Monoamine Oxidase Type A Research Articles

Differential effects of clorgyline on catecholamine and indoleamine metabolites in the cerebrospinal fluid of rhesus monkeys

The effects of acute and chronic administration of clorgyline, an irreversible inhibitor of monoamine oxidase type A (MAO-A), on the deaminated metabolites of norepinephrine, dopamine and serotonin were examined in rhesus monkey cerebrospinal fluid (CSF). Acute clorgyline treatment resulted in highly significant, dose-dependent reductions in 3-methoxy-4-hydroxyphenylglycol (MHPG) of 50% (1 mg/kg) and 68% (2 mg/kg) compared to pretreatment values. Chronic clorgyline administration (0.25 to 0.5 mg/kg × 24 days) resulted in a 67% reduction in CSF MHPG. In contrast, the concentrations of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were less affected by acute clorgyline administration, being reduced significantly only after the 2 mg/kg dose, which lowered 5-HIAA 27% and HVA 48%. Chronic clorgyline treatment had no significant effect on the CSF concentrations of HVA and 5-HIAA. These data, which suggest that MAO-A inhibition by clorgyline in vivo is more closely associated with changes in the noradrenergic than the serotonergic or dopaminergic systems in nonhuman primates, are in general agreement with the effects of clorgyline on CSF and urinary biogenic amine metabolites in man. They differ from several in vitro studies which indicate a primary role of MAO-A in the metabolism of serotonin and of MAO-B in norepinephrine degradation in primate brain. The discrepancies may reflect modulating effects of synaptic feedback mechanisms on the actions of clorgyline in vivo or perhaps a failure of CSF metabolites to adequately reflect brain amine metabolism changes. The lack of change in platelet MAO-B activity during clorgyline treatment together with the minimal changes in HVA concentrations indicate that the selective inhibitory effects of clorgyline on MAO-A were maintained during chronic administration of low drug doses.

Effect of Ovariectomy and Estrogen Treatment on Uterine Benzylamine Oxidase and Monoamine Oxidase Type A

The activity of monoamine oxidase type A (MAO-A) of rat uteri is known to be modulated by sex steroids but no information is available with regard to benzylamine oxidase (BzAO). Thus, uterine MAO-A and BzAO activities were assayed in ovariectomized (3 weeks) and ovariectomized plus estrogen treated rats (17 beta-estradiol, 10 micrograms/kg/day, i.p. for three days). Compared with sham operated controls, MAO-A activity (total and specific) was decreased by ovariectomy and restored partially by estrogen treatment. In contrast, BzAO activity was not influenced selectively. Total BzAO activity followed changes in uterine weight such that the specific activity of BzAO, per mg tissue, was not statistically different between the three experimental groups. Although changes in the specific activity of BzAO were found on a protein and DNA basis, these changes reflect primarily alterations in protein and DNA contents and not BzAO activity. Since BzAO appears to be insensitive to direct modulation by sex steroids and may be located predominantly in uterine blood vessels, it is speculated that the enzyme may serve as a marker for hormonal influences on the vascularity and structure of the uterine vascular bed.

Inhibition of rat brain monoamine oxidase type A by 2-aminotetralin and tetrahydroisoquinoline analogues of dopamine.

The in vitro inhibition of rat brain monoamine oxidase type A (MAO-A) by various dopamine analogues is reported and compared to some established inhibitors of the enzyme. The estimated IC50's were found to be in the range 10(-5)-10(-3) mol/l. This makes these compounds more than 10 000 times less potent than the selective MAO-A inhibitor harmaline and more than 10 times less potent than the selective MAO-B inhibitors pargyline and deprenyl. When the brain concentrations that are reached after peripheral administration of these drugs are taken into account it is unlikely that inhibition of MAO is relevant to their effects as has been suggested. Also the endogenous brain concentrations of some tetrahydroisoquinolines are probably too low to produce an inhibition of the enzyme.

Selective effects of neonatal hypothyroidism on monoamine oxidase activities in the rat brain.

Hypothyroidism of mild intensity was obtained with prenatal and neonatal submission of Long-Evans rats to an iodide-rich diet. Chronic daily administration of methimazole to iodide-supplemented Long-Evans pups or to iodine-deprived Charles-River rats through the first 29-30 days of age provoked severe hypothyroidism. Monoamine oxidase type A (MAO-A) and not type B (MAO-B) activity was consistently, although slightly (by approximately 20%), increased in the hypothyroid brain. Triiodothyronine (T3)-induced hyperthyroidism did not affect MAO activity. Replacement therapy with T3 did not normalize MAO-A activity in hypothyroidism. Methimazole displayed a competitive and reversible in vitro inhibition of MAO-A but not MAO-B activity. Although this effect was obtained at concentrations far higher than those estimated to reach the brain after a single injection of the goiterogen, the occurrence of accumulation processes in the metabolism-deficient hypothyroid neonate rats cannot be excluded. Thus, MAO-A activity might be either directly depressed during the goiterogenic treatment, or increased as the result of some kind of rebound effect after interruption of methimazole administration.