Ethanol inhibits the activity of the B form of monoamine oxidase in human platelet and brain tissue

Ethanol selectively inhibits the activity of the B-form of monoamine oxidase (MAO) in membranes obtained from human platelet and brain. When endogenous concentrations of phenylethylamine are used as substrate, significant inhibition is induced by concentrations of ethanol that are attainable after ethanol ingestion (50 mM). The mechanism of ethanol's inhibition of MAO activity appears to involve perturbation of membrane lipids surrounding the enzyme.     

Cardiovascular activity of rasagiline, a selective and potent inhibitor of mitochondrial monoamine oxidase B: comparison with selegiline

Selegiline is used for treating Parkinson's disease. Despite its efficacy, the clinical use of selegiline in combination with l-dihydroxphenylalanine in Parkinsonian patients is hampered by cardiovascular complications, such as hypotension. This study was designed to compare in rats the cardiovascular effects of selegiline and rasagiline, their metabolites l-methamphetamine and aminoindan (TVP-136), respectively, and the second rasagiline metabolite non-monoamine oxidase (MAO) inhibitor TVP-1022 (N-propargyl-1S(-)aminoindan). Intravenous (i.v.) administration of selegiline and rasagiline (1 mg kg(-1)) to anaesthetized rats (thiobutabarbital, 100 mg kg(-1), i.p.) did not affect mean arterial pressure (MAP), carotid blood flow (CBF) or carotid vascular resistance (CVR). Selegiline (10 mg kg(-1), i.v.) decreased MAP, CBF and increased CVR. In contrast, rasagiline (10 mg kg(-1), i.v.) caused a small transient decrease in MAP, while CBF and CVR were unchanged. l-methamphetamine (1 mg kg(-1), i.v.) administration provoked a dramatic and long-lasting depressor response, decreased CBF and increased CVR. In contrast, injection of aminoindan or TVP-1022 at a similar dose produced gradual nonsignificant decreases in MAP and CBF. Chronic oral treatment (21 days) of awake rats with selegiline at 10 mg kg(-1) decreased systolic blood pressure (SBP), diastolic blood pressure (DBP), and MAP, whereas heart rate was unaffected. Since the effective MAO-B inhibitory and clinical dose of rasagiline is about one-tenth that of selegiline, administration of 1 mg kg(-1) day(-1) rasagiline resulted in moderate decreases in SBP, DBP, and MAP, which were significantly lower than those caused by the 10 mg kg(-1) day(-1) dose of selegiline. These findings indicate that rasagiline, when given at doses equivalent to selegiline, is less likely to be hypotensive.     

Effect of lignocaine on monoamine oxidase activity of brain and liver

In vivo administration of a single dose (100-150 mg/kg, i.p.) of lignocaine produces no change in MAO activity, while long-term treatment (50 mg/kg/day for 15 and 30 consecutive days, i.p.) produces a slight but appreciable inhibition of MAO activity with tyramine or serotonin but not with benzylamine as substrate in both rat brain and liver mitochondria. Lignocaine (2-20 mM) inhibits (in vitro) both brain and liver mitochondrial MAO activity, using tyramine, serotonin and benzylamine as substrates, in a concentration-dependent manner. Furthermore, lignocaine produces a marked in vitro inhibition of serotonin and tyramine oxidation in MAO-A and not in MAO-B preparation of rat brain. Ackermann-Potter plots of MAO indicate that lignocaine-induced inhibition of MAO activity is reversible in nature. Lineweaver-Burk plots show that lignocaine (2-10 mM) produces a significant increase in Km and decrease in Vmax of MAO for tyramine and serotonin in both brain and liver. Similarly Km and Vmax values are changed using benzylamine as substrate in the presence of relatively higher concentrations of lignocaine (5-20 mM). These results suggest that lignocaine-induced inhibition of mitochondrial membrane-bound MAO activity of both neuronal and non-neuronal tissues is associated with its conformational change.     

Effect of chronic administration of morphine on monoamine oxidase activity in discrete regions of the brain of rats

The effect of chronic administration of morphine on the activity of monoamine oxidase in specific regions of the brain of rats has been investigated. It was found that, shortly after the last administration of morphine, brain monoamine oxidase (EC 1.4.3.4) was drastically reduced in rats which had been chronically treated with morphine and which had exhibited a hyperactivity syndrome manifested by compulsive gnawing and spasmodic jumping. The lowest values were seen at approximately 30 min and they returned to nearly normal levels by 6 hr after the last injection. In contrast, no significant changes were observed in the activity of this enzyme in animals that did not exhibit this syndrome after morphine administration.     

Acute dieldrin exposure in relation to brain monoamine oxidase activity and concentration of brain serotonin and 5-hydroxyindoleacetic acid

Rainbow trout, White Leghorn chickens and golden hamsters were administered dieldrin or the vehicle in various dosages and routes of injection. Whole brain serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations were measured. In separate experiments, monoamine oxidase (MAO) activity was determined in brain homogenates incubated with pargyline or dieldrin. Serotonin content increased maximally at 10 mg/kg dieldrin. Brain MAO activity was significantly decreased by dieldrin in chicken and hamster, but trout enzyme activity was unaffected. The 5-HIAA content reflected MAO inhibition and interference with 5-HIAA transport from brain.     

Interaction of psychotropic drugs with monoamine oxidase in rat brain

Literature observations indicate that some psychotropic drugs may have inhibitory activity towards monoamine oxidase (MAO). This study was undertaken to assess the potency, isozyme selectivity and mechanism of inhibition of representative first- and second-generation antidepressant drugs towards rat brain MAO-A and MAO-B. Five tricyclic antidepressants (imipramine, trimipramine, clomipramine, amitriptyline and doxepine) and three selective serotonin reuptake inhibitors (fluoxetine, fluvoxamine and citalopram) were examined. They showed inhibitory activity towards MAO-A and MAO-B, with clear selectivity for MAO-B (Ki in the micromolar range). Their mechanism of inhibition was competitive towards MAO-B and of a mixed competitive type towards MAO-A. The results suggest that some of the drugs examined might also contribute an MAO inhibitory effect in chronically treated patients.     

Hydrogen peroxide production in mouse tissues after acute d-amphetamine administration. Influence of monoamine oxidase inhibition

The toxicity of amphetamines is conditioned by a complex array of mechanisms, involving the increase of neurotransmission (e.g. leading to hyperthermia) and enzymatic and non-enzymatic oxidation of amphetamines and biogenic amines. Considering that all these processes may increase the generation of hydrogen peroxide (H2O2) by metabolic or non-metabolic redox pathways, the main objective of this work was to evaluate d-amphetamine-induced H2O2 production in mice liver, kidney and heart. The contribution of monoamine oxidase (MAO) to H2O2 production after d-amphetamine administration was studied using the MAO inhibitor pargyline. H2O2 production was measured indirectly using the catalase-H2O2 complex I irreversible inhibitor 3-amino-1,2,4-triazole (AT). Using this method, the measurement of residual catalase activity following administration of AT permits the monitoring of H2O2 production in vivo. Charles River CD-1 mice (30-35 g body weight) were injected with AT just before the injection of d-amphetamine sulphate (20 mg/kg). d-Amphetamine stimulated the production of H2O2 in all tissues studied, although to different degrees. MAO inhibition by itself led to a remarkable decrease of basal H2O2 production in the kidney and a slight decrease in the liver, although no effect was observed in the heart. d-Amphetamine-induced H2O2 production in the heart and kidney was reduced in MAO-inhibited mice. However, in the liver, H2O2 production was transiently potentiated at 30 min under MAO inhibition. In conclusion, d-amphetamine administration leads to an increase in H2O2 production in mouse liver, kidney and heart, and monoamine oxidase plays an important role in this effect.     

Specific changes in type A and B monoamine oxidase activity in different tissues of hypophysectomized rats

MAO activity was tested in four organs of young male rats 16 days after hypophysectomy. Five monoamines were used as substrates. In the adrenal glands and the thyroid gland MAO activity towards the substrates preferably deaminated by MAO-A was severely decreased. In the adrenal glands, but not in the thyroid gland, the effect of hypophysectomy could be simulated with dexamethasone, a steroid which inhibits ACTH secretion. A significant rise in MAO activity towards substrates for MAO-A and MAO-B occurred in the heart of hypophysectomized rats. There was little change in the MAO activity of whole brain homogenates after hypophysectomy.     

Time-dependent changes in brain monoamine oxidase activity and in brain levels of monoamines and amino acids following acute administration of the antidepressant/antipanic drug phenelzine

Phenelzine (PLZ) is a non-selective monoamine oxidase (MAO) inhibitor commonly used to treat depression and panic disorder. Acute administration of PLZ produces several neurochemical changes, including an increase in brain levels of the catecholamines norepinephrine (NE) and dopamine (DA), of 5-hydroxytryptamine (5-HT), and of the amino acids alanine and gamma-aminobutyric acid (GABA). The goal of the present series of experiments was to characterize the time course of these PLZ-induced changes. Male Sprague-Dawley rats were sacrificed 6, 24, 48, 96, 168, or 336 hr after acute PLZ administration (15 or 30 mg/kg, i.p., based on free base weight). Whole brain levels of monoamines and amino acids were determined using HPLC, and MAO A and B activities were determined using a radiochemical procedure. The results indicated that PLZ changed amino acid levels 6 and 24 hr after injection, but not 48 hr later. In contrast, the effects of PLZ on MAO activity and monoamines were longer-lasting. For example, PLZ-induced increases in dopamine and 5-HT were observed 1 week after injection, and PLZ-induced inhibition of MAO activity persisted for 2 weeks. Thus, in addition to demonstrating that the effects of PLZ on MAO activity and monoamines were long-lasting, these results indicate that the effects of PLZ on MAO activity and on brain levels of monoamines and amino acids are temporally dissociated. These findings regarding the long-term effects of PLZ on neurochemistry will have considerable critical implications for the design and interpretation of behavioral studies of the acute effects of PLZ.     

Effects of prenatal methylmercury exposure on brain monoamine oxidase activity and neurobehaviour of rats

Monoamine oxidase (MAO) regulates levels of dopamine, serotonin, and noradrenaline in the nervous tissue and is required for proper neuronal development. The purpose of this study was to determine if oral exposure of adult female rats to methylmercury (MeHg) at 0.5 or 1 mg/kg/day before and during pregnancy would affect MAO activity in various brain regions of the offspring. Offspring neurobehaviour performance was also assessed. The brain MAO activity of female offspring was reduced at both MeHg doses with significantly lower values noted in the brainstem region. No significant MeHg dose effects on MAO activity were observed in the male offspring. Neurobehavioural evaluations indicated that MeHg exposure altered auditory startle in the female offspring. Rat whole embryos (gestational day 13.5) cultured with 750 microg/L MeHg in vitro significantly decreased total MAO activity by 15%. In conclusion, this study demonstrated that exposure to MeHg in rats before and/or during gestation resulted in a reduction of MAO activity in the developing embryo and brainstem of the female offspring with accompanying changes in auditory startle response. Evaluation of MAO activity may serve as an indicator for neurotoxicity following developmental exposure to MeHg and should be further investigated.     

Localization of monoamine oxidase A and B and semicarbazide-sensitive amine oxidase in human peripheral tissues

Monoamine oxidase (MAO) A and B and semicarbazide-sensitive amine oxidase (SSAO) localizations in peripheral human tissues were compared by immunohistochemistry. The primary antibodies used were mouse monoclonal anti-human MAO-A (6G11/E1) and anti-human MAO-B (3F12/G10/2E3) and a rabbit polyclonal anti-bovine SSAO antibody. Immunoreactivities of the samples, obtained from 6 routine autopsy cases, showed different distributions in the tissues studied (heart, lung, duodenum, liver, pancreas, spleen, thyroid gland, adrenal gland and kidney). The relative MAO-A, MAO-B and SSAO distributions indicated a widespread distribution of these enzymes in the human body that is characterized by a matching cellular pattern in only few tissues. These differences suggest that each amine oxidase may play a specific function in, at least some, peripheral tissues.     

Characteristics of mitochondrial and synaptosomal monoamine oxidase in monkey brain

Enzymic properties of monoamine oxidase (MAO) from monkey brain were studied. High MAO activity was observed in the mesencephalon and dienecephalon of the brain. Highest activity in every region of the brain was found with tyramine as a substrate. Monkey brain mitochondrial MAO showed a different substrate specificity and different Km and Vmax values than the enzyme from mice, rats, guinea pigs and rabbits. The pH activity curves were all bell-shaped, but the pH optima were remarkably different with the various substrates used. The activities of various substrates at pH 7.2 were compared with those at the pH optimum. At the pH optima, the activity was about 1.2-fold higher with tyramine and dopamine, 2-fold higher with beta-phenylethylamine (beta-PEA) and 3-fold higher with serotonin (5-HT) and benzylamine. These results were almost similar when synaptosomes from monkey brain were used. MAO activities with 5-HT and beta-PEA were strongly inhibited by much lower concentrations of clorgyline and deprenyl, respectively. Plateau-shaped inhibition curves by these inhibitors were obtained with tyramine as the substrate. These results indicate that both the A- and B-form of MAO appear to be uniformly distributed in monkey brain, and the A-form of MAO represents approximately 35% and 50% of the total MAO activity in mitochondria and synaptosomes, respectively.     

当归注射液对老年小鼠脑、肝脏MAO-B活性的影响

当归注射液不同剂量给老年小鼠灌胃,每天1次,连用4周,可显著降低老年小鼠脑、肝脏MAO-B活性。结果提示、当归注射液具有延缓衰老作用。