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PubMed1999

Striatal dopamine metabolism in monoamine oxidase B-deficient mice: a brain dialysis study.

We have studied striatal dopamine (DA) metabolism in monoamine oxidase (MAO) B-deficient mice using brain microdialysis. Baseline DA levels were similar in wild-type and knock-out (KO) mice. Administration of a selective MAO A inhibitor, clorgyline (2 mg/kg), increased DA levels and decreased levels of its metabolites in all mice, but a selective MAO B inhibitor, l-deprenyl (1 mg/ kg), had no effect. Administration of 10 and 50 mg/kg L-DOPA, the precursor of DA, increased the levels of DA similarly in wild-type and KO mice. The highest dose of L-DOPA (100 mg/kg) produced a larger increase in DA in KO than wild-type mice. This difference was abolished by pretreating wild-type mice with l-deprenyl. These results suggest that in mice, DA is only metabolized by MAO A under basal conditions and by both MAO A and B at high concentrations. This is in contrast to the rat, where DA is always metabolized by MAO A regardless of concentration.

Animals↗
PubMed1988

Interactions of tricyclic antidepressant drugs with human and rat monoamine oxidase type B.

The effect of tricyclic antidepressant drugs on the deamination of phenylethylamine and benzylamine by monoamine oxidase (MAO) type B was investigated in vitro in human brain cortex, human platelet, and rat brain preparations. These drugs inhibited MAO activity as expected; however, an atypical biphasic response was observed with the tertiary amine tricyclic, clomipramine, and, to a somewhat lesser extent, with two other tertiary amine tricyclics, imipramine and amitriptyline, when benzylamine was used as the substrate in human tissue preparations. This atypical biphasic pattern was not found when we used the secondary amine antidepressant drugs, desipramine, desmethylclomipramine, or fluoxetine, or used phenylethylamine as the substrate, or used rat rather than human brain tissue. For the tricyclics exhibiting normal inhibition patterns, the same rank order of inhibition was observed with benzylamine as a substrate in all three types of tissue; however with phenylethylamine, differences in inhibition were found between rat and human tissues. These tricyclic-MAO interactional data suggest that secondary and tertiary amine tricyclics interact differently with human MAO type B, that rat and human MAO type B are not functionally identical, and also support other data that phenylethylamine and benzylamine are deaminated by different mechanisms.

Animals↗
PubMed1994

Monoamine oxidase and homovanillic acid in boys with predispositions to substance abuse.

Both dopaminergic dysregulation and abnormalities in monoamine oxidase (MAO) have been postulated as etiological factors in substance abuse. This study assessed whether MAO activity differed in sons of substance-abusing fathers compared with sons of nonsubstance-abusing fathers. It also assessed the levels of homovanillic acid (HVA), the metabolite of dopamine, and MAO in a group of substance-using/-abusing boys compared with peers without this history in the same setting. Sixty-five boys admitted to a residential center were evaluated on blood tests for HVA and MAO, and on a series of diagnostic instruments and questionnaires designed to elicit information about parental substance abuse and about the subject's own substance use/abuse. The results indicated tentatively that younger (< 12.0 years) sons of substance-abusing fathers had higher levels of MAO than younger sons of nonsubstance-abusing fathers. Levels of MAO in older (> or = 12.0 years) sons of substance-abusing and nonsubstance-abusing fathers did not differ. Boys with histories of significant use/abuse of substances themselves had significantly higher MAO levels and significantly lower HVA levels than peers of the same age without substance use/abuse histories.

Adolescent↗
PubMed1990

Blood platelet monoamine oxidase activity, serotonin uptake and release rates in anorexia and bulimia patients and in healthy controls.

Platelet monoamine oxidase (MAO) activity, serotonin uptake rate and serotonin efflux rate have all been suggested to be markers for central serotonergic mechanisms. Platelet MAO activity is associated with certain personality traits, with low activity linked to traits such as impulsiveness, sensation-seeking and avoidance of monotony, all possible expressions of low central serotonergic activity. Low platelet serotonin uptake rate has been connected to unipolar depression and the rate of efflux, in the presence of the ATP uncoupler CCP, higher in bipolar depressives than in controls. Platelet MAO was found to be lower in 16 consecutive female inpatients fulfilling the DSM-III criteria for bulimia nervosa than in 12 female controls. Rates of serotonin uptake and efflux in the presence of CCP were, on the other hand, similar to the controls. In the controls there were no correlations between platelet MAO activity and any of the other parameters estimated. Vmax for the platelet uptake of serotonin correlated positively with the Km for the uptake, but not with any other parameter. The uninfluenced rate of efflux of serotonin correlated positively with the efflux in the presence of the ATP uncoupler CCP.

Adolescent↗
PubMed1981

Studies on the pargyline-binding site of different types of monoamine oxidase.

[3H]Pargyline has been covalently linked to active sites of both type A and type B monoamine oxidase (MAO) obtained from various tissues. Rat heart and human placenta were chosen to represent predominantly type A MAO, pig and bovine livers to represent type B MAO, and rat liver and brain to represent mixed type A and type B MAO's. The [3H]pargyline-MAO adducts were isolated and hydrolyzed by proteolytic enzymes, and the labelled peptides (pargyline-binding sites) separated and compared by paper chromatography and by paper electrophoresis at various pH values. Only one common pargyline peptide was obtained from all the different MAO's. The alternative A and B sites were assessed after preincubation of rat liver MAO with the selective inhibitors deprenyl (to block the B site) and clorgyline (to block the A site). Following proteolysis of the [3H]pargyline of both type A and type B MAO from this pretreated rat liver, MAO has been purified by a series of chromatographic and electrophoretic procedures. Micro-Edman degradation, followed by dansylation, revealed the amino acid sequence to be Ser-Gly-Gly-Cys(X)-Tyr. It is concluded that the primary structures immediately surrounding the pargyline-binding sites are identical for both type A and type B MAO in these tissues.

Amino Acid Sequence↗
PubMed1990

Sensitive assays for the determination of monoamine oxidase and phenol sulphotransferase activity in small tissue samples.

A method to assay phenol sulphotransferase (PST) and monoamine oxidase (MAO) in brain (anterior pituitary gland, hypothalamus) and liver specimens as small as 4 mg is described. The specimens were homogenized (sonicated) in various volumes of a buffer, the smallest being 100 microL, to obtain the homogenates. MAO assay was carried out using 30 microL of the homogenate and for PST assay, 30 microL of either the homogenate or, in the case of liver, the supernatant (100,000 x g for 60 min). The radiolabeled products of the enzymatic reactions were separated from the radiolabeled substrates by high-pressure liquid chromatography (HPLC) and the radioactivity of the eluted products measured directly by a radioisotope detector coupled to the HPLC system. The constraint of the assay protocol was not the weight of the specimens but the volume of buffer used in the preparation of the homogenate. Although 100 microL was a convenient working volume, the tissue can also, with care, be sonicated in a 50 microL buffer. With extremely small specimens, weighed fractions of the specimens could be sonicated directly in the control and experimental incubation mixtures bypassing the preparation of the homogenate. Thus, the overall method offers, for the first time, a reliable and adaptable means for measuring MAO and PST in small to extremely small tissue specimens.

Animals↗
PubMed1996

Monoamine oxidase B expression is selectively regulated by dexamethasone in cultured rat astrocytes.

The influence of dexamethasone on monoamine oxidase (MAO) A and B expression and activity was investigated in primary cultures of rat type 1 astrocytes cultured under serum free, defined conditions. Dexamethasone treatment resulted in a dose- and time-dependent induction of MAO-B, but not of MAO-A, activity. The selective MAO-B increase was substantially reduced by the antagonist RU 486, thus suggesting a glucocorticoid receptor-mediated action of the hormone. Kinetic analysis showed an increase in Vmax of MAO-B with no change in apparent K(m). The dexamethasone-induced selective rise in MAO-B activity appeared to be due to enhanced enzyme synthesis, since MAO-B mRNA was markedly increased by dexamethasone treatment and the recovery of MAO-B activity after its irreversible inhibition by deprenyl was more pronounced in the presence than in the absence of the hormone. Furthermore, the dexamethasone effect was abolished by the protein synthesis inhibitors actinomycin D or cycloheximide. The present study demonstrates that dexamethasone is able to selectively induce MAO-B in type 1 astrocytes and leads to speculation of a possible role for glucocorticoids in the increase in brain MAO-B associated with neurodegenerative disorders, such as Parkinson's and Alzheimer's diseases.

Animals↗
PubMed1990

Binding of [3H]brofaromine to monoamine oxidase A in vivo: displacement by clorgyline and moclobemide.

Short duration of action, displaceability by endogenously released monoamines, and absence of cumulation of effect of the selective inhibitor of monoamine oxidase type A (MAO-A), brofaromine (CGP 11305 A), indicate reversibility of its interaction with the enzyme in vivo. However, its in vitro interaction with the enzyme showed features commonly associated with irreversible inhibition. To clarify this issue, the in vivo binding of [3H]brofaromine to MAO-A in areas of the rat brain, and in rat heart and liver was investigated. Specific binding, defined by pretreatment with the irreversible inhibitor, clorgyline, was between 15 and 75% of total binding depending ont eh tissue and the time elapsed after injection of radioactivity. In brain and heart tissue, unlabelled brofaromine, another reversible inhibitor of MAO-A, moclobemide and clorgyline were able to displace [3H]brofaromine when administered after the labelled compound with ED50s of 1-3 mg/kg p.o., 3 mg/kg p.o. and 0.3-1 mg/kg s.c., respectively. In the liver, brofaromine and moclobemide and the inhibitor of drug-metabolizing enzymes, proadifen (SK&F 525 A), were able to significantly inhibit [3H]brofaromine binding. Clorgyline was only marginally effective, suggesting that, in this organ, [3H]brofaromine binds predominantly to such enzymes. In conclusion, the binding of [3H]brofaromine to MAO-A in rat brain and heart in vivo was found to be displaceable by other MAO inhibitors and is therefore reversible. In the liver, the compound bound predominantly to other sites, probably microsomal drug-metabolizing enzymes.

Animals↗
PubMed1976

Molecular biology of neurological and psychiatric disorders. I. Effect of parkinsonism, age, sex and L-dopa on platelet monoamine oxidase.

Since there is substantial evidence for a nigrostriatal dopamine defect in Parkinson's disease and since monoamine oxidase (MAO) appears to be essential for the degradation of dopamine, we investigated whether this enzyme is involved in the pathogenesis of this disease or in the therapeutic action of L-dopa. To gain a solid basis for our analysis we studied some properties of platelet MAO, at present the only practical in vivo source for human MAO. Substrate and inhibitor pattern clearly pointed to a predominant B-type character of this enzyme. By using 3 substrates, m-iodobenzylamine, p-methoxybenzylamine, and tyramine, we found a marked age and sex difference in MAO activity. In untreated parkinsonian patients, platelet MAO was slightly reduced as compared with age- and sex-matched controls. Treatment with L-dopa induced a further reduction of platelet MAO activity in both sexes, but more in men than in women. We conjecture that the action of L-dopa on parkisonian patients is twofold: L-dopa is known to enhance the release of gonadotropins and thus to increase the production of sex hormones which in turn are capable of reducing MAO activity. Dopamine, formed from L-dopa, may thus have a better chance for survival in reaching the dopaminergic receptor. A new form of therapy, based on this concept, is proposed.

Adolescent↗
PubMed2000

Metabolism and pharmacokinetics, in the rat, of (R)-N-(2-Heptyl)Methyl-propargylamine (R-2HMP), a new potent monoamine oxidase inhibitor and antiapoptotic agent.

(R)-N-(2-Heptyl)-N-methylpropargylamine (R-2HMP) is a monoamine oxidase inhibitor and putative antiapoptotic agent analogous to (R)-deprenyl. In the rat, the major amine metabolites of R-2HMP have been identified as (R)-N-2-heptylmethylamine (R-2HMA), (R)-N-2-heptylpropargylamine (R-2HPA), and (R)-2-heptylamine (R-2HA). After R-2HMP was administered s.c. to male Wistar rats, it was observed that the greatest concentration was of the original drug followed in decreasing order by R-2HMA, R-2HPA, and R-2HA in brain, liver, and plasma at all times after administration. The greatest concentrations of the three metabolites were found in brain followed by liver and plasma, and the peak concentrations occurred between 15 and 30 min after administration. After oral administration, the liver contained the greatest concentrations of drug and metabolites, and, again, the peak concentrations occurred at about 15 min. In all cases, depropargylation appears to occur at a faster rate than demethylation. After s.c. administration, R-2HMP and its metabolites exhibited biexponential redistribution and elimination losses. Half-lives of the compounds in brain for the redistribution phase were: R-2HMP, 10 min; R-2HMA, 11 min; R-2HPA, 16 min; and R-2HA, 15 min.

Administration, Oral↗
PubMed1992

Monoamine oxidases of the brains and livers of macaque and cercopithecus monkeys.

We assessed the two forms of monoamine oxidase (MAO), MAO-A and MAO-B, in discrete regions of the brain and in cerebral micro- and macrovessels, choroid plexus, and liver of three species of monkeys: African Green, rhesus, and cynomolgus. MAO was determined by specific [3H]pargyline binding which is stoichiometric and irreversible and by measuring the rate of oxidation of several substrates. Cerebral micro- and macrovessels had low MAO content. Regional brain MAO did not vary by more than one-fold in the brains of each of the three species of monkeys and was higher in the basal ganglia than in the cerebral cortex or cerebellum. MAO in the choroid plexus was low, while the liver had higher MAO activity than any of the brain samples. The vast majority of MAO in all the tissues that we examined was of the MAO-B type, and specific [3H]pargyline binding correlated well with the oxidation rate of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. These results show marked similarities in brain MAO distribution between monkey and man. Or the three monkey species, the African Green monkey had the lowest MAO activity in its cerebral microvessels, which constitute the blood-brain barrier, although the small number of observations in each group did not allow statistical analyses of the differences.

Animals↗
PubMed1998

Dopamine-degrading activity of monoamine oxidase is not detected by histochemistry in neurons of the substantia nigra pars compacta of the rat.

Monoamine oxidase (MAO) activity was examined in neurons of the substantia nigra pars compacta (SNC) of the rat using a histochemical method, and compared to MAO activity in neurons of the locus coeruleus (LC) and dorsal raphe nucleus (DR). Using dopamine as a substrate, dopamine-degrading MAO activity was not detected in any SNC neurons, although LC and DR neurons were intensely stained for this activity. We further examined MAO activity in these neurons using other substrates, including serotonin (an MAO type A preferential substrate), beta-phenylethylamine (an MAO type B preferential substrate), and tyramine (a substrate common to both MAO types A and B). As for dopamine, no SNC neurons were stained for MAO activity using any of these other substrates. In contrast, LC neurons were intensely stained when either serotonin or tyramine was used, and DR neurons were darkly stained when either beta-phenylethylamine or tyramine was used. The lack of evidence of MAO activity in the SNC is surprising given that there are densely packed tyrosine hydroxylase (TH)-immunoreactive neurons in the SNC (i.e., dopaminergic neurons). By comparison, in the LC and DR the distribution patterns of the MAO-stained neurons were similar to those of TH-immunolabeled neurons (i.e., noradrenergic neurons) and serotonin-immunoreactive neurons, respectively. Our results suggest that dopamine-degrading MAO activity and MAO types A and B activities in SNC dopamine neurons are very low compared to MAO activity in LC noradrenaline neurons and in DR serotonin neurons.

Animals↗
PubMed1983

Hemodynamics and monoamine oxidase activity in spontaneously hypertensive rats (SHR).

The relationship between the onset of hypertension and changes in monoamine oxidase (MAO) activity in the brains and hearts of spontaneously hypertensive rats (SHR) were studied. After 7-weeks-old, blood pressure of SHR increased rapidly and reached a level of 170 to 180 mmHg; but following 4 weeks of propranolol treatment (10 mg/kg/day), blood pressure decreased significantly compared to that of untreated SHR. Heart/body weights ratio of SHR was higher than that of normotensive Wistar Kyoto rats (WKY). MAO activities in the brain stem, the medulla oblongata and pons of the SHR were significantly higher than those in WKY at 7 weeks of age, and MAO activity in the brain stem of the propranolol-treated SHR was significantly lower than that in the untreated SHR. Propranolol inhibited MAO activity in brain tissue in vitro, and the I50 values of propranolol were identical (1 X 10(-4) M) in SHR and WKY. In both the WKY strain and the SHR, the Vmax values of heart MAO increased with age, and the Vmax values of SHR were twice those of WKY. Km values for tyramine of heart MAO in WKY and SHR were approx. 100 microM and 140 microM, respectively; however, these values were not age-dependent. It was concluded that an increase in MAO activity in SHR brain stem may trigger a reduction in noradrenaline content and that propranolol may be responsible for its restoration, thus reducing peripheral sympathetic activity; moreover, the increase in MAO activity in the hearts of SHR may be of genetic origin.

Animals↗
PubMed2003

[Relationship between the Fnu4HI site polymorphism of monoamine oxidase A gene and Parkinson's disease].

OBJECTIVE: To study the association between the polymorphism of human monoamine oxidase type A (MAO-A) gene and Parkinson's disease(PD). METHODS: Fnu4HI restriction fragment length polymorphism(RFLP) and PCR-RFLP were used to detect the mutation of MAO-A gene. The frequencies of alleles and genotypes at the MAO-A Fnu4HI locus on the X chromosome in different PD group were compared with those of the control group. RESULTS: It was found that the frequencies of G allele in the patients with PD and controls were 0.613 and 0.527 respectively, P=0.039 "the frequencies of TT genotype were 0.303 and 0.415(P=0.014), and the frequencies of GG genotype were 0.564 and 0.451 respectively(P=0.021). When the patients were divided into two groups by age-onset, significant difference in the allelic and genotypic frequencies was observed only between early-onset PD group and control group. And when the PD patients were grouped by sex, significant difference was observed only between male PD group and male control group (the frequencies of G allele being 0.669 and 0.500 respectively, P=0.005). CONCLUSION: This study revealed significant differences between PD group and control group in allelic and genotypic frequencies. The findings supported the hypothesis about an association between MAO-A gene and PD, suggesting that age at onset of PD and gender predisposition might be related to the putative association, and Fnu4HI SNP be a risk factor for PD.

Alleles↗
PubMed1994

Platelet monoamine oxidase B activity in workers exposed to styrene.

A cross-sectional study was conducted to evaluate monoamine oxidase type B (MAO-B) activity in platelets as a biomarker of effect of styrene and perchloroethylene exposures. MAO-B is an enzyme system involved in dopamine catabolism, the impairment of which has been postulated as a mechanism of styrene-induced neurotoxicity. We previously observed an inverse association between blood styrene and MAO-B among reinforced plastics manufacturing workers. The present study included 59 male boat plant workers exposed to styrene (exposure range < 1-144 ppm, 8-h TWA). Two comparison groups comprised six male dry cleaning workers exposed to perchloroethylene (PCE; exposure range < 2-37 ppm) and 14 male laundry workers not exposed to either agent. Respiratory protection was not used by any of the styrene- or PCE-exposed workers; thus, air concentrations were regarded as valid exposure indicators. MAO-B activity (pmol/10(8) cells/h) was measured in peripheral blood platelets, using phenylethylamine as substrate. Only small overall mean differences in MAO-B were observed among the three groups; mean values were 4.21, 4.51, and 4.12 for the styrene-exposed, PCE-exposed, and laundry workers, respectively. Despite the absence of gross differences among the groups, styrene exposure was inversely related to MAO-B. Mean values for four increasing exposure group quartiles were: 5.60, 4.13, 3.69, and 3.44. The Spearman rank correlation coefficient for styrene with MAO-B was -0.41. Adjustment for age, medication use, smoking, and alcohol consumption had only a minimal effect on this trend.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1999

Lack of protection of monoamine oxidase B-deficient mice from age-related spatial learning deficits in the Morris water maze.

Monoamine oxidase B (MAO-B) increases in brain in response to aging and neurodegeneration. Whether such increases represent a risk factor to further neuronal damage or simply represent epiphenomena remains unclear. L-deprenyl, an inhibitor of MAO-B, has been shown to improve learning in aged rodents. However, recent data suggests this may occur through mechanisms independent of its enzymatic inhibition. This study investigates visualspatial learning of MAO-B deficient mice and examines what effects absence of MAO-B has on age-related cognitive decline. Learning was tested in the Morris Water Maze in male transgenic MAO-B knockout mice (KO) ages 2 months (n = 9), 7 months (n = 7), and 17 months (n = 8). Performance was compared to that of wild type (WT) littermates. Animals were given four 60 second trials per day with the submerged platform in the "North" position. Animals received 7 days of learning in which they were introduced into the pool facing the wall, alternating between the "East" and "West" positions. A single probe trial followed on day 8, followed by continuation of the original learning paradigm on days 9 and 10. Subsequently, the platform position was changed to the diagonally opposite quadrant and learning continued on days 11-13, followed by a cue phase in which the platform was made visible. Total distance traveled and latency to the platform was increased in 7- and 17- month old mice, most significantly at the beginning of the acquisition phase. This effect reappeared again in 17- month old mice during the reversal phase. No predominant genotypic differences in latency or distance were observed during any phase of the experiment. Our results show that presence or absence of MAO-B does not appear to alter performance in the Morris water maze. Furthermore, presence or absence of MAO-B does not provide protection from the age-dependent deficits in spatial learning.

Aging↗
PubMedDate not supplied

Menstrual cycle and ovarian hormone effects on plasma and platelet monoamine oxidase (MAO) and plasma dopamine-beta-hydroxylase (DBH) activities in the rhesus monkey.

Dopamine-B-hydroxylase (DBH) and monoamine oxidase (MAO) in plasma and platelets were studied in six female rhesus monkeys during three complete menstrual cycles. The same monoamine enzymes of seven bilaterally ovariectomized females were compared with a group of controls. A difference was found in platelet MAO between a mid-menstrual-cycle peak and a perimenstrual trough in these animals, while plasma MAO was unchanged. DBH showed an inverted cyclical variation to that demonstrated by platelet MAO. The ovariectomized females showed significant differences from the controls, confirming the effects of the ovarian sex steroid hormones on platelet MAO and plasma DBH. The variation in these peripheral enzymes may be reflective of changes in brain monoamine systems, which may play some role in the behavioral changes observed during the menstrual cycle in primates.

Animals↗