Showing papers on "Monoamine oxidase B published in 1987"

Mapping human brain monoamine oxidase A and B with 11C-labeled suicide inactivators and PET.

Abstract: The regional distributions of monoamine oxidase (MAO) types A and B have been identified in human brain in vivo with intravenously injected 11C-labeled suicide enzyme inactivators, clorgyline and L-deprenyl, and positron emission tomography. The rapid brain uptake and retention of radioactivity for both 11C tracers indicated irreversible trapping. The anatomical distribution of 11C paralleled the distribution of MAO A and MAO B in human brain in autopsy material. The corpus striatum, thalamus, and brainstem contained high MAO activity. The magnitudes of uptake of both [11C]clorgyline and L-[11C]deprenyl were markedly reduced in one subject treated with the antidepressant MAO inhibitor phenelzine. A comparison of the brain uptake and retention of the 11C-labeled inactive (D-) and active (L-) enantiomers of deprenyl showed rapid clearance of the inactive enantiomer and retention of the active enantiomer within MAO B-rich brain structures, in agreement with the known stereoselectivity of MAO B for L-deprenyl. Prior treatment with unlabeled L-deprenyl prevented retention of L-[11C]deprenyl. Thus, suicide enzyme inactivators labeled with positron emitters can be used to quantitate the distribution and kinetic characteristics of MAO in human brain structures.

Immunocytochemical localization of monoamine oxidases A and B in human peripheral tissues and brain.

Abstract: Monoamine oxidases (MAO; EC 1.4.3.4.) A and B occur in the outer mitochondrial membrane and oxidize a number of important biogenic and xenobiotic amines. Monoclonal antibodies specific for human MAO A or B and immunocytochemical techniques were used to visualize the respective enzymes in human placenta, platelets, lymphocytes, liver, brain, and a human hepatoma cell line. MAO A was observed in the syncytiotrophoblast layer of term placenta, liver, and a subset of neurons in brain, but was not observed in platelets or lymphocytes, which are known to lack type A enzyme. MAO B was observed in platelets, lymphocytes, and liver, but not in placenta, which contains little or no MAO B. MAO B was also observed in a subset of neurons in the brain that was distinct from that which contained MAO A. MAO A and MAO B were also observed in some glia. Unlike most tissues examined, liver cells appeared to contain both forms of the enzyme. These studies show that MAO A and MAO B can be specifically visualized by immunocytochemical means in a variety of human cells and tissues and can provide a graphic demonstration of the high degree of cell specificity of expression of the two forms of the enzyme.

L-deprenyl in Alzheimer's disease. Preliminary evidence for behavioral change with monoamine oxidase B inhibition.

Abstract: Since monoamine neurotransmitter disturbances exist in some cases of dementia of the Alzheimer's type (DAT), monoamine-enhancing drugs may ameliorate some symptoms of DAT. L-Deprenyl is a monoamine oxidase (MAO) inhibitor that is generally free of undesired effects. At low doses (10 mg/d) it selectively inhibits MAO-B, an enzyme whose level is elevated in the brains of patients with DAT who are studied post mortem. At higher doses it has more complex effects, including inhibition of MAO-A plus MAO-B. We administered 10 mg/d and 40 mg/d of L-deprenyl to 17 patients with DAT in a double-blind, placebo-controlled, serial treatment. Total Brief Psychiatric Rating Scale scores decreased significantly during 10-mg/d treatment, with decreases in measures of anxiety/depression, tension, and excitement. Approximately one half of the patients' conditions were judged to be improved clinically, with evidence of increased activity and social interaction along with reduced tension and retardation. Similar but smaller changes were observed during 40-mg/d treatment. The behavioral changes were associated with improvement in performance on a complex cognitive task requiring sustained effort. There were minimal physiologic and side effects. The greater effect of low-dose L-deprenyl therapy suggests that it is the inhibition of MAO-B, and not MAO-A, that may be important in the behavioral effects of L-deprenyl administration to patients with DAT.

Effect of chronic nicotine administration on monoamine and monoamine metabolite concentrations in rat brain.

Abstract: The effects on rat brain tissue monoamine and monoamine metabolite concentrations of chronic nicotine administration at two doses (3 and 12 mg/kg/day) using constant infusion were studied. After 21 days of treatment, tissue concentrations of dopamine (DA), norepinephrine (NE), 5-hyroxytryptamine (5-

Amine oxidases and their endogenous substrates (with special reference to monoamine oxidase and the brain).

Abstract: The roles of MAO, BzO, DAO and PAO in the metabolism of endogenous substrates and the functional implications of their action and inhibition is reviewed, the emphasis being on MAO on one hand and on brain on the other. The major issues are the following: 1. There is no discrete subdivision into substrates selective for MAO-A, MAO-B, or mixed ones, but rather a continuum. 2. Tissue differences in substrate specificity are not likely to be due to molecular variability of MAO. For the deamination of DA, 5-HT and PEA at least, the relative participation of either MAO form in a given tissue is primarily determined by the relative abundance of the two forms; only at 10-5M and above, substrate concentration begins to matter also. 3. In vivo, compartmentation is of paramount importance: since there seems to be more MAO-A than B inside monoaminergic neurons, DA, 5-HT and NA are predominantly metabolized by MAO-A if metabolism occurs mainly intraneuronally. Conversely, since MAO-B is more abundant extraneuronally, e.g. in glia cells, the relative participation of this form increases if a significant portion of these amines is deaminated outside monoaminergic neurons. 4. In vivo, monoamine deamination is reduced concomitantly with the degree of MAO inhibition, whereas signs of increased transmitter function are only observed if enzyme inhibition is at least 80%. This is likely to be the result of the action of compensatory mechanisms such as feedback inhibition of transmitter release and synthesis. 5. BzO is particularly abundant in vascular tissue, lung and bone. Low levels are found in brain. Endogenous substrates and physiological function are not known. DAO also occurs only in minimal amount in brain, if at all. Its principal substrates are histamine and the polyamines, and the disposal of these amines is probably its main function. Of the PAO’s, the type of enzyme found in the rat liver attacks the secondary amino groups and may have a more prominent role in the metabolism of polyamines in the brain than in the periphery. Bovine plasma PAO, which attacks primary amino groups, is only found in the serum of ruminants, but not other species. Its function in the metabolism of polyamines is not known.

L-Deprenyl in Alzheimerʼs disease: preliminary evidence for behavioral change with monoamine oxidase B inhibition

Abstract: Since monoamine neurotransmitter disturbances exist in some cases of dementia of the Alzheimer's type (DAT), monoamine-enhancing drugs may ameliorate some symptoms of DAT. L-Deprenyl is a monoamine oxidase (MAO) inhibitor that is generally free of undesired effects. At low doses (10 mg/d) it selectively inhibits MAO-B, an enzyme whose level is elevated in the brains of patients with DAT who are studied post mortem. At higher doses it has more complex effects, including inhibition of MAO-A plus MAO-B. We administered 10 mg/d and 40 mg/d of L-deprenyl to 17 patients with DAT in a double-blind, placebo-controlled, serial treatment. Total Brief Psychiatric Rating Scale scores decreased significantly during 10-mg/d treatment, with decreases in measures of anxiety/depression, tension, and excitement. Approximately one half of the patients' conditions were judged to be improved clinically, with evidence of increased activity and social interaction along with reduced tension and retardation. Similar but smaller changes were observed during 40-mg/d treatment. The behavioral changes were associated with improvement in performance on a complex cognitive task requiring sustained effort. There were minimal physiologic and side effects. The greater effect of low-dose L-deprenyl therapy suggests that it is the inhibition of MAO-B, and not MAO-A, that may be important in the behavioral effects of L-deprenyl administration to patients with DAT.

Stopped-flow studies on the mechanism of oxidation of N-methyl-4-phenyltetrahydropyridine by bovine liver monoamine oxidase B.

Abstract: The kinetic mechanism of monoamine oxidase B involves either a binary or a ternary complex, depending on the substrate. In this study, stopped-flow kinetic data provide direct evidence for ternary complexes not only of reduced enzyme, oxygen, and product but also of reduced enzyme, oxygen, and substrate, both for benzylamine and for the tertiary amine 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). However, the mechanism for a given substrate is not exclusive but, rather, is determined by competition between the alternate pathways as a result of different rate constants for the oxidation of the reduced enzyme, the reduced enzyme-product complex, and the reduced enzyme-substrate complex, as well as the different dissociation constants for the complexes. Comparison of the rate constants obtained from the stopped-flow studies with steady-state data indicates that the overall rate of reaction for the oxidation of MPTP by monoamine oxidase is dominated by the reductive step, but for benzylamine the steady-state rate is determined by a complex function of the rates of both the reductive and oxidative half-reactions.

Hepatic and extrahepatic metabolism of deprenyl, a selective monoamine oxidase (MAO) B inhibitor, of amphetamines in rats: sex and strain differences

Abstract: 1. Deprenyl is metabolized by rat liver microsomes into methamphetamine (MAP), amphetamine (AP) and nor-deprenyl, and by lung and kidney microsomes into MAP.2. Treatment of rats with phenobarbital (PB), but not 3-methyl-cholanthrene (3-MC), resulted in significant increases in hepatic metabolism of deprenyl to MAP and AP, and in a slight increase in the pulmonary metabolism of the drug to MAP. Neither treatment showed any effect on the renal metabolism of deprenyl.3. The inhibitory effect of deprenyl on monoamine oxidase (MAO) B activity of liver was decreased and increased by pretreatment of rats with PB and SKF 525-A, respectively. However, inhibition by deprenyl of MAO-B activity of extrahepatic tissues was not affected by such treatments, except the lung where PB decreased the potency of the drug.4. Sex differences in the hepatic metabolism of deprenyl to amphetamines were seen in all three strains of rats, Sprague-Dawley, Wistar and Donryu. However, no sex differences observed in the extrahepatic met...

Antioxidant therapy in Parkinson's disease.

Abstract: It is postulated that endogenous oxidative mechanisms are a major factor in the continuing death of dopaminergic neurons and the progression of Parkinson's disease. Scientific evidence in support of, and negating, the free radical auto-toxicity and dopamine toxicity concepts is reviewed. There is conflicting evidence whether free radicals are involved in the toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and attempts to prevent the toxicity of MPTP with antioxidant therapy have had variable results. The oxidation of dopamine by monoamine oxidase produces toxic metabolites however animal studies with high dose longterm levodopa and MPTP have failed to show clear evidence for autoxidation. Firm supportive evidence is obtained from the monoamine oxidase B inhibitor experience which demonstrated a block of the toxicity of MPTP in animals and probable prolongation of the course of human Parkinson's disease. The scientific data available is inconclusive but there is significant hope of retarding progressive catecholaminergic neuron degenerative changes by augmenting the free radical scavenging system with antioxidants (such as Vitamin E) and slowing catecholamine oxidation by monoamine oxidase B inhibition. Careful clinical trials with these agents must be performed.

The current status of monoamine oxidase and its inhibitors.

Abstract: The enzyme monoamine oxidase (MAO) plays an important role in the inactivation of both dietary amines and also of neurotransmitter amines. A study of the properties of irreversible inhibitors of this enzyme suggests that the enzyme exists in two broad types--MAO-A and MAO-B. Although irreversible inhibitors of MAO were once widely used as antidepressant agents, they fell from favour because of adverse reactions after the ingestion of amine-containing foodstuffs ("the cheese reaction"). However, these inhibitors (phenelzine and tranylcypromine) are probably best for the treatment of atypical depression providing the patient is aware of dietary reactions. A new series of reversible, MAO-A selective inhibitors are being developed which do not exhibit serious dietary interactions. These reversible inhibitors show promise as rapidly acting antidepressant agents. An atypical irreversible MAO-B selective inhibitor, selegiline (deprenyl) does not exhibit an adverse reaction on the ingestion of amine-containing foods. This drug has been used as an adjuvant in the treatment of Parkinson's disease since it allows the dose of L-dopa to be reduced by approximately 25%. More important, selegiline may slow the degeneration of dopaminergic neurons that is characteristic of Parkinson's disease.

1,2,3,6-tetrahydro-1-methyl-4-(methylpyrrol-2-yl)pyridine: studies on the mechanism of action of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Abstract: Two analogs of the nigrostriatal neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were examined for their deleterious effects on nigrostriatal neurons. 1,2,3,6-Tetrahydro-1-methyl-4-(methylpyrrol-2-yl)pyridine (TMMP), but not 1-methyl-4-(1-methylpyrrol-2-yl)-4-piperidinol, caused persistent depletion of striatal dopamine and induced histologic evidence of nerve terminal degeneration in mice. These findings differ diametrically from results previously reported for the two analogs. TMMP produced larger dopamine depletions than MPTP when the two drugs were given in equivalent doses. Further experiments demonstrated that TMMP is preferentially oxidized by mouse brain monoamine oxidase B to a water-soluble compound, most likely the pyridinium ion species. Prior treatment of mice with either the monoamine oxidase inhibitor pargyline or the dopamine reuptake inhibitor bupropion blocked the ability of TMMP to deplete striatal dopamine. Thus, the pharmacologic profile of TMMP closely resembles that of MPTP. That TMMP and MPTP induce dopamine depletions by a similar mechanism tends to support the proposed neurochemical sequence of events thought to lead to the expression of MPTP-induced neurotoxicity. The authors' observations provide further evidence that MPTP is not unique in its capability to damage nigrostriatal neurons.

Selective decreases in MAO-B activity in post-mortem brains from schizophrenic patients with type II syndrome.

Abstract: The activities of the A and B forms of the enzyme monoamine oxidase (MAO, E.C. 1.4.3.4) have been assessed with the substrates 5-hydroxytryptamine and benzylamine respectively in seven areas of the brains of 39 patients with schizophrenia and 44 control subjects. Whereas previous studies have found the enzyme unchanged in brain in schizophrenia, in this study there was a modest but significant decrease in the activity of MAO-B in frontal and temporal cortices and in amygdala. This decrease could not be accounted for by neuroleptic medication, age, sex or post-mortem variables. In a series of 22 patients who had been assessed in life, the reduction in MAO-B activity was found to be associated specifically with the presence of negative symptoms (flattening of affect and paucity of speech). The findings are therefore consistent with other evidence for structural and neurochemical change in the temporal lobe that have been associated with the type II (defect state) syndrome of schizophrenia. The change in enzyme activity is unlikely to be related to a change in monoamine metabolism but may reflect a disturbance in glial function. The change in MAO-B activity in brain in this study is confined to particular areas of brain and a subgroup of patients; it is thought to be entirely unrelated to earlier reports of reductions of enzyme activity in platelets, which are probably attributable to prolonged neuroleptic medication.

Monoamine oxidase B inhibition and the "cheese effect".

Abstract: The absence of initiation of "cheese effect" (potentiation of sympathomimetic action of tyramine) by 1-deprenyl (selective monoamine oxidase, MAO-B inhibitor) was regarded to be an intrinsic property of this inhibitor. However, availability of other selective MAO-B inhibitors have clearly shown that this is not the case, since the "cheese effect" is associated with the selective inhibition of MAO-A, the enzyme responsible for intraneuronal oxidation of noradrenaline. Following inhibition of neuronal MAO-A, noradrenaline in the cytoplasmic intraneuronal pool can increase to high levels. Since tyramine releases noradrenaline into the cytoplasm and not by exocytosis, its action is potentiated by inhibition of neuronal MAO-A.

The functional coupling of neuronal and extraneuronal transport with intracellular monoamine oxidase

Abstract: “Metabolizing systems” are responsible for the quick inactivation of noradrenaline released from adrenergic nerve endings: a transport mechanism (uptake1 or uptake2) is arranged in series with the intracellular enzyme (monoamine oxidase, MAO; catechol-O-methyltransferase, COMT). In the perfused rat heart, kenzyme-values were determined, i.e., those rate constants which characterize the unsaturated intracellular enzymes. In the extraneuronal metabolizing system kcomt > kmao for noradrenaline and adrenaline, while rather similar rate constants were obtained for dopamine. However, for the neuronal deaminating system, kmao is considerably higher than kmao for the extraneuronal system. Second, in the rat vas deferens it is demonstrated that inhibition of neuronal MAO leads to very pronounced rises of the axoplasmic noradrenaline concentration—and this is again a reflection of the high activity of neuronal MAO. In a third series of experiments (with the rat vas deferens), the evidence indicates that the neuronal inward transport of substrates of MAO fails to saturate the enzyme. This is the functional consequence of the high activity of neuronal MAO. It is concluded that a) neuronal MAO activity is very high, and—as a consequence—b) axoplasmic noradrenaline levels are very low.

N‐propargylbenzylamine, a major metabolite of pargyline, is a potent inhibitor of monoamine oxidase type B in rats in vivo: a comparison with deprenyl

Abstract: In an effort to explore the contribution of the metabolites of pargyline towards the in vivo inhibition of monoamine oxidase (MAO), the effects of pargyline and its major metabolites on the production and metabolism of a number of biogenic amines were studied in rats. The administration of pargyline gave rise to three major ethyl acetate extractable metabolites: benzylamine, N-methylbenzylamine and N-propargylbenzylamine (NPB). Only NPB demonstrated in vivo monoamine oxidase inhibitory properties at an acute dose of 30 mg kg-1. The acute effects of pargyline, NPB, and deprenyl on urine and brain concentrations of a number of biogenic amines (phenylethylamine (PEA), m- and p-tyramine, noradrenaline (NA), dopamine, and 5-hydroxytryptamine (5-HT) and their metabolites were evaluated. Increased urine and brain concentrations of PEA were considered to represent in vivo inhibition of type B MAO while decreased concentrations of NA and 5-HT metabolites were regarded as indicators of an in vivo inhibition of MAO type A. NPB, like deprenyl and pargyline, significantly increased urine and brain PEA while only pargyline reduced 5-HT metabolism, suggesting that the metabolism of pargyline to NPB may contribute towards the MAO type B inhibitory effects of pargyline in vivo. Since the therapeutic benefits of MAO inhibitors in clinical practice usually require some period of chronic treatment, the chronic effects of repeated 14 daily doses of the above MAO inhibitors on central and peripheral biogenic amines were evaluated at the following times: during treatment, one day and five days after termination of treatment. The biochemical changes observed during the course of chronic NPB, pargyline and deprenyl treatments generally follow the expected in vitro characteristics of these drugs, but the detailed changes observed suggest clear differences. For example, the in vivo effect of pargyline on urine 5-hydroxyindoleacetic acid excretion was considerably weaker than its effect on the excretion of NA and dopamine metabolites. These changes are opposite to the in vitro effects of pargyline on 5-HT, dopamine and NA oxidative deamination. Inhibitions of the metabolism of all the amines studied were clearly observed during chronic MAOI treatments, but these effects were less evident five days after the end of treatment, suggesting an almost normal metabolism of biogenic amines. It is concluded that while MAO inhibitors may be the primary compound responsible for MAO inhibition, the effects of their metabolites in some cases may also play equally important roles in the regulation of monoamines both in the periphery and the brain. Thus, as demonstrated here, NPB was found to be as potent as pargyline and deprenyl with regard to its in vivo MAO type B inhibitory properties.

Antidepressant monoamine oxidase inhibitors enhance serotonin but not norepinephrine neurotransmission.

Abstract: Monoamine oxidase inhibitors (MAOIs) were the first effective drugs in the treatment of major depression (Klein et al. 1980). Given their inhibiting action on the catabolism of monoaminergic neurotransmitters, they constitute unique tools for investigating the neurobiological basis of the antidepressant response.

Platelet monoamine oxidase activity in patients with Huntington's disease.

Abstract: SUMMARY 1. Platelet monoamine oxidase (MAO) activity was investigated in 30 patients with Huntington's disease and compared with the activity in a control group. 2. Significantly elevated activity was found in the patients (P < 0.05; t-test) when same sex contrasts were carried out to account for the well known influence of sex on MAO activity. 3. The mean MAO activity in male patients was 23.5±6.0 nmol/mg protein per h and female patients was 29.5 ± 8.9 nmol/mg protein per h using tyramine as the substrate. 4. The possible influence of environmental factors on the results is discussed.