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1-Benzyl-2-methyl-5-methoxytryptamine (BAS) inhibits monoamine oxidase in man. This finding confirms the findings of Woolley in mice. Since BAS, a tranquilizing agent, and Marsilid, a psychoenergizer, are both monoamine oxidase inhibitors, doubt is cast upon the hypothesis, that the stimulatory effect of Marsilid is due to its ability to inhibit monoamine oxidase.
A robust, sensitive and reliable radiochemical assay for monoamine oxidase is described, and the procedures necessary to ensure the validity of the results obtained are discussed. Methods for determining the activities of the two forms of monoamine oxidase, A and B, separately, are outlined and some alternative assay methods are considered.
The number of monoamine oxidase molecules in human blood platelets has been estimated by titrating them with the irreversible monoamine oxidase inhibitor pargyline to be about 900 per thrombocyte and 200--300 per thrombocyte mitochondrion. It has also been calculated that monamine oxidase constitutes about 1/5,000 of the platelet mitochondrial outer membrane surface. Molecular turnover numbers for benzylamine and tyramine have been estimated to be about 1,470 and 720, respectively.
Monoamine oxidase (MAO, EC 1.4.3.4), a flavine-containing enzyme catalyzing the oxidative deamination of monoamines, is located in the outer mitochondrial membrane and exhibited in virtually all tissues of mammals. As the family of MAO substrates includes both important neurotransmitters and hormones (i.e. serotonin, dopamine, adrenaline, noradrenaline) as well as biologically active dietary amines, such as tyramine (an indirectly acting sympathomimetic amine) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP a Parkinsonian producing exogenous neurotoxin), it is commonly accepted that MAO may play a critical role in the regulation of central nervous system activity and contribute to the pathogenesis of human neurodegenerative and depressive disorders. Fifty years ago the first generation of MAO inhibitors was developed and applied in therapy as anti-depressive compounds. However, for many years MAO inhibitors were considered useless in therapy due to the serious side effects induced by these drugs. Recently, MAO and its inhibitors are again in the center of scientific and pharmacological interest, providing new drugs for the therapy of Parkinson's disease, Alzheimer's disease, and various types of depression. Moreover, a beneficial pharmacological action of currently available MAO inhibitors, extending far beyond the MAO-B inhibitory properties, encourages investigators to search for new compounds exhibiting no side effects.This article gives a brief overview of the physiological importance of MAO and the biochemical and pharmacological potential of its inhibitors, with a consideration of their importance in the therapy of various disorders in humans.
Monoamine oxidase activity in blood platelets was measured, with [(14)C]tryptamine as substrate, in 13 monozygotic twin pairs discordant for schizophrenia and in 23 normal volunteers. The monoamine oxidase activity of both schizophrenic and nonschizophrenic co-twins was significantly lower than it was for the normals, and it was highly correlated between twins. In addition, there was a significant inverse correlation between a measure of the degree of the schizophrenic disorder and the monoamine oxidase activity. These data suggest, but do not prove, that reduced platelet monoamine oxidase activity may provide a genetic marker for vulnerability to schizophrenia.
The influence of some monoamine oxidase inhibitors (phenelzine, transamin [tranylcypromine], nialamide) on the structure of the sleep-wakefulness cycle of the cat was studied. It was shown that these monoamine oxidase inhibitors elicit and increase in slow-wave sleep in the sleep-wakefulness cycle due to complete suppression of paradoxical sleep and significant decrease in wakefulness. After the cessation of the action of the monoamine oxidase inhibitors, a selective rebound of wakefulness is observed against the background of complete or partial absence of paradoxical sleep. The gives grounds for the hypothesis that during partial deprivation of wakefulness under the influence of monoamine oxidase inhibitors an intensification occurs on the accumulation of specific need for this physiological state, the satisfaction of which is accomplished as the result of its rebound in the post-deprivational cycle, i.e., after the termination of the EEG of the synchronizing effect of the monoamine oxidase inhibitors.
Monitoring platelet monoamine oxidase activity in plasma of depressed patients receiving monoamine oxidase inhibitors is used as an indicator of therapeutic dosage and efficacy. In this study enzyme activity in platelets vs platelet rich plasma was compared. An aliquot of platelet rich plasma (PRP) was incubated with 4-hydroxy-3-methoxy-benzylamine as substrate. After stopping the enzymatic reaction, m-hydroxybenzaldehyde was added to the mixture as internal standard. The reaction mixture was extracted with toluene to isolate vanillin, the deamination product of the substrate, and the internal standard. The toluene layer was collected and back extracted into dilute tetramethylammonium hydroxide. An aliquot of the aqueous layer was chromatographed on a non-silica resin base reversed phase column with an alkaline phase. The peaks were detected by an absorbance detector at 350 nm. There was no significant difference in the decrease of monoamine oxidase activity when determined using platelet rich plasma versus washed platelets.
In the human brain, monoamine-derived 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolines and 1,2,3,4-tetrahydroisoquinolines have been identified and their enzymatic methylation into N(2)-methylisoquinolines has been also confirmed. N-methylated 6,7-dihydroxyisoquinolines were found to be oxidized into 6,7-dihydroxy-N-methylisoquinolinium ions. The effects of the isoquinolinium ions on type A and B monoamine oxidase were examined, using enzyme samples isolated from human brain synaptosomal mitochondria. 1,2-Dimethyl-6,7-dihydroxyisoquinolinium ion (N-methylsalsolinium ion) and 2-methyl-6,7-dihydroxyisoquinolinium ion (N-methylnorsalsolinium ion), were found to be potent inhibitors of type A monoamine oxidase. The inhibition was competitive to the substrate, while the isoquinolinium ions were much weaker inhibitors of type B and the inhibition was non-competitive to the substrate. Isoquinolinium ions without catechol structure, N(2)-methylisoquinolinium ion and 1,2-dimethylisoquinolinium ion also inhibited both type A and B monoamine oxidase. 1,2-Dimethylisoquinolinium was the most potent inhibitor among examined isoquinolines, followed by the N-methylsalsolinium ion. The activity-structure relationship of the isoquinolines with and without catechol structure was examined in terms of potency and selectivity of inhibition to type A and B monoamine oxidase. Catechol structure was found to increase the selectivity of inhibition to type A, as shown by comparison of N-methylsalsolinium ion with 1,2-dimethylisoquinolinium ion. N-Methylsalsolinium ion inhibited type A MAO more selectively than 1,2-dimethylisoquinolinium ion, which inhibited type A and type B with almost the sam values of the inhibitor constant.(ABSTRACT TRUNCATED AT 250 WORDS)
3-Amino-1-phenylprop-1-ene (cinnamylamine) and some derivatives were examined as substrates for monoamine oxidases A and B in mitochondria. All of the amines examined were readily oxidized by monoamine oxidase B but much less readily by monoamine oxidase A. E-Cinnamylamine was found to have Km 0.025 mM and Vmax. 3.9 nmol/min per mg of mitochondrial protein. Corresponding values with monoamine oxidase A were 0.026 mM and 0.85 nmol/min per mg respectively. Despite their different stereochemistry, E- and Z-N-methylcinnamylamines were almost equally effective as substrates for monoamine oxidase B. The characteristic u.v. absorbance and high absorption coefficient of cinnamaldehyde, the product produced by enzymic oxidation of cinnamylamine, is utilized in a sensitive continuous spectrophotometric assay for both enzymes in the rat and for the assay of a purified monoamine oxidase B from bovine liver.
Two methods have been employed to localize monoamine oxidase activity in the cells of rat liver, using either 2-(2'-benzothiazolyl)-5-stryl-3-(4'-phtalhydrazidyl) tetrazolium chloride (BSPT) or ferricyanide as electron acceptor. With both methods monoamine oxidase activity was found both in the inner and the outer mitochondral membrane, although the outer membrane appeared the most probable location. In addition the BSPT method but not the ferricyanide method, revealed monoamine oxidase activity in the endoplasmatic reticulum. The results obtained by the two methods have been compared and are discussed in view of available biochemical data on monoamine oxidase.
N1-Monoacetylspermine, N1,N12-diacetylspermine and N1-monoacetylspermidine were found to be good substrates for rat liver polyamine oxidase, but not for rat liver mitochondrial monoamine oxidase. N8-Monoacetylspermidine, monoacetylcadaverine, monoacetylputrescine and monoacetyl-1,3-diaminopropane were oxidized by the monoamine oxidase when the substrate concentration was 10.0 mM, but not by the polyamine oxidase. All the acetylpolyamines except N1,N12-diacetylspermine were also oxidized by hog kidney diamine oxidase although their affinities for the oxidase appeared low. The present data suggest that acetylpolyamines are not easily metabolized in vivo by either monoamine oxidase or diamine oxidase in mammalian tissues although N1-monoacetylspermine, N1,N12-diacetylspermine and N1-monoacetylspermidine are attacked by polyamine oxidase.
PC12 (phaeochromocytoma derived) cells possess the catecholamine synthesizing enzymes as well as the ability to store and release the catecholamines in response to K+. However, their monoamine oxidase activity and catecholamine release in response to tyramine has not been examined previously. PC12 cells have monoamine oxidase activity which oxidizes type A (noradrenaline and serotonin) and type A-B (dopamine, tyramine and kynuramine) substrates, and is selectively inhibited by clorgyline (IC50 approximately 10(-6) M). In contrast, PC12 cell monoamine oxidase hardly oxidizes phenylethylamine a type B substrate, and is relatively insensitive to inhibition by the selective monoamine oxidase type B inhibitor, 1-deprenyl (IC50 approximately 10(-6) M). By the above criteria it is apparent that the monoamine oxidase in PC12 is solely type A. The kinetics of the oxidase are similar to those of monoamine oxidase type A reported in other tissues including the adrenergic neuron, having apparent Km values of 400, 280, 170 and 227 microM for noradrenaline, dopamine, serotonin and tyramine. The apparent Km value for phenylethylamine is 235 microM. On the other hand, isolated chromaffin cells have the B form of monoamine oxidase with high affinity (Km approximately 25 microM) for phenylethylamine and low affinities for noradrenaline (Km approximately 1100 microM) and adrenaline (Km approximately 1700 microM). This enzyme form is selectively inactivated by the monoamine oxidase type B inhibitor, 1-deprenyl. In similar fashion to peripheral adrenergic neurons, PC12 cells share the capacity to express a tyramine releasable pool of catecholamines, a property entirely lacking in mature cultured chromaffin cells, even though the latter cells are capable of taking up tyramine by a cocaine sensitive process.(ABSTRACT TRUNCATED AT 250 WORDS)
1. The question of cellular localizations of monoamine oxidase and catechol-o-methyl transferase, enzymes involved in the metabolism of noradrenaline, has been investigated by following the changes in the enzyme activity of the smooth muscle of the cat nictitating membrane after sympathetic denervation. Any falls in enzyme activity coinciding with the time course for degeneration of the sympathetic nerve endings (2-3 days) can reasonably be ascribed to a former localization of the enzyme within the sympathetic nerve.2. Monoamine oxidase activity of the inferior and medial smooth muscle was significantly reduced 3 days after sympathectomy and remained reduced 14 days after sympathectomy.3. A correlation was found between the fall in monoamine oxidase activity and the endogenous noradrenaline concentration of the contralateral normal muscle, indicating that the higher the endogenous noradrenaline concentration, the greater the fall in monoamine oxidase activity after denervation.4. It was concluded that the fall in monoamine oxidase activity after denervation indicated a former localization of the enzyme within the sympathetic nerve endings.5. The fall in monoamine oxidase activity of the denervated muscle was significantly less measured with benzylamine as a substrate than with tyramine. This suggested that the neuronal monoamine oxidase may have different properties than the extraneuronal enzyme.6. A small fall in the catechol-o-methyl transferase activity of denervated smooth muscle was found and a correlation between the fall in enzyme activity and endogenous noradrenaline indicated that in this smooth muscle a proportion of the catechol-o-methyl transferase activity may be of presynaptic origin.
Monoamine oxidase (MAO) A is a key enzyme for the degradation of neurotransmitters serotonin, norepinephrine, and dopamine. There are three consensus glucocorticoid/androgen response elements and four Sp1-binding sites in the human monoamine oxidase A 2-kb promoter. A novel transcription factor R1 (RAM2/CDCA7L) interacts with Sp1-binding sites and represses MAO A gene expression. Luciferase assays show that glucocorticoid (dexamethasone) and androgen (R1881) increase MAO A promoter and catalytic activities in human neuroblastoma and glioblastoma cells. Gel-shift analysis demonstrates that glucocorticoid/androgen receptors interact directly with the third glucocorticoid/androgen response element. Glucocorticoid/androgen receptors also interact with Sp1-binding sites indirectly via transcription factor Sp1. In addition, dexamethasone induces R1 translocation from the cytosol to the nucleus in a time-dependent manner in both the neuroblastoma and wild-type UW228 cell lines but not in R1 knock-down UW228 cells. In summary, this study shows that glucocorticoid enhances monoamine oxidase A gene expression by 1) regulation of R1 translocation; 2) direct interaction of the glucocorticoid receptor with the third glucocorticoid/androgen response element; and 3) indirect interaction of glucocorticoid receptor with the Sp1 or R1 transcription factor on Sp1-binding sites of the MAO A promoter. Androgen also up-regulates MAO A gene expression by direct interaction of androgen receptor with the third glucocorticoid/androgen response element. Androgen receptor indirectly interacts with the Sp1, but not R1 transcription factor, on Sp1-binding sites. This study provides new insights on the differential regulation of MAO A by glucocorticoid and androgen.
Monoamine neurotransmitters are important in the development of the immature mammalian brain, prior to assuming their role as neurotransmitters. The endogenous levels of these transmitters are highly regulated by the enzyme monoamine oxidase (MAO). Thus, any change in this enzyme should have a profound effect on brain development. In order to test this hypothesis, we treated developing rat pups with the monoamine oxidase inhibitors (MAO-Is), clorgyline (MAO-A, 3 mg/kg), and deprenyl (MAO-B, 3 mg/kg) throughout gestation (MAO-I-birth), or throughout gestation and to sacrifice (MAO-I-sac). The animals were analyzed for serotonin and dopamine terminal density, using 3H-paroxetine and 3H-GBR 12935, respectively. Whereas there were no changes in the development of the dopamine system, the serotonin system was severely affected, particularly in the cortex that showed a significant reduction of innervation at 30 days postnatal. The animals reached all normal development milestones on schedule, and had no changes in measures of anxiety (% light/dark); however, the animals showed increased open field activity and deficits in a passive avoidance paradigm, which may be a measure of impulsivity. The MAO-I-sac animals were severely impaired, showing stereotypic behavior, seizures, and eventually visual impairments. Our results are discussed in terms of relevance to human disease states, such as atypical Norrie's disease, impulsivity, and hyperactivity. As well, our results should be used to caution against the use of MAO-Is in women of child-bearing age.
The degradative fate of monoamine oxidase in endogenous and transplanted mitochondrial outer membrane has been compared in rat hepatocyte monolayers. Monoamine oxidase was specifically irreversibly radiolabelled by the suicide inhibitor [3H]pargyline. Hepatocyte monolayers were cultured in conditions in which rates of protein catabolism like those in vivo are maintained [Evans & Mayer (1983) Biochem. J. 216, 151-161]. Incubation of hepatocyte monolayers for 17 h with [3H]pargyline specifically radiolabels mitochondrial monoamine oxidase, as shown by Percoll-gradient fractionation of broken hepatocytes. Monoamine oxidase is degraded at a similar rate to that observed in liver in vivo (t1/2 approx. 63 h). The effects of leupeptin, methylamine and colchicine on the degradation of endogenous radiolabelled enzyme has been studied over prolonged culture periods. Culture of hepatocytes for periods of up to 80 h with inhibitors was not cytotoxic, as demonstrated by measurements of several intrinsic biochemical parameters. Leupeptin, methylamine and colchicine inhibit the degradation of endogenous monoamine oxidase by 60, 38 and 18% respectively. Monoamine oxidase in mitochondrial-outer-membrane vesicles introduced into hepatocytes by poly(ethylene glycol)-mediated vesicle-cell transplantation is degraded at a similar rate (t1/2 55 h) to the endogenous mitochondrial enzyme. Whereas leupeptin inhibits the degradation of endogenous and transplanted enzyme to a similar extent, methylamine and colchicine inhibit the degradation of transplanted enzyme to a much greater extent (85 and 56% respectively). Fluorescence microscopy (with fluorescein isothiocyanate-conjugated mitochondrial outer membrane) shows that transplanted mitochondrial outer membrane undergoes internalization and translocation to a sided perinuclear site, as observed previously with whole mitochondria [Evans & Mayer (1983) Biochem. J. 216, 151-161]. The effects of the inhibitors on the distribution of transplanted membrane material in the cell and inhibition of proteolysis show the importance of cytomorphology for intracellular protein catabolism.
The laser dye rhodamine 123 has been used to establish that the binding of [3H]pargyline to monoamine oxidase is a more sensitive indicator of mitochondrial perturbation than measurements of protein synthesis, secretion, or degradation. The amount of monoamine oxidase labelled depends on the antibiotic used. The labelling was considerably lower in the presence of gentamycin than in the presence of either chloramphenicol or of penicillin and streptomycin. The accumulation of gentamycin within the cells was the cause of the reduced labelling of monoamine oxidase which was not accompanied by an alteration in the metabolism of pargyline. The gentamycin effect can be prevented by incubating the cells in medium supplemented with methylamine prior to adding the monoamine oxidase inhibitor. Long term culture of cells with gentamycin can result in the cell culture medium becoming dark brown. Under these conditions the monoamine oxidase labelling is increased due to an inhibition of pargyline metabolism. The results indicate that the choice of antibiotic is important in patients being treated with both antibiotics and monoamine oxidase inhibitors.
The effect of different antidepressants (MAO inhibitors, monoamine uptake inhibitors, new drugs) on the activity of bovine brain monoamine oxidase was investigated. The type A MAO activity was found to be selectively inhibited by the morpholine derivative, moclobamide (IC50-10(-5) M). Pyrazidol, inkazan, imipramine, and iproniazide also had an inhibitory effect on the enzyme activity, but their action was not selective. Zymelidine and norzymelidine (10(-4) M) slightly reduced the deamination of serotonin and 2-phenylalanine. The hydrazine derivatives, N 33 and N 34 showed the same effects. The morpholine derivative, viloxazine had no effect on the MAO activity of bovine brain. It is inferred that not only classic MAO inhibitors but also antidepressants of different structure are capable of inhibiting brain monoamine oxidase.