Showing papers on "Monoamine oxidase B published in 1984"

Protection against the dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine by monoamine oxidase inhibitors.

Abstract: 1-Methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) causes degeneration of the dopaminergic nigrostriatal pathway in several animal species, including humans1,2, monkeys3,4 and mice5–7. Changes observed after MPTP administration include marked decrements in the neostriatal content of dopamine and its major metabolites, dihydroxyphenylacetic acid and homovanillic acid, and a greatly diminished capacity of neostriatal synaptosomes to take up 3H-dopamine5,6. In contrast, there is no pronounced loss of serotonin in the neostriatum or of dopamine and its metabolites in other brain areas in MPTP-treated animals. The oxidative metabolism of MPTP to 1-methyl-4-phenyl pyridine, a positively charged species, has been suggested as a critical feature in the neurotoxic process8. Moreover, in rat brain preparations, the monoamine oxidase (MAO) inhibitor pargyline and the specific MAO-B inhibitor deprenil can prevent the formation of 1-methyl-4-phenyl-pyridine from MPTP, while the specific MAO-A inhibitor clorgyline has no such effect9, suggesting that MAO, and specifically MAO-B, is responsible for the oxidative metabolism of MPTP. We now report that pargyline, nialamide and tranylcypromine, which inhibit both MAO-A and MAO-B, when administered to mice before MPTP, protect against MPTP-induced dopaminergic neurotoxicity. Deprenil is also protective, but clorgyline is not. Our data are consistent with the premise that MAO-B has a crucial role in MPTP-induced degeneration of the nigrostriatal dopaminergic neuronal pathway.

Postmortem monoamine oxidase enzyme kinetics in the frontal cortex of suicide victims and controls

Abstract: Serotonin, a preferred monoamine oxidase (MAO) A substrate may be deficient centrally in suicide victims. In postmortem samples of frontal cortex from suicide victims we demonstrated receptor changes in the serotonergic system supportive of this hypothesis. These changes were not accompanied in this series of brain samples by alterations in either MAO A or B enzyme kinetics. Thus brain MAO A is not a useful indicator of altered serotonergic function in suicide victims. We did confirm an age-related increase in cortical MAO B but not MAO A enzyme concentrations in both controls and suicide victims. Language: en

MDL 72145, an enzyme-activated irreversible inhibitor with selectivity for monoamine oxidase type B.

Abstract: MDL 72145, (E)-2-(3',4'-dimethoxyphenyl)-3-fluoroallylamine hydrochloride, was designed and synthesised as a potential enzyme-activated irreversible inhibitor of monoamine oxidase (MAO). In vitro, the compound displayed time-dependent pseudo-first-order irreversible inhibitory characteristics with high selectivity for the B form of rat brain mitochondrial MAO. At 10 degrees C the Ki and tau 50 values for the B enzyme were 40 microM and 1.7 min, respectively, while these same kinetic constants for the A enzyme were 131 microM and 14.5 min, respectively. Selective protection against inactivation of the two forms of MAO by MDL 72145 was obtained by preincubating the enzyme with suitable concentrations of the selective A and B substrates, 5-hydroxytryptamine and benzylamine.

Isolated chromaffin cells from adrenal medulla contain primarily monoamine oxidase B.

Abstract: Cultured chromaffin cells from bovine adrenal medulla were found to contain primarily the B form of monoamine oxidase. This monoamine oxidase B enzyme was somewhat distinct from B enzymes from other sources, in that noradrenaline was a much poorer substrate than serotonin. Nonetheless, studies with selective inhibitors of the A form (clorgyline) and the B form [(-)-deprenyl] confirmed that chromaffin cell monoamine oxidase was the B form. The observation that chromaffin cell monoamine oxidase has poor affinity for catecholamines is consistent with physiological needs that require the cell to synthesize and store large amounts of catecholamines.

Effect of alpha-methylation on inactivation of monoamine oxidase by N-cyclopropylbenzylamine.

Abstract: Monoamine oxidase (MAO) was shown previously [Silverman, R. B., & Hoffman, S. J. (1980) J. Am. Chem. Soc. 102, 7126-7128] to catalyze the oxidation of N-cyclopropylbenzylamine (N-CBA) at two sites on the molecule. Oxidation at the benzyl methylene gave benzaldehyde and cyclopropylamine; oxidation of the cyclopropyl group, which involved cyclopropyl ring cleavage, led to inactivation of the enzyme. In this paper it is shown that methylation of the benzyl methylene dramatically alters this partition ratio in favor of enzyme inactivation. Contrary to a previous report [Alles, G., & Heegaard, E. V. (1943) J. Biol. Chem. 147, 487-503], it is shown here that alpha-methylbenzylamine is a substrate for MAO; consequently, N-cyclopropyl-alpha-methylbenzylamine (N-C alpha MBA) is a good candidate for mechanism-based inactivation. N-Cyclopropyl[7-14C]benzylamine, N-cyclopropyl-alpha-methyl[phenyl-14C]benzylamine, N-[1-3H]-cyclopropylbenzylamine, and N-[1-3H]cyclopropyl-alpha-methylbenzylamine are synthesized, and product formation following MAO inactivation is quantified. The results obtained with these compounds indicate that with N-C alpha MBA, alpha-methylbenzyl oxidation (which produces acetophenone and cyclopropylamine) is only 1% that of cyclopropyl oxidation (which gives enzyme inactivation), whereas with N-CBA the amount of oxidation at the corresponding sites is equal. It also is shown that the Ki values for (R)-(+)- and (S)-(-)-alpha-methylbenzylamine are similar, suggesting that dimethylation of N-CBA should not interfere with binding to MAO.(ABSTRACT TRUNCATED AT 250 WORDS)

Inactivation of cytochrome P-450 and monoamine oxidase by cyclopropylamines.

Abstract: (1984) Inactivation of Cytochrome P-450 and Monoamine Oxidase by Cyclopropylamines Drug Metabolism Reviews: Vol 15, No 5-6, pp 1163-1182

Platelet monoamine oxidase activity and genetic vulnerability to schizophrenia.

Abstract: Platelet monoamine oxidase (MAO) activity, determined in 102 patients with chronic schizophrenia, 223 first-degree relatives, and 88 normal control subjects, was shown to be a heritable and stable trait and was significantly lower in patients than in normal control subjects. Within families, MAO activity distinguished ill from well relatives. However, the considerable overlap in enzyme activity between affected and unaffected individuals limits the usefulness of low MAO activity as a major risk factor in schizophrenia.

Platelet and fibroblast monoamine oxidase in alcoholism

Abstract: Monoamine oxidase (MAO) activity has been reported to be low in platelets (MAO B) and brain (MAO A and B) of some patients with alcoholism compared to control subjects. Whether the decreased platelet MAO activity found in alcoholism is secondary to the effect of alcohol or exists before alcohol abuse is not clear. The hypothesis that altered MAO A activity is determined by an abnormality in the genetic regulation of the enzyme can be tested by measuring MAO A activity in human fibroblasts cultured under controlled conditions. We first studied the kinetic parameters of platelet MAO B activity in patients hospitalized for treatment of alcoholism. Vmax was 38% lower in the patients (n = 14) than in normal controls (n = 22), but the enzyme affinity (Km) for the substrate tyramine was unchanged. Patients with the five lowest levels of platelet MAO activity had MAO activity measured from fibroblasts cultured from skin punch biopsies. Their fibroblast MAO activity was within the normal range, showing a dissociation between platelet MAO B and fibroblast MAO A activities and suggesting that MAO A activity is not low for genetic reasons in alcoholic subjects who do have low platelet MAO B activity.

Effect of nonselective and selective inhibitors of monoamine oxidases A and B on pethidine toxicity in mice

Abstract: The LD50 of pethidine was determined in mice pretreated (4 h) either with the nonselective monoamine oxidase (MAO) inhibitor, phenelzine or with clorgyline, a selective inhibitor of MAO A or deprenyl, a selective inhibitor of MAO B. Phenelzine or combined clorgyline plus deprenyl pretreatments decreased pethidine LD50. Clorgyline or deprenyl alone did not affect pethidine toxicity. Whole brain 5-hydroxytryptamine (5-HT) concentrations were measured in the pretreated mice. 5-HT levels were approximately doubled (P less than 0.001) after phenelzine or clorgyline plus deprenyl treatment, but not after clorgyline or deprenyl given alone. These results indicate that both MAO A and MAO B need to be inhibited to increase pethidine toxicity and brain 5-HT levels. They support the involvement of 5-HT in the toxic interaction between pethidine and MAO inhibitors.

Identfiication of N-acetyl and hydroxylated N-acetyltranylcypromine from tranylcypromine-dosed rat urine

Abstract: Mechanism of the monoamine oxidase inhibition by tranylcypromine was studied in relation to its metabolism to reactive species. A metabolic study performed to collect general biotransformation pathway in rats provided GC/MS evidence for the detection of two new metabolites, N-acetyl and hydroxylated N-acetyltranylcypromine.

Effect of a reversible and selective MAO-A inhibitor (cimoxatone) on diurnal variation in plasma prolactin level in man

Abstract: Prolactin (PRL) secretion is stimulated by serotonin (5-HT) and inhibited by dopamine (DA). 5-HT is generally recognized as a substrate for type A monoamine oxidase (MAO), whereas DA is considered as a substrate for either A or B, or both forms of MAO, depending on the species and tissues used. The effect of cimoxatone, a reversible, selective MAO-A inhibitor, on diurnal variation in plasma PRL level was investigated in healthy adults after a single 40 mg oral dose, as an indirect approach to investigating whether DA is preferentially a substrate for Type A or B MAO in man. The circadian rhythm in PRL, stress conditions and diet were taken into account in the present study, which was placebo-controlled. There was a slight but significant reduction in circulating PRL in the six subjects, which persisted for at least 9 h after cimoxatone. However, the duration of the decrease in plasma PRL was shorter than the inhibition of MAO-A. The results are not inconsistent with the presence of both forms of MAO in the human hypothalamus and with DA as a substrate for both forms in this region, if it is assumed that the hypothalamic concentrations of the drug during the period 0-9 hours was sufficiently high to inhibit DA deamination by both forms of MAO.

The role of monoamine oxidase A in the metabolism and function of noradrenaline and serotonin

Abstract: Monoamine oxidase (MAO) inhibitors were among the first psychotropic drugs to be discovered and introduced into clinical use either alone or in combination with serotonin (5-hydroxytryptamine) (5-HT) precursors for the treatment of depressive illness (Youdim & Finberg, 1982). The result of MAO inhibition is that brain 5-HT and noradrenaline (NA) are elevated and the pharmacological effects of indirectly acting amines of dietary origin (e.g. tyramine and phenylethylamine) are potentiated, whether or not the indirectly acting amines are substrates for MAO. Perhaps the most common effect is the hypertensive response produced by dietary tyramine in individuals medicated with MAO inhibitors (MAOIs). Since this syndrome was first recognized in patients who ingested certain cheeses which contained high levels of tyramine, the syndrome is referred to as the ‘cheese effect’. The ‘cheese effect’ occurs because these indirectly acting amines, which are also substrates for the neurotransmitter uptake system, release noradrenaline (NA) into neuronal cytoplasm where it is normally deaminated by MAO before egress from the neurone occurs.

[Inhibition of monoamine oxidase A and B in the heart and brain of the rat with amitriptyline, pargyline and pirlindol].

Abstract: The inhibition of monoamine oxidase (MAO) A and B by amitriptyline, pargyline and pirlindole was measured in heart and brain homogenates of rats with tryptamine and beta-phenylethylamine as substrates. The tricyclic antidepressant amitriptyline inhibited MAO B stronger in the brain (Ki = 8.41 X 10(-6) mol/l) as well as in the heart (Ki = 7.03 X 10(-5) mol/l) compared to the A-form (1.51 X 10(-4) and 1.03 X 10(-4) mol/l, respectively). Pargyline diminished the activity of both enzyme forms of the heart in the same range (4.29 and 1.60 X 10(-6) mol/l), whereas in the brain the B-form was blocked in a more pronounced manner, too (5.80 X 10(-8) and 4.01 X 10(-6) mol/l, respectively). In contrast to amitriptyline and pargyline pirlindole inhibited the MAO with tryptamine as a substrate in the brain 100 times (2.49 X 10(-7) mol/l) and in the heart nearly 1000 times (3.42 X 10(-8) mol/l) more than with phenylethylamine as a substrate (5.21 and 5.99 X 10(-5) mol/l, respectively). These results show that amitriptyline and pargyline are relatively selective inhibitors of MAO B, whereas pirlindole blocks the A-form of MAO much stronger than MAO B.

Endogenous substrates and inhibitors of monoamine oxidase

Abstract: Monoamine oxidase (MAO) (EC 1.4.3.4) acts on a wide range of endogenous monoamine substrates including the neurotransmitters, noradrenaline (NA), dopamine (DA), 5-hydroxytryptamine (5-HT) and adrenaline (see Costa & Sandler, 1972), tele-methylhistamine (Elsworth et al, 1980) and the ‘trace amines’, phenylethylamine (PEA), phenyl-ethanolamine, o-, m- and p-tyramine, tryptamine, 5-methoxytryptamine, N-methyltryptamine, di-methyltryptamine and the octopamines (Usdin & Sandler, 1976; Boulton et al, 1984), and the list is by no means complete. Unlike DA, NA and 5-HT, which are present in the rat brain in a concentration of the order of 500 ng g_1, the trace amines are only represented at a level of less than 10 ng g_1, and as yet have no proven role. Although it is possible that they are merely byproducts of metabolism, without biological function, it seems rather more likely that some act in a modulatory fashion in connection with specific neuronal pathways.