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Showing papers on "Monoamine oxidase B published in 1986"


Journal ArticleDOI
TL;DR: Individual variations in plateletMAO B activities do not reflect individual variations in either cerebral cortical MAO B or MAO A activities in patients with epilepsy who undergo neurosurgery, and there was a significant positive correlation between cerebral corticalMAO A and MAOB activities.
Abstract: Monoamine oxidase (MAO) exists in two forms, MAO A and MAO B. Both are present in human brain, but the human platelet contains only MAO B. We studied whether individual variations in the activity of human platelet MAO B reflect individual variations in cerebral cortical MAO activities. Optimal conditions were determined for the measurement of MAO activities in both the platelet and cerebral cortex, obtained from 14 patients with epilepsy during clinically indicated neurosurgery. There was no significant correlation between the activities of MAO B in the cerebral cortex and platelets of these patients. Platelet MAO B activities also failed to correlate significantly with cerebral cortical MAO A activities. However, there was a significant positive correlation between cerebral cortical MAO A and MAO B activities. Individual variations in platelet MAO B activities do not reflect individual variations in either cerebral cortical MAO B or MAO A activities in patients with epilepsy who undergo neurosurgery.

117 citations


Journal ArticleDOI
TL;DR: The inhibitory effect of the drug on hepatic MAO-B activity was annulled by pretreatment of rats with PB, but not 3-MC, and augmented by Pretreatment with SKF 525-A, but to a lesser extent by methimazole.
Abstract: 1. Deprenyl, a selective inhibitor of monoamine oxidase type B (MAO-B), was metabolized in rats to methamphetamine (MAP), amphetamine (AP) and their corresponding p-hydroxylated metabolites, p-hydroxy-MAP and p-hydroxy-AP. Recovery of metabolites in 24 h urine was 25% of the dose, and there was no urinary excretion of unchanged deprenyl.2. Deprenyl was converted into MAP, AP and nordeprenyl when incubated in vitro with rat-liver microsomes in the presence of NADPH. This metabolism was inhibited in an atmosphere of N2 and by CO, and by SKF 525-A, but to a lesser extent by methimazole.3. Liver microsomes from phenobarbital (PB)-treated rats, but not 3-methylcholan-threne (3-MC)-treated rats, stimulated the metabolism of deprenyl in vitro to MAP and AP, but not to nordeprenyl. In contrast, microsomes from SKF 525-A-treated rats showed decreased activity in the metabolism of deprenyl to all three metabolites.4. The inhibitory effect of the drug on hepatic MAO-B activity was annulled by pretreatment of rats wi...

104 citations


Journal ArticleDOI
TL;DR: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a thermal breakdown product of a meperidine-like narcotic used by drug abusers as a heroin substitute, produces Parkinsonian symptoms in humans and primates.
Abstract: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a thermal breakdown product of a meperidine-like narcotic used by drug abusers as a heroin substitute, produces Parkinsonian symptoms in humans and primates. The nigrostriatal toxicity is not due to MPTP itself but to one or more oxidation products resulting from the action of monoamine oxidase (MAO) on this tertiary allylamine. Both MAO A and B catalyse the oxidation of MPTP to the 1-methyl-4-phenyl-2,3-dihydropyridinium species (MPDP+), which undergoes further oxidation to the fully aromatic 1-methyl-4-phenylpyridinium species (MPP+). These bio-oxidations are blocked by selective inhibitors of MAO A and B. Additionally, MPTP, MPDP+ and MPP+ are competitive inhibitors of MAO A and B. The A form of the enzyme is particularly sensitive to this type of reversible inhibition. Both MAO A and B also are irreversibly inactivated by MPTP and MPDP+, but not by MPP+. This inactivation obeys the characteristics of a mechanism-based or 'suicide' process. The inactivation, which is accompanied by the incorporation of radioactivity from methyl-labelled MPTP, is likely to result from covalent modification of the enzyme.

93 citations


Journal Article
TL;DR: Biochemical changes induced by MPTP again seem primarily limited to those induced by damage to the nigro-striatal dopamine containing system, whereas in Parkinson's disease pathology is more widespread.
Abstract: The ability of MPTP to induce persistent parkinsonism in man may provide a vital clue to the cause of the idiopathic disease However, the peripheral administration of MPTP to rodent species only produces losses in brain dopamine content and damage to the nigrostriatal system in high doses and no persistent motor deficits have been observed In contrast, in primates, the administration of MPTP rapidly induces a persistent parkinsonian syndrome accompanied by evidence for selective damage to the nigro-striatal dopamine containing system Other neurotransmitter systems appear unaffected by MPTP treatment The MPTP-treated primate responds to the administration of L-DOPA and other antiparkinsonian drugs and may provide a useful test-bed for the development of novel antiparkinsonian medication Administration of MPTP to primates causes an accumulation of MPP+ in a variety of brain areas The accumulation of MPP+ and the neurotoxic actions of MPTP in primates can be prevented by the prior administration of monoamine oxidase inhibitors The ability of monoamine oxidase inhibitors to prevent MPTP toxicity is related to the metabolism of MPTP by monoamine oxidase B, probably extraneuronally in glia, to produce MPDP+ and subsequently MPP+ In rodent synaptosomal preparations MPP+ is a substrate for the dopamine uptake mechanism and so would be selectively accumulated in brain dopamine neurones Administration of MPTP to animals results in the production of a partial model of idiopathic Parkinson's disease as it occurs in man MPTP treatment produces the major symptoms of Parkinson's disease in primates but the pathology is limited to the nigro-striatal system, whereas in Parkinson's disease pathology is more widespread Biochemical changes induced by MPTP again seem primarily limited to those induced by damage to the nigro-striatal dopamine containing system MPP+ (or another metabolite of MPTP) may be responsible for the neurotoxicity of MPTP but not all neurones which accumulate products of MPTP metabolism are damaged The nigro-striatal system may be peculiarly sensitive to the effects of MPTP

86 citations


Journal ArticleDOI
TL;DR: 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 tyramines by a cocaine sensitive process.

58 citations


Journal Article
TL;DR: The treatment for two or four weeks with 0.25 mg/kg sc (-)deprenyl, a specific MAO B inhibitor, enhanced the turnover rate of dopamine and the fractional rate constant of dopamine efflux, reflecting an increased utilization rate of this amine in the striatum.
Abstract: The action of clorgyline and (-)deprenyl on the dynamics of dopaminergic and serotonergic transmission in the rat brain was compared. It was found, that daily administration of 0.25 mg/kg sc clorgyline, a specific MAO A inhibitor, reduced the turnover rate of both dopamine and serotonin after two weeks of injections. The treatment for two or four weeks with 0.25 mg/kg sc (-)deprenyl, a specific MAO B inhibitor, enhanced the turnover rate of dopamine and the fractional rate constant of dopamine efflux, reflecting an increased utilization rate of this amine in the striatum. Beside the augmentation of the dopamine turnover rate, the dopaminergic tone was also elevated by the reduction of the dopamine uptake in the striatum. Two week injections with the same dose of (-)deprenyl did not change the dynamics of serotonergic transmission.

57 citations


Journal ArticleDOI
TL;DR: Observations do not favour the hypothesis that idiopathic Parkinson's disease is due to excessive conversion of a precursor compound to an active neurotoxin by monoamine oxidase B, and it is found that MAO-B activity was significantly lower in the platelets of heavy cigarette smokers than in Platelets of non-smokers.

56 citations


Journal ArticleDOI
TL;DR: It is shown that glucocorticoid hormones and cellular aging selectively affect the amount of MAO A at the level of active enzyme synthesis or degradation, and the finding that the expression of the two forms ofMAO in human fibroblasts can be independently regulated supports the growing evidence that MAO and MAO B are separate molecular entities.
Abstract: Two forms of monoamine oxidase (MAO A and MAO B) exist which, although similar in a number of properties, can be distinguished on the basis of their substrate specificity, inhibitor sensitivity, kinetic parameters, and protein structure. These properties were used to study the molecular mechanism(s) by which glucocorticoid hormones and "aging," known to alter MAO activity in vivo, regulated the expression of MAO A and MAO B in cultured human skin fibroblasts. The addition of dexamethasone or hydrocortisone to cultures resulted in a dose- and time-dependent increase in total MAO activity, whereas the removal of hormone from cultures resulted in a time-dependent decrease in activity toward control levels. The response to dexamethasone was affected by culture conditions such as serum concentration, feeding frequency, and cellular "age." Cellular aging, in the absence of hormone, also resulted in increased levels of total MAO activity. The effects of hormones and aging on total MAO activity appeared to be selective for MAO A. The 6- to 14-fold increases in total activity were paralleled by similar increases in the activity and amount of active MAO A but less than 2- to 3-fold increases in the activity and amount of MAO B. Altered synthesis or degradation of the active enzyme appeared to account for the effects of hormones, aging, and various culture conditions on MAO activity. Inhibitor sensitivity, substrate affinity, electrophoretic mobility, and molecular turnover number of either form of the enzyme were not altered during dexamethasone treatment or during cellular aging. However, rates of active MAO synthesis were affected by hormone treatment and feeding frequency, rates of active MAO degradation by serum concentration, and rates of active MAO synthesis or degradation by aging. In summary, we have shown that glucocorticoids and cellular aging selectively affect the amount of MAO A at the level of active enzyme synthesis or degradation. Further, our finding that the expression of the two forms of MAO in human fibroblasts can be independently regulated supports the growing evidence that MAO A and MAO B are separate molecular entities.

48 citations


Journal ArticleDOI
Ingrid Fagervall1, Svante B. Ross1
TL;DR: The rate of the recovery of the deaminating activities inside and outside the serotonergic and noradrenergic neurones in hypothalamus after phenelzine and clorgyline inhibition was the same (50% recovery after 12-15 days), which indicates similar rate of synthesis of MAO in different cell types.

43 citations


Journal ArticleDOI
TL;DR: Analysis of the inhibitory process of the compound MPTP showed the compound to be considerably more efficient as a substrate than as an irreversible inhibitor, with about 17000 mol of product being formed per mol of enzyme inactivated.
Abstract: The compound 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which produces symptoms resembling Parkinson9s disease in humans, acts both as a substrate and an enzyme-activated irreversible inhibitor of the B-form of monoamine oxidase from rat liver. Analysis of the inhibitory process showed the compound to be considerably more efficient as a substrate than as an irreversible inhibitor, with about 17000 mol of product being formed per mol of enzyme inactivated. The half-time of the inhibitory process was about 22 min. With the A-form of the enzyme, the compound had a lower Km value and a considerably lower maximum velocity than the corresponding values obtained with the B-form. Under the conditions used in the present work the inhibition of the A-form of the enzyme was largely reversible.

42 citations


Journal ArticleDOI
TL;DR: It is suggested that the increase in MAO B activity in the caudate nucleus may reflect neurochemical changes that are responsible for the choreiform movements of Huntington's disease.
Abstract: Activity (Vmax) of monoamine oxidase (MAO) B in necropsy samples from the head of the caudate nucleus was 260% higher in patients dying with Huntington's disease (HD) than in controls (P less than 0.05). No differences in MAO A enzyme kinetics were found. MAO B, but not MAO A, was increased (26%) in the frontal cortex from patients dying with HD compared to control subjects. MAO A and B kinetics in caudate nucleus and frontal cortex from a group of schizophrenics did not differ from controls. Postmortem delay, the effect of neuroleptics, or nonspecific degeneration artifacts did not explain these findings. It is suggested that the increase in MAO B activity in the caudate nucleus may reflect neurochemical changes that are responsible for the choreiform movements of Huntington's disease. Lower cortical MAO B activity in the schizophrenic group may reflect the effects of neuroleptics.

Journal ArticleDOI
TL;DR: Tryptamine was found to be a substrate for both forms of the enzyme in human liver, kidney cortex and medulla and in seven different brain regions, suggesting that both form of monoamine oxidase would contribute to the metabolism of tryptamine in human tissues.

Journal ArticleDOI
TL;DR: Findings of equivalent efficacy of MAOIs in ADD are in contrast to previous studies with neurotransmitter system selective agents, which showed only weak effects, and suggest that multiple neurotransmitter alterations may be required for stimulant drug effects in ADD.
Abstract: Fourteen boys (mean age, 9.2 +/- 1.5 years) with Attention Deficit Disorder (ADD) With Hyperactivity were treated with dextroamphetamine sulfate or a monoamine oxidase inhibitor (MAOI) (six received clorgyline, eight received tranylcypromine sulfate) for four weeks each in a double-blind, cross-over study that included a two-week placebo washout between active drug periods. The MAOIs had immediate, clinically significant benefit and were clinically indistinguishable from dextroamphetamine. Most children responded to both stimulant and MAOI. These findings of equivalent efficacy of MAOIs in ADD are in contrast to our previous studies with neurotransmitter system selective agents, which showed only weak effects, and suggest that multiple neurotransmitter alterations may be required for stimulant drug effects in ADD. The immediate response to MAOIs indicates a different mechanism from that mediating antidepressant effect. The MAOIs may be useful alternate treatments in selected cases of ADD.

Journal ArticleDOI
TL;DR: Estimations of the amounts of the two forms by determining the concentrations of the inhibitors clorgyline, (-)-deprenyl, J-508 or pargyline necessary to give complete inhibition were shown to give overestimates of the true values because of the non-specific binding of these inhibitors to sites other than the monoamine oxidase active site.


Journal ArticleDOI
TL;DR: This assay has been used to show that the rate of oxidation of MPTP parallels that of phenylethylamine in a range of human and rodent tissues, providing strong evidence that this reaction is predominantly catalysed by monoamine oxidase B (MAO-B).

Journal ArticleDOI
TL;DR: The results presented in this study suggest that minaprine inhibits MAO A mainly after being converted into active metabolites, suggesting that MAO inhibitory activity is mediated by one or more other non-identified metabolites.

Journal ArticleDOI
TL;DR: (E)-β-Fluoromethylene-m-tyrosine and related amino acids were synthesized from acetophenone derivatives and shown to be dual enzyme-activated inhibitors of monoamine oxidase.

Journal ArticleDOI
TL;DR: A monoclonal antibody has been generated to human liver monoamine oxidase (MAO) B by fusion of mouse myeloma cells with spleen cells from a mouse immunized with a mixture of semi-purified MAO A and MAO B, showing an intracellular particulate distribution as demonstrated by immunoperoxidase staining.
Abstract: A monoclonal antibody has been generated to human liver monoamine oxidase (MAO) B by fusion of mouse myeloma cells with spleen cells from a mouse immunized with a mixture of semi-purified MAO A and MAO B. The antibody, 3F12/G10, an immunoglobulin G1, reacts with its antigen in cryostat sections of human liver, showing an intracellular particulate distribution as demonstrated by immunoperoxidase staining. The antibody indirectly precipitates [3H]pargyline-labelled human MAO B both from liver and platelet extracts but fails to precipitate MAO A from liver extracts. The antibody does not recognise rat liver MAO B, showing that the determinant is not universally expressed on MAO B. The antibody has no effect on the catalytic activity of MAO B. Other monoclonal antibodies were generated but they are directed to a protein with a subunit Mr of 54 000, a contaminant of the MAO preparation. One of these antibodies, A8/C2, an IgG2a, reacts with the same protein in both rat and human liver extracts.

Journal ArticleDOI
TL;DR: The data provide no reason to suppose that MDL 72145 would be very different in clinical use from L‐deprenyl which is both effective and well‐tolerated as an adjunct to the L‐DOPA‐based therapy of Parkinson's disease.
Abstract: The potential of a new, potent, irreversible and selective inhibitor of monoamine oxidase type B, (E)-2-(3,4-dimethoxyphenyl)-3-fluorallyamine (MDL 72145), to augment the effects of L-DOPA in an animal model which reproduces the biochemical defect of Parkinson's disease has been evaluated. In rats bearing unilateral 6-hydroxydopamine lesions of the nigro-striatal dopamine pathways, both MDL 72145 and clorgyline, a selective inhibitor of MAO A, augmented the contralateral turning response to L-DOPA combined with carbidopa. The potential of inhibitors of MAO to interact adversely in the periphery with L-DOPA was investigated in the pithed rat; L-DOPA was given either intravenously or intraduodenally. Clorgyline consistently potentiated L-DOPA when given 18 h before testing. Neither MDL 72145 nor the selective inhibitor of MAO B, L-deprenyl, augmented the cardiovascular effects of intraduodenally administered L-DOPA. The data provide no reason to suppose that MDL 72145 would be very different in clinical use from L-deprenyl which is both effective and well-tolerated as an adjunct to the L-DOPA-based therapy of Parkinson's disease.

Journal ArticleDOI
TL;DR: This enzyme is functional since 5-HT levels, as identified by immunocytochemical procedures, are low in the squid nervous system and show significant increases in pargyline treated squids.



Journal ArticleDOI
TL;DR: 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 16μM respectively.
Abstract: 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.

Journal ArticleDOI
TL;DR: It is concluded that deprenyl potentiates the inhibition by 5-methoxytryptamine of 3H-5HT release, by preventing its inactivation through MAO B.
Abstract: The 5-hydroxytryptamine (5HT) receptor agonist, 5-methoxytryptamine, inhibited in a concentration-dependent manner the electrically-evoked release of 3H-5HT from superfused rat hypothalamic slices, with an IC50 of 560 nmol/l, without affecting the spontaneous outflow of radioactivity. In the presence of the selective monoamine oxidase B (MAO B) inhibitor, (-)-deprenyl (1 mumol/l), the concentration-effect curve for 5-methoxytryptamine was shifted significantly to the left, and the IC50 was decreased to 25 nmol/l. Under the same experimental conditions, the potency of the 5HT receptor agonist lysergic acid diethylamide (LSD) at inhibiting the electrically-evoked release of 3H-5HT was the same in the presence as well as in the absence of (-)-deprenyl. The IC50 values for LSD were 34 nmol/l in the absence of deprenyl, and 31 nmol/l in the presence of the MAO B inhibitor. It is concluded that deprenyl potentiates the inhibition by 5-methoxytryptamine of 3H-5HT release, by preventing its inactivation through MAO B. Since 5-methoxytryptamine may be present in the pineal gland of some species, the potent effects of this 5-HT receptor agonist on serotoninergic neurotransmission may be of physiological relevance.

Journal ArticleDOI
TL;DR: The effects of the specific dopaminergic neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, were studied on the kinetics of [3H]mazindol binding to striatal membranes of C57 black mice and this data suggests that MPTP exerts its toxic effects via MPP+ which is concentrated intraneuronally via the dopamine uptake system.

Journal ArticleDOI
TL;DR: The present results indicate that both MAO-A-selective inhibitors also inhibit SSAO in vitro, but their properties as S SAO inhibitors differ from those as MAO -A inhibitors.
Abstract: In vitro studies demonstrated that two selective monoamine oxidase (MAO)-A inhibitors, amiflamine and FLA 788(+), have been shown to inhibit semicarbazide-sensitive amine oxidase (SSAO) in rat testis

Journal ArticleDOI
TL;DR: Results indicate that this compound may also inhibit SSAO activity, but by a mechanism different from that for MAO-B, and confirm an earlier hypothesis that compounds that inhibit both MAO and SSAo have totally different modes of action on these two different amine oxidases.

Journal ArticleDOI
TL;DR: Mice treated with MDL 72145 prior to MPTP did not exhibit the decrement in the neostriatal content of dopamine and its metabolites normally seen after MPTP administration, adding further support to the concept that the oxidation of MPTP by MAO-B to its corresponding pyridinium analog, 1-methyl-4-phenylpyrid inium (MPP+), is an important feature of the neurotoxic process.

Journal ArticleDOI
TL;DR: The affinity of budipine for the MPTP receptor binding site was determined as a K1 value of 2.2ΜM, which supports the theory that the MP TP receptor binding sites is identical with membrane bound MAO B.
Abstract: 1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) is a selective neurotoxin which produces degeneration of the nigrostriatal bundles in the central nervous system of man and animals. In these areas of the brain are concentrated the receptor binding sites for [3H]MPTP. 1-Alkyl-4, 4-diphenylpiperidines displace [3H]MPTP from these binding sites with K1 values in the micromolar range. The t-butyl analogue in this class of substances, budipine, is a novel therapeutic agent for Parkinsonism whose mechanism has not yet been fully clarified. The affinity of budipine for the MPTP receptor binding site was determined as a K1 value of 2.2ΜM. Other 4, 4-diphenylpiperidine derivatives such as 1-methyl-4, 4-diphenylpiperidine and 1-i-propyl-4, 4-diphenylpiperidine have substantially lower affinities. Monoamine oxidase inhibitors such as deprenyl, pargyline and harmaline have affinities to the MPTP receptors which parallel their affinity for the B type of monoamine oxidase (MAO B). This supports the theory that the MPTP receptor binding sites is identical with membrane bound MAO B.