Activities of tryptophan hydroxylase, dopa decarboxylase, and monoamine oxidase as correlated with the appearance of monoamines in developing rat pineal gland.
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Intra- and extraneuronal monoamine oxidase.
By use of monoamine reuptake inhibitors, it is possible to study the intra- and extraneuronal components of monoamine deamination in brain. In both man and rat, the ratios of activities of MAO-A/MAO-B are higher intra- than extraneuronally . As a result of this difference in cellular localisation in the brain, loss of neurones produces a change in the ratios of activities of MAO-A/MAO-B. It is also possible selectively to inhibit the activity of MAO-A within a given neurone population. The alpha-methyl substituted monoamine amiflamine has been shown to inhibit MAO-A within serotoninergic neurones at lower doses than are required for inhibition in other neurones. The usefulness of this compound in the elucidation of the functions of intra- and extraneuronal MAO are discussed.
Animals↗
[Possible mechanism of selective inhibition of rat liver mitochondrial monoamine oxidase by chlorgiline and deprenyl].
The inhibition of the deamination of serotonin (the main substrate of monoamine oxidase (MAO) type A) by chlorgiline and deprenyl and of beta-phenylethylamine (the main substrate of the B type MAO) by fragments of rat liver mitochondrial membrane as well as the influence of 4-ethylpyridine on this process were studied. It was shown that the MAO activity of the mitochondrial membrane fragments was highly sensitive to chlorgiline, when serotonin was used as substrate, whereas a high sensitivity toward deprenyl was observed with beta-phenylethylamine as substrate. 4-Ethylpyridine (5.10(-3) M), a competitive and reversible inhibitor of the MAO activity, inhibited deamination of serotonin and beta-phenylethylamine by 34 and 30%, respectively. In experiments with chlorgiline (the specific inhibitor of MAO type A) 4-ethylpyridine (5.10(-3) M) introduced into the samples after preincubation of mitochondria with increasing concentrations of chlorgiline (30 min, 23 degrees C) decreased the inhibition by chlorgiline of the deamination of beta-phenylethylamine, but sharply increased the inhibitory effect of chlorgiline on the oxidation of serotonin. In analogous experiments with deprenyl (the specific inhibitor of MAO type B) 4-ethylpyridine (5.10(-3) M) decreased the inhibitory effect of deprenyl not only on the deamination of serotonin (substrate of MAO A), but also on the oxidation of beta-phenylethylamine (the main substrate of MAO type B). The decrease in the inhibitory effect of deprenyl on the deamination of beta-phenylethylamine after the addition of 4-ethylpyridine may be intensified upon preincubation of deprenyl with mitochondria in the presence of 4-ethylpyridine. The data obtained demonstrate the difference in the type and mechanism of inhibition of the deamination of serotonin by chlorgiline as well as in the type and mechanism of oxidation of beta-phenylethylamine by deprenyl. The possible mechanism of selective blocking of MAO activity by chlorgiline and deprenyl was discussed in terms of our previous data on the existence in the active center of mitochondrial MAO of specific sites for substrate binding, differing in their structure-functional characteristics.
Animals↗
Effect of long-term treatment with selective monoamine oxidase A and B inhibitors on dopamine release from rat striatum in vivo.
Acute inhibition of monoamine oxidase B (MAO-B) in the rat does not affect striatal dopamine (DA) metabolism, but chronic MAO-B inhibition with deprenyl has been reported to increase the release of striatal DA, as shown using in vitro techniques. To see whether chronic MAO-B inhibition also causes an increase in DA release in vivo, rats were treated for 21 days with either deprenyl (0.25 mg/kg), TVP-1012 [R(+)-N-propargyl-1-aminoindan mesylate; 0.05 mg/kg], an irreversible inhibitor of MAO-B that is not metabolized to amphetamines, clorgyline (0.2 mg/kg), or saline (all doses once daily by subcutaneous injection). Concentric 4-mm-long microdialysis probes were implanted in the left striatum under pentobarbital/chloral hydrate anesthesia on day 21, and microdialysate DA, 3,4, dihydroxyacetic acid (DOPAC), and 4-hydroxy-3-methoxyphenyl acetic acid (HVA) were determined in the conscious animals on day 22. Baseline levels of DA were as follows: control, 0.34 +/- 0.04 (n = 13); deprenyl, 0.88 +/- 0.10 (n = 8, p < 0.01); TVP-1012, 0.94 +/- 0.20 (n = 7, p < 0.01); clorgyline, 0.90 +/- 0.12 (n = 7, p < 0.01) pmol/20 min. Levels of DOPAC and HVA were reduced only in the clorgyline-treated group. The incremental release of DA induced by depolarizing concentration of K+ (100 mM bolus of KCl in perfusate) was significantly greater in clorgyline- and deprenyl-treated rats and elevated (nonsignificantly) in TVP-1012-treated rats. Chronic treatment with the MAO-B inhibitors reduced striatal MAO-B activity by 90%, with 15% (TVP-1012) or 40% (deprenyl) inhibition of MAO-A. Clorgyline inhibited MAO-A by 95%, with 30% inhibition of MAO-B. A single dose of deprenyl (0.25 mg/kg, 24 h before microdialysis) had no significant effect on striatal efflux of DA. The results show that DA metabolism was reduced only by clorgyline, whereas neuronal release of DA was enhanced by both MAO-A and MAO-B inhibitors on chronic administration. The enhanced DA release by chronic MAO-B inhibition does not appear to be dependent on production of amphetamine-like metabolites of the inhibitor. Possible mechanisms for the release-enhancing effect of the MAO-B inhibitors include elevation in levels of endogenous beta-phenylethylamine, or an inhibition of DA reuptake, which develops only on chronic administration, because both deprenyl and TVP-1012 have only very weak effects on amine uptake in acute experiments.
3,4-Dihydroxyphenylacetic Acid↗
A comparison of the pharmacological and biochemical properties of substrate-selective monoamine oxidase inhibitors.
1. M&B 9302, E-250, NSD 2023, and Lilly 51641, substrate-selective inhibitors of monoamine oxidase (MAO), and two non-selective inhibitors of MAO (tranylcypromine and phenelzine) have been compared in the rat for activity in (i) inhibiting rat brain monoamine oxidase in vitro and in vivo using tyramine, 5-hydroxytryptamine (5-HT) and benzylamine as substrates; (ii) increasing brain levels of noradrenaline (NA) and 5-HT and (iii) antagonizing tetrabenazine-induced sedation.2. Concentrations of M&B 9302 and Lilly 51641 required to produce 50% inhibition of 5-HT oxidation by brain mitochondrial MAO were 1.4 x 10(-8)M and 2.5 x 10(-7)M respectively. Higher concentrations were required to inhibit tyramine oxidation whilst benzylamine oxidation was inhibited only at concentrations above 10(-5)M.3. E-250 showed the reverse substrate-selectivity in inhibiting the oxidation of benzylamine at concentrations below that required to inhibit the oxidation of 5-HT. NSD 2023 showed little substrate selectivity in vitro.4. Qualitatively similar results were obtained in vivo, except that NSD 2023 showed more marked substrate-selectivity.5. All the inhibitors except E-250 produced a dose-related rise in brain 5-HT levels. Only phenelzine and Lilly 51641 showed a linear relationship between NA levels and dose.6. All the drugs antagonized, in dose-related fashion, the effects of tetrabenazine in reducing locomotor activity. E-250 and NSD 2023 failed to restore locomotor activity to control levels whilst in high doses the other inhibitors, when given before tetrabenazine, produced a considerable increase in locomotor activity.7. Antagonism of tetrabenazine sedation appears to be correlated with (a) inhibition of the enzyme species that oxidize 5-HT and NA but not with inhibition of the enzyme species that oxidize benzylamine; (b) the rise in brain 5-HT levels rather than NA levels.
Amines↗
Inhibition of rat liver mitochondrial monoamine oxidase by chloramphenicol and 2-amino-1-p-nitrophenylpropane-1,3-diol.
Inhibition of rat liver mitochondrial monoamine oxidase by chloramphenicol and its hydrolytic product, 2-amino-1-p-nitrophenylpropane-1,3-diol, was studied. The enzyme activity and its inhibition by these two compounds were optimum at pH 7.0 after preincubation for 60 min, the time needed for maximum enzyme--inhibitor complex formation. Enzyme activity could be restored after prolonged dialysis. Monamine oxidase inhibition by chloramphenicol and its hydrolytic product was noncompetitive and reversible. Deamination of various monamines was not to the same degree by these compounds. Of the different antimicrobials studied, only chloramphenicol and its hydrolytic produced has a strong inhibitory effect on monoamine oxidase.
Animals↗
Specific genetic deficiencies of the A and B isoenzymes of monoamine oxidase are characterized by distinct neurochemical and clinical phenotypes.
Monoamine oxidase (MAO) exists as two isoenzymes and plays a central role in the metabolism of monoamine neurotransmitters. In this study we compared the neurochemical phenotypes of previously described subjects with genetically determined selective lack of MAO-A or a lack of both MAO-A and MAO-B with those of two subjects with a previously described X chromosome microdeletion in whom we now demonstrate selective MAO-B deficiency. Mapping of the distal deletion breakpoint demonstrates its location in intron 5 of the MAO-B gene, with the deletion extending proximally into the Norrie disease gene. In contrast to the borderline mental retardation and abnormal behavioral phenotype in subjects with selective MAO-A deficiency and the severe mental retardation in patients with combined MAO-A/MAO-B deficiency and Norrie disease, the MAO-B-deficient subjects exhibit neither abnormal behavior nor mental retardation. Distinct neurochemical profiles characterize the three groups of MAO-deficient patients. In MAO-A-deficient subjects, there is a marked decrease in deaminated catecholamine metabolites and a concomitant marked elevation of O-methylated amine metabolites. These neurochemical changes are only slightly exaggerated in patients with combined lack of MAO-A and MAO-B. In contrast, the only biochemical abnormalities detected in subjects with the MAO-B gene deletion are a complete absence of platelet MAO-B activity and an increased urinary excretion of phenylethylamine. The differences in neurochemical profiles indicate that, under normal conditions, MAO-A is considerably more important than MAO-B in the metabolism of biogenic amines, a factor likely to contribute to the different clinical phenotypes.
Adult↗
Determination of monoamines and both forms of monoamine oxidase in the rat's substantia nigra during postnatal development.
Changes in biogenic amine content in the substantia nigra and in both forms of monoamine oxidase in substantia nigra and striatum of the rat during postnatal development (15-180 days) have been studied. Dopamine and serotonin had the same levels at day 15, however, each monoamine showed a different developmental profile. Dopamine levels and their metabolites (except 3-methoxytyramine) decreased during postnatal development. Serotonin levels and their main metabolite, 5-hydroxyindolacetic acid, underwent an increase during all stages studied. There were no statistically significant changes in noradrenaline levels until day 180 when they increased with respect to day 15. The highest activity of the monoamine oxidase-A in substantia nigra coincided with the highest 5-hydroxyindolacetic acid:serotonin ratio. Monoamine oxidase-A in the striatum did not change contrary to that which happened in substantia nigra. The monoamine oxidase-B:monoamine oxidase-A ratio increased during development both in the substantia nigra and the striatum. The significance of these changes is discussed.
Aging↗
Monoamine oxidase and aldehyde dehydrogenase activity in the striatum of rats after 6-hydroxydopamine lesion of the nigrostriatal pathway.
Monoamine oxidase and aldehyde dehydrogenase activity were significantly reduced in the striatum of rats 8 days after lesion of the nigrostriatal nerve pathway caused by 6-hydroxydopamine. Evidence is presented for the existence of an intraneuronal 'dopamine monoamine oxidase' and intraneuronal aldehyde dehydrogenase. Dopamine concentrations were reduced to 10% of their control values.
Aldehyde Oxidoreductases↗
Gender difference in the interaction of smoking and monoamine oxidase B intron 13 genotype in Parkinson's disease.
We tested for gender-specific interactions between smoking and genetic polymorphisms of monoamine oxidase B (MAO-B) intron 13 (G or A allele), monoamine oxidase A (MAO-A) EcoRV (Yor N allele), and dopamine D2 recepor (DRD2) Taq1B (B1 or B2 allele) in a case-control study of 186 incident idiopathic Parkinson's disease (PD) cases and 296 age- and gender-matched controls. The odds ratios (ORs) for PD risk for ever smokers versus never smokers were 0.27 (95% CI: 0.13-0.58) for men of genotype G, and 1.26 (0.60-2.63) for men of genotype A (interaction chi2 = 8.14, P = 0.004). In contrast, for women, the OR for ever smokers versus never smokers were 0.62 (95% CI: 0.25-1.34) and 0.64 (95% CI: 0.18-2.21) for women of genotype GG/GA and AA, respectively (interaction chi2 = 0.001, P = 0.975). No interactions were detected between smoking and either MAO-A EcoRV or DRD2 Taq1B genotypes. These results suggest that a strong gender difference exists with respect to the modifying effect of MAO-B genotype on the smoking association with PD.
Adult↗
Sertraline is metabolized by multiple cytochrome P450 enzymes, monoamine oxidases, and glucuronyl transferases in human: an in vitro study.
The oxidative and conjugative metabolism of sertraline was examined in vitro to identify the enzymes involved in the generation of N-desmethyl, deaminated, and N-carbamoyl-glucuronidated metabolites in humans. In human liver microsomes, sertraline was N-demethylated and deaminated by cytochrome P450 (P450) enzymes with overall K(m) values of 98 and 114 microM, respectively, but the intrinsic clearance for N-demethylation was approximately 20-fold greater than for deamination. Using P450 isoform-selective inhibitors and recombinant heterologously expressed enzymes, it was demonstrated that several P450 enzymes catalyzed sertraline N-demethylation, with CYP2B6 contributing the greatest extent, and lesser contributions from CYP2C19, CYP2C9, CYP3A4, and CYP2D6. For deamination, data supported a role for CYP3A4 and CYP2C19. Purified human monoamine oxidases A and B also catalyzed sertraline deamination with comparable K(m) values (230-270 microM). Monoamine oxidase B catalyzed the reaction approximately 3-fold faster than did monoamine oxidase A. Sertraline N-carbamoyl glucuronidation was measured in human liver microsomes in bicarbonate buffer and under a CO2 atmosphere (K(m) = 50 microM) and was catalyzed at the fastest rate by recombinant human UGT2B7. The observation that multiple enzymes appear to be involved in sertraline metabolism suggests that there should be no single agent that could substantially alter the pharmacokinetics of sertraline, nor should there be any single drug-metabolizing enzyme genetic polymorphism (e.g., CYP2D6, CYP2C19, CYP2C9, UGT1A1) that could profoundly impact the pharmacokinetics of sertraline.
Cytochrome P-450 Enzyme Inhibitors↗
Equol and other compounds from bovine urine as monoamine oxidase inhibitors.
Equol, its methylated derivative, and a carbazole, all isolated from bovine urine, are relatively potent inhibitors of monoamine oxidase with IC50 values of 158, 28, and 16 microM respectively (using 83 microM tyramine as substrate). The probable dietary origin of these compounds suggests that "natural" monoamine oxidase inhibitors may be more widespread than had previously been suspected.
Animals↗
[Inhibitory monoamine oxidases of the new generation].
This review deals with the new generation of selective and partly reversible monoamine oxidase (MAO) inhibitors. In contrast to the non selective inhibitors, used in the year 1957-1970, the selective inhibitors bind to and block only one of the two isoenzymes, MAO-A or MAO-B. The MAO-A inhibitors and part of the MAO-B inhibitors differ also from the classic drugs by their reversibility. The inhibition of MAO-A cause the rise of norepinephrine, dopamine and serotonin in the synaptic cleft, of MAO-B only of dopamine. The new inhibitors diminish also to some extent the reuptake of monoamines. The molecular action mechanism of the new drug generation is the same as in the non-selective drugs: increase of monoamines, near to the receptor, leads, after a number of intermediate steps, to activation of functional proteins in the cell. The selective block of one of the isoenzymes does not stop the metabolism of tyramine (from cheese, red wine), because this toxic compound is metabolised by both isoenzymes. The control of therapy with MAO-A inhibitors is easier, because of their reversibility. Selective inhibitors of MAO have found a secure place in therapy of depression (inh. of MAO-A, esp. Moclobemide) and Parkinson's disease (inh. of MAO-B, at this time mainly selegiline). Discussed is possible use of selective MAO-inhibitors for achieving an increase in cognitive function and protections of neurone cells from biochemical lesions.
Animals↗
The effects of stereoisomers of 2- and 9- aminobenzonorbornenes on food intake, brain serotonin concentration and monoamine oxidase activity in the rat.
To evaluate the importance of the conformation of amphetamine in eliciting its various central nervous system effects, the conformationally defined analogs of amphetamine. In this series of isomeric amines, the exo-2 and anti-9 isomers resemble the fully extended conformation of amphetamine, whereas the endo-2 and syn-9 isomers resemble the folded conformation. The exo-2 and anti-9 isomers were equally as effective in reducing food intake in the rat, but were much less potent than amphetamine. The endo-2 and syn-9 isomers had no effect on food intake up to a dose of 40 mg/kg. These latter two isomers also caused very little inhibition of monoamine oxidase in vitro. The exo-2 and anti-9 isomers, however, were nearly as effective as amphetamine in inhibiting monoamine oxidase type A, but only amphetamine and the anti-9 isomer inhibited monoamine oxidase type B. The effects at anorectic doses on brain serotonin (5-HT) concentration were also studied. Although amphetamine had no effect on the 5-HT concentration and fenfluramine decreased its concentration, the exo-2 and anti-9 isomers caused a significant increase in brain 5-HT. The anti-9 isomer caused a 14% increase in 5-HT, whereas the exo-2 isomer gave a 49% increase over controls. The data suggest that the fully extended conformation of amphetamine is preferred over the folded conformation for eliciting its biological responses, although the rigid analogs were less potent than amphetamine.
Amphetamine↗
Norepinephrine, monoamine oxidase, and acetylcholinesterase in the rat jugular vein compared with other blood vessels.
The observation that the rat jugular vein relaxed in response to norepinephrine but not to field stimulation prompted us to evaluate the extent of innervation in this tissue. The norepinephrine concentration in the jugular vein was about 10% of that in the mesenteric artery and vein. The low levels of norepinephrine were not due to higher monoamine oxidase activity relative to the enzyme activity in other blood vessels. In the jugular vein, as in heart and brain, serotonin was preferred substrate for monoamine oxidase whereas in the femoral vein, mesenteric vein, and mesenteric artery, phenylethylamine oxidation was greater. Based on kinetic and inhibitory studies with LY51641, a selective type A inhibitor, monoamine oxidase activity was not found to be uniform throughout the cardiovascular system. In addition to low levels of norepinephrine, acetylcholinesterase activity in the jugular vein was only 5 and 13% of the activity in the portal vein and mesenteric artery, respectively. Thus, we provide strong evidence that our inability to generate a response to field stimulation in the rat jugular vein results from the lack of functional innervation in this tissue. This information adds to the usefulness of this preparation for comparative studies of agents acting on the smooth muscle without the added complication of neuronal uptake mechanisms.
Acetylcholinesterase↗
Differential distribution of type A and B monoamine oxidase in neuronal tissues.
Various neuronal tissues of the albino rabbit were assayed for type A and type B monoamine oxidase, using norepinephrine and 2-phenylethylamine as substrates, respectively. There was an apparent positive correlation between the sympathetic character of peripheral nerves and the presence of type A monoamine oxidase activity. Type A enzyme activity was 15 fold higher in the superior cervical ganglion than in the vagus nerve. Type B activity was more uniformly distributed.
Animals↗
Evidence that a preferred substrate for type B monoamine oxidase mediates stimulus properties of MAO inhibitors: a possible role for beta-phenylethylamine in the cocaine cue.
In the experiment, rats were trained to discriminate 5 mg/kg cocaine HCl from saline in a two-bar drug discrimination procedure. Stimulus generalization experiments were carried out with six inhibitor drugs of monoamine oxidase. The rank order of absolute potency of these drugs in inducing stimulus generalization with cocaine was: tranylcypromine (ED50 in mg/kg; 1.2)>pheniprazine (3.5)>deprenyl (5)>pargyline (28)>nialamide (approximately 170); at up to 40 mg/kg, clorgyline failed to produce 50% generalization. All six drugs also potentiated tryptamine in producing body tremors and clonic seizures, the rank order of potency being tranylcypromine (0.081)>clorgyline (0.14) greater than or equal to pheniprazine (0.15)>pargyline (1.97)>deprenyl (15.5)>nialamide (18.7). Tryptamine is a common substrate for both type A and type B monoamine oxidase, so that tryptamine potentiation may serve to determine the relative specificity of the doses at which the inhibitor drugs generalized with cocaine. The present data may suggest that endogenous substances which are preferred substrates for type B monoamine oxidase in rat brain can exert control of behavior by virtue of cocaine-like stimulus properties. beta-Phenylethylamine, more so than dopamine, appears to be candidate substance for mediating the discriminative stimulus properties of cocaine and, perhaps, of other central nervous system stimulants.
Animals↗
[Effect of various monoamine oxidase inhibitors on the structure of the sleep-wakefulness cycle of the cat].
The effect of some monoamine oxidase inhibitors (phenelzine, transamine, nialamide) on the structure of the cat sleep--wakefulness cycle involved an increase of slow-wave sleep at the expense of totally inhibited REM sleep and substantial reduction of wakefulness. Following this effect, selective rebound of wakefulness occurred against the background of total or partial absence of REM sleep. The partial deprivation of wakefulness induced with monoamine oxidase inhibitors seem to entail an accumulation of a specific need in the given physiological state, the gratification of which is effected through its rebound in the post-deprivation cycle.
Animals↗