes, and epithelial and smooth muscle cells. Cardiomyocytes contained both MAO isoforms, but with more, albeit moderate, labelling for MAO-A. Both isoforms were expressed equally in duodenal villi, crypts, muscularis externa and mucosa; lower level expression occurred in mucosal and submucosal cells. MAO-A and -B mRNA were detected in endothelia, adventitia and media of a renal interlobular artery, but protein immunoreactivities were chiefly in the adventitia. The data reveal widespread tissue distribution of MAO mRNAs and proteins, but indicate that presence of MAO mRNAs does not invariably reflect quantitatively its protein expression.     

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.     

Quinoline and quninaldine as naturally occurring inhibitors specific for type A monoamine oxidase

Type A monoamine oxidase (MAO-A) in human placental mitochondria was competitively inhibited by naturally occurring substances, quinoline and quinaldine, using kynuramine as substrate. Quinoline had a higher affinity for MAO than kynuramine. MAO-A in human brain synaptosomal mitochondria was also competitively inhibited by quinoline, while type B MAO (MAO-B) was reversibly and non-competitively inhibited by quinoline. Quinoline inhibited MAO-A much more potently than MAO-B. Of several compounds structurally similar to quinoline, isoquinoline noncompetitively inhibited MAO-A and -B activity.     

Plasma 5-Hydroxyindoleacetic Acid as an Indicator of Monoamine Oxidase-A Inhibition in Rat Brain and Peripheral Tissues

We have examined the changes induced by the monoamine oxidase (MAO; EC 1.4.3.4) inhibitors tranylcypromine, clorgyline, and deprenyl on MAO activity and 5-hydroxytryptamine (serotonin, 5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) content in rat brain and blood (plasma and whole blood). The decreases of MAO-A activity observed in the liver and lungs after different doses of clorgyline or tranylcypromine correlated significantly (r > 0.80 in all cases) with the decline of plasma 5-HIAA. This was unaffected by 0.25 and 5 mg kg^?1 of deprenyl, indicating that 5-HT was deaminated exclusively in the periphery by MAO-A. It is interesting that very potent and significant correlations (r > 0.75) were found between plasma 5-HIAA and MAO-A activity, 5-HIAA and 5-HT content in brain tissue. These results suggest that plasma 5-HIAA can be used confidently as a peripheral indicator of the inhibition of MAO-A in brain. This may represent a favorable alternative to the analysis of 5-HIAA in CSF in psychiatric patients undergoing antidepressant treatment with nonspecific MAO inhibitors or with the new selective MAO-A inhibitors.     

Localization of rat striatal monoamine oxidase activities towards dopamine,serotonin and kynuramine by gradient centrifugation and nigro-striatal lesions

Subfractionation of the crude synaptosomal-mitochondrial fraction of rat striatum in a continuous sucrose gradient in a zonal rotor led to the following results. The distribution pattern of monoamine oxidase (MAO) activity towards dopamine (DA) was very similar to the pattern of MAO activity towards serotonin (5HT), but differed from the pattern of MAO activity towards kynuramine (KYN). As 5HT is specifically deaminated by MAO-A while KYN is a common MAO substrate, this supports earlier suggestions that in rat striatal preparations DA is deaminated preferentially by MAO-A. The patterns of the MAO activities towards DA and 5HT were clearly dissimilar, despite considerable overlap, to the patterns of tyrosine hydroxylase (TH) and DOPA decarboxylase (DD) activity, both marking the presence of striatal dopaminergic synaptosomes. The peak activities were separated and all patterns were symmetrical without showing a shoulder. This indicates that rat striatal MAO activity towards DA and 5HT is not specifically or for the greater part localized in dopaminergic terminals. We also investigated the effects of electrolytic and 6-hydroxydopamine lesions of the substantia nigra, both causing extensive degeneration of striatal dopaminergic terminals as appeared from the large decrease of striatal TH and DD activity. However, neither type of lesion induced a reduction of the MAO activity towards any of the substrates used. It is concluded towards DA and 5HT (probably MAO-A activity) present in dopaminergic terminals is very low compared with the total activity of this enzyme in rat striatal tissue.     

Adipogenesis-related increase of semicarbazide-sensitive amine oxidase and monoamine oxidase in human adipocytes

A strong induction of semicarbazide-sensitive amine oxidase (SSAO) has previously been reported during murine preadipocyte lineage differentiation but it remains unknown whether this emergence also occurs during adipogenesis in man. Our aim was to compare SSAO and monoamine oxidase (MAO) expression during in vitro differentiation of human preadipocytes and in adipose and stroma-vascular fractions of human fat depots. A human preadipocyte cell strain from a patient with Simpson-Golabi-Behmel syndrome was first used to follow amine oxidase expression during in vitro differentiation. Then, human preadipocytes isolated from subcutaneous adipose tissues were cultured under conditions promoting ex vivo adipose differentiation and tested for MAO and SSAO expression. Lastly, human adipose tissue was separated into mature adipocyte and stroma-vascular fractions for analyses of MAO and SSAO at mRNA, protein and activity levels. Both SSAO and MAO were increased from undifferentiated preadipocytes to lipid-laden cells in all the models: 3T3-F442A and 3T3-L1 murine lineages, human SGBS cell strain or human preadipocytes in primary culture. In human subcutaneous adipose tissue, the adipocyte-enriched fraction exhibited seven-fold higher amine oxidase activity and contained three- to seven-fold higher levels of mRNAs encoded by MAO-A, MAO-B, AOC3 and AOC2 genes than the stroma-vascular fraction. MAO-A and AOC3 genes accounted for the majority of their respective MAO and SSAO activities in human adipose tissue. Most of the SSAO and MAO found in adipose tissue originated from mature adipocytes. Although the mechanism and role of adipogenesis-related increase in amine oxidase expression remain to be established, the resulting elevated levels of amine oxidase activities found in human adipocytes may be of potential interest for therapeutic intervention in obesity.     

Inhibition of Type A Monoamine Oxidase by Methylquinolines and Structurally Related Compounds

Abstract: A series of methylquinolines (MQ) were found to inhibit markedly type A monoamine oxidase (MAO) in human brain synaptosomal mitochondria. 4-MQ and 6-MQ inhibited type A MAO (MAO-A) competitively and 7- and 8-MQ inhibited MAO-A noncompetitively. Among these four isomers of MQ, 6-MQ was the most potent inhibitor; the K _i value toward MAO-A was 23.4 ± 1.8 μ M , which was smaller than the K _m value toward kynuramine, ± amine substrate, 46.2 ± 2.8 μ M . On the other hand, MQ were very weak inhibitors of type B MAO (MAO-B) and 8-MQ did not inhibit MAO-B in brain synaptosomal mitochondria. The inhibition of MAO-A proved to be reversible; by dialysis the inhibition of MQ was completely reversible. The affinity of these isomers of MQ toward MAO-A or -B was confirmed further with human liver mitochondria as sources of MAO-A and -B and with human placental mitochondria and rat pheochromocytoma PC12h cell line as sources of MAO-A. The relationship of the chemical structure of structurally related quinoline and isoquinoline derivatives to inhibition of the activity of type A or B MAO was examined.     

Serotonin Receptor 6 Mediates Defective Brain Development in Monoamine Oxidase A-deficient Mouse Embryos

Monoamine oxidases A and B (MAO-A and MAO-B) are enzymes of the outer mitochondrial membrane that metabolize biogenic amines. In the adult central nervous system, MAOs have important functions for neurotransmitter homeostasis. Expression of MAO isoforms has been detected in the developing embryo. However, suppression of MAO-B does not induce developmental alterations. In contrast, targeted inhibition and knockdown of MAO-A expression (E7.5–E10.5) caused structural abnormalities in the brain. Here we explored the molecular mechanisms underlying defective brain development induced by MAO-A knockdown during in vitro embryogenesis. The developmental alterations were paralleled by diminished apoptotic activity in the affected neuronal structures. Moreover, dysfunctional MAO-A expression led to elevated levels of embryonic serotonin (5-hydroxytryptamine (5-HT)), and we found that knockdown of serotonin receptor-6 (5-Htr6) expression or pharmacologic inhibition of 5-Htr6 activity rescued the MAO-A knockdown phenotype and restored apoptotic activity in the developing brain. Our data suggest that excessive 5-Htr6 activation reduces activation of caspase-3 and -9 of the intrinsic apoptotic pathway and enhances expression of antiapoptotic proteins Bcl-2 and Bcl-XL. Moreover, we found that elevated 5-HT levels in MAO-A knockdown embryos coincided with an enhanced activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and a reduction of proliferating cell numbers. In summary, our findings suggest that excessive 5-HT in MAO-A-deficient mouse embryos triggers cellular signaling cascades via 5-Htr6, which suppresses developmental apoptosis in the brain and thus induces developmental retardations.     

4-(O-Benzylphenoxy)-N-Methylbutylamine (Bifemelane) and Other 4-(O-Benzylphenoxy)-N-Methylalkylamines as New Inhibitors of Type A and B Monoamine Oxidase

4-(O-Benzylphenoxy)-N-methylbutylamine (Bifemelane, BP-N-methylbutylamine), a new psychotropic drug, was found to inhibit monoamine oxidase (MAO) in human brain synaptosomes. It inhibited type A MAO (MAO-A) competitively and type B (MAO-B) noncompetitively. BP-N-methylbutylamine had a much higher affinity to MAO-A than an amine substrate, kynuramine, and it was a more potent inhibitor of MAO-A than of MAO-B. The Ki values of MAO-A and -B were determined to be 4.20 and 46.0 microM, respectively, while the Km values of MAO-A and -B with kynuramine were 44.1 and 90.0 microM, respectively. The inhibition of MAO-A and -B by BP-N-methylbutylamine was found to be reversible by dialysis of the incubation mixture. MAO-A in human placental and liver mitochondria and in a rat clonal pheochromocytoma cell line, PC12h, was inhibited competitively by BP-N-methylbutylamine, while MAO-B in human liver mitochondria was inhibited noncompetitively, as in human brain synaptosomes. BP-N-methylbutylamine was not oxidized by MAO-A and -B. The effects of other BP-N-methylalkylamines, such as BP-N-methylethylamine, -propylamine, and -pentanylamine, on MAO activity were examined. BP-N-methylbutylamine was the most potent inhibitor of MAO-A, and BP-N-methylethylamine and -propylamine inhibited MAO-B competitively, whereas BP-N-methylbutylamine and -pentanylamine inhibited it noncompetitively. Inhibition of these BP-N-methylalkylamines on MAO-A and -B is discussed in relation to their chemical structure.     

Multiple forms of monoamine oxidase in rabbit platelets.

Rabbit platelets were found to contain both types A and B MAO activities. The specific enzymatic activity of rabbit platelet MAO was higher for the substrate serotonin than for phenylethylamine. The K_m's for rabbit platelet MAO indicated that the MAO-B enzyme was similar to human platelet MAO and that both MAO-A and MAO-B enzymes in the rabbit platelet are similar to the corresponding forms in the rabbit brain. The drugs clorgyline and deprenyl confirmed the existence of types A and B MAO in the platelet and furthermore indicated that the type A form accounted for approximately 90% of the total enzymatic activity. Amitriptyline at low (micromolar) concentrations selectively inhibited MAO-B activity in both rabbit platelets and brain.     

Gonadal Influences on the Sexual Differentiation of Monoamine Oxidase Type A and B Activities in the Rat Brain

Abstract: The sex-dependent differentiation of monoamine oxidase (MAO) in the hypothalamus of 60-day-old, Charles River rats was found to involve only type A (MAO-A), and not type B (MAO-B) enzyme. In vivo inhibition of type A by clorgyline, and type B by (−)deprenyl, however, tended to decrease the specific activity of both types of MAO to a smaller extent in the female than in the male hypothalamus. When masculinization was prevented by neonatal administration of estradiol (E) to males, hypothalamic MAO-A and MAO-B activities increased in both control and MAO-inhibited rats. Androgenization of females, however, had little effect on the MAO activity. Whereas the effects of neonatal estrogenization were attributable neither to a direct influence of E nor to a sexual difference in the peripheral clearance of the MAO-inhibitor used, single, high doses of steroids to adult, but not to newborn rats, did acutely affect the kinetics of MAO-A. The activity of MAO-A was also decreased by high concentrations of E or TS in vitro. The imprinting for patterns of hypothalamic MAO-A and MAO-B in the two sexes results, probably, from genetic predetermination. Neonatal changes in the homeostasis of gonadal hormones may result in type-MAO nonspecific effects in adulthood, whereas the short-term effects of high concentrations of steroids may be selective for the A form.     

Calcium disodium edetate enhances type A monoamine oxidase activity in monkey brain

The effects of metal chelators on monoamine oxidase (MAO) isozymes, MAO-A and MAO-B, in monkey brain mitochondria were investigated in vitro. MAO-A activity increased to about 40% with 0.1 μM calcium disodium edetate (CaNa₂EDTA) using serotonin as a substrate, and this activation was proportional to the concentration of CaNa₂EDTA. On the other hand, MAO-A activities were decreased gradually with an increasing concentration of o-phenanthroline and diethyldithiocarbamic acid, but these metal chelators had no effect on MAO-B activity in monkey brain. The activation of MAO-A activity by CaNa₂EDTA was reversible. CaNa₂EDTA did not activate both MAO-A and MAO-B activities in rat brain mitochondria. Zn and Fe ions were found in the mitochondria of monkey brain. Zn ions potently inhibited MAO-A activity, but Fe ions did not inhibit either MAO-A or MAO-B activity in monkey brain mitochondria. These results indicate that the activating action of CaNa₂EDTA on MAO-A was the result of the chelating of Zn ions contained in mitochondria by CaNa₂EDTA. These results also indicate the possibility that Zn ions may regulate physiologically the level of serotonin and norepinephrine content in brain by inhibiting a MAO-A activity.