Showing papers on "Monoamine oxidase B published in 2000"

5-hydroxytryptamine and the pulmonary circulation: receptors, transporters and relevance to pulmonary arterial hypertension

Abstract: Circulating 5-hydroxytryptamine (5-HT) is produced mainly in the enterochromaffin cells of the intestine 5-HT is also, however, locally released from pulmonary neuroendocrine cells and neuroepithelial bodies distributed throughout the airways Secretion of large amounts of 5-HT from these cells occurs in response to airway hypoxia and increased local 5-HT may contribute to secondary pulmonary arterial hypertension [PAH] (Johnson & Georgieff, 1989) Normally, plasma levels of free 5-HT are extremely low as circulating 5-HT is stored within the platelets Human blood platelets contain a relatively specific uptake mechanism for 5-HT (the 5-HT transporter [5-HTT]) at the plasma membrane, intracellular storage organelles (dense bodies) and a metabolizing enzyme (monoamine oxidase B) The ‘Serotonin hypothesis of PAH' was developed in the 1960's after an outbreak of PAH was observed in patients taking aminorex, a diet pill that increases 5-HT availability by inducing platelet release of 5-HT, inhibiting its reuptake and inhibiting monoamine oxidase activity Since then there has been increasing interest in the role of 5-HT in the development of PAH Here we review pharmacological evidence that suggests changes in 5-HT availability, 5-HT-induced vasoconstriction, 5-HT-induced mitogenesis and 5-HT transporter activity are associated with the development of PAH

Variability and validity of polymorphism association studies in Parkinson's disease.

Abstract: Background: In recent years, interest in gene–environment interactions has spurred a great number of association studies on polymorphism of different genes. Objective: To review case-control studies of genetic polymorphisms in PD, and perform meta-analysis of individual gene polymorphism. Methods: The authors searched the Medline database (PubMed) for publications (English language) from January 1966 to November 1999 for association studies in PD. The key words used were “PD” and “polymorphism.” The authors supplemented the search with relevant references quoted in these published articles. Those with four or more independent studies of a specific gene polymorphism were subjected to meta-analysis, with the exception of cytochrome-P450 enzyme polymorphisms, for which meta-analyses results were already available in the literature. Results: The authors identified 84 studies on 14 genes, including dopamine receptors ( DRD2 and DRD4 ), dopamine transporter ( DAT ), monoamine oxidase ( MAOA and MAOB ), catechol-O-methyltransferase ( COMT ), N-acetyltransferase 2 ( NAT2 ), APOE , glutathione transferase ( GSTT1 , GSTM1 , GSTP1, and GSTZ1 ), and mitochondrial genes ( tRNA Glu and ND2 ). Four polymorphisms showed significant association with PD: slow acetylator genotypes of NAT2 (PD:control OR = 1.36), allele >188bp of the MAOB (GT) n polymorphism (OR = 2.58), the deletion allele of GSTT1 (OR = 1.34), and A4336G of tRNA Glu (OR = 3.0). No significant differences were found for the other genes. Conclusion: Significant associations with PD were found in polymorphisms of NAT2, MAOB, GSTT1, and tRNA Glu . Although significant association does not imply a causal relationship between the presence of the polymorphisms and PD pathogenesis, their pathophysiologic significance should be studied further.

Pathological gambling and DNA polymorphic markers at MAO-A and MAO-B genes.

Abstract: This study was conducted to detect a possible association of MAOA and/or MAOB genes with pathological gambling (PG). DNA polymorphisms in MAOA and MAOB genes were screened by molecular analysis in 68 individuals (47 males and 21 females) meeting ICD-10 and DSM-IV criteria for pathological gambling and 68 healthy comparison controls matched for age and sex. There were no significant differences between pathological gamblers and healthy volunteers in overall allele distribution at the MAOA gene polymorphism. However there was a significant association between allele distribution and the subgroup of severe male gamblers (n = 31) compared to the males in the group of healthy volunteers (chi2 = 5246; df = 1; P < 0.05 [Bonferroni corrected]). No association was found between the MAOB polymorphic marker and PG. Allele variants at the MAOA, but not the MAOB gene may be a genetic liability factor in PG, at least in severe male gamblers. Molecular Psychiatry(2000) 5, 105-109.

Comparative effects of melatonin, L-deprenyl, Trolox and ascorbate in the suppression of hydroxyl radical formation during dopamine autoxidation in vitro.

Abstract: Degeneration of nigrostriatal dopaminergic neurons is the major pathogenic substrate of Parkinson's disease (PD). Inhibitors of monoamine oxidase B (MAO-B) have been used in the treatment of PD and at least one of them, i.e., deprenyl, also displays antioxidant activity. Dopamine (DA) autoxidation produces reactive oxygen species implicated in the loss of dopaminergic neurons in the nigrostriatal pathway. In this study we compared the effects of melatonin with those of deprenyl and vitamins E and C in preventing the hydroxyl radical (8OH) generation during DA oxidation. The rate of production of 2,3-dihydroxybenzoate (2,3-DHBA) in the presence of salicylate, an *OH scavenger, was used to detect the in vitro generation of *OH during iron-catalyzed oxidation of DA. The results showed a dose-dependent effect of melatonin, deprenyl and vitamin E in counteracting DA autoxidation, whereas vitamin C had no effect. Comparative analyses between the effect of these antioxidants showed that the protective effect of melatonin against DA autoxidation was significantly higher than that of the other compounds tested. Also, when melatonin plus deprenyl were added to the incubation medium, a potentiation of the antioxidant effect was found. These findings suggest that antioxidants may be useful in brain protection against toxicity of reactive oxygen species produced during DA oxidation, and melatonin, alone or in combination with deprenyl, may be an important component of the brain's antioxidant defenses to protect it from dopaminergic neurodegeneration.

Platelet monoamine oxidase activity is related to MAOB intron 13 genotype.

Abstract: Monoamine oxidases (MAO) play a critical role in the degradation of endogenous and exogenous amines throughout the body. There are two distinct MAO isoforms, MAO-A and MAO-B, which both are encoded in genes on the X chromosome. Alterations in MAO-B activity have previously been connected with several neurological disorders. Platelet MAO (trbc-MAO) is exclusively of the B-type and the catalytic activity of this enzyme is under strong, yet unknown, genetic control. Specific trbc-MAO activity has been reported to be increased in certain neurodegenerative diseases and to correlate with personality traits such as sensation seeking and impulsiveness. In the present study, we investigated if trbc-MAO activity is associated with genotype at a variable region (A/G dimorphism) in intron 13 of the human gene encoding MAO-B. The MAOB intron 13 allele status and levels of trbc-MAO were determined for 55 Caucasian non-smoking males. Individuals with the "A-allele" displayed significantly lower enzyme activity than individuals with the "G-allele", i.e. 11.4 ± 0.6 nmol/1010 platelets/min compared with 13.5 ± 0.6 (mean ± SEM, p = 0.019). The present results suggest that the MAOB genotype may be involved in determining trbc-MAO activity.

Use of monoamine oxidase inhibitors for the manufacture of drugs intended for the treatment of obesity

Abstract: The present invention relates to the use of reversible selective inhibitors of monoamine oxidase A (MAO-A), reversible selective inhibitors of monoamine oxidase B (MAO-B) or reversible mixed inhibitors of MAO-A and MAO-B in the manufacture of drugs intended for the treatment of obesity.

Association analysis between mood disorder and monoamine oxidase gene.

Abstract: To ascertain whether mood disorders, including bipolar and unipolar, are genetically associated with the monoamine oxidase A (MAOA) or monoamine oxidase B (MAOB) gene in the Chinese population, 132 cases of mood disorder and 88 normal controls were genotyped for the MAOA(CA)n, MAOB(GT)n, and MAOB(TG)n loci by the method of amplification fragment length polymorphism. Among 132 cases with mood disorder, eight alleles (size: 112–126 bp) of locus MAOA(CA)n, 12 alleles (size: 168–198 bp) of locus MAOB(GT)n, and nine alleles (size: 195–213 bp) of locus MAOB(TG)n were observed. Comparison of the allele frequency of the three loci showed no difference between mood disorder cases and normal controls on average. When each group was stratified into several subgroups, significant differences were found. On the MAOA(CA)n locus, the frequency of 116 bp allele was higher in the female bipolar disorder cases (0.2581) compared with that in the female unipolar disorder patients (0.1154) (Z=2.15, p<0.05). On the MAOB(GT)n locus, the frequency of 180 bp allele was higher in bipolar disorder patients (0.1579) than that in normal controls (0.0678) (Z=2.05, p<0.05). The frequency of this allele was even higher in female bipolar disorder patients (0.1719) than that in female normal controls (0.0541). On the MAOB(TG)n locus, the frequency of 205 bp allele was higher in female bipolar disorder patients (0.6406) than that in female normal controls (0.4375) (Z=2.17, p<0.05). For the unipolar disorder patients, the frequency of this allele was higher in female cases (0.5222) than that in male cases (0.1818) (Z=3.49, p<0.05). As for association studies, significant association between bipolar disorder and MAOB gene was detected. For the 180 bp allele of MAOB(GT)n, the relative risk (RR) of biploar versus normal control was 2.58 (p<0.05), and the RR of female bipolar disorder versus female normal control was 3.63 (p<0.05). For the 205 bp allele of MAOB(TG)n, the RR of female bipolar disorder versus female normal control was 2.29 (p<0.05). Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:12–14, 2000. © 2000 Wiley-Liss, Inc.

Structure-activity relations in the oxidation of phenethylamine analogues by recombinant human liver monoamine oxidase A.

Abstract: The interaction of recombinant human liver monoamine oxidase A (MAO A) with a series of phenethylamine substrate analogues has been investigated by steady-state and stopped-flow kinetic techniques. Substrate analogues with para substituents exhibit large deuterium kinetic isotope effect on k(cat), on k(cat)/K(m), and on the limiting rate of enzyme reduction in reductive half-reaction experiments. These kinetic isotope effect values range from 5 to 10 with the exception of tyramine, which exhibited smaller steady-state isotope effects (2.3-3.5) than that observed on the rate of flavin reduction (6.9). The stopped-flow data show that imine release from the reduced enzyme is slower than the rate of catalytic turnover. Phenethylamine oxidation by MAO A can be described as the C-H bond cleavage step being rate limiting in catalysis and with oxygen reacting with the reduced enzyme-imine complex. In the case of tyramine, the product release from the oxidized enzyme-imine complex contributes to the rate limitation in catalysis. The binding affinities of a series of para-substituted phenethylamine analogues to MAO A show an increase in affinity of the deprotonated amine with increasing van der Waals volume of the substituent. The limiting rate of enzyme reduction decreases with increasing van der Waals volume of the substituent in a linear manner with no observable electronic contribution as observed previously with benzylamine reduction of MAO A [Miller, J. R., and Edmondson, D. E. (1999) Biochemistry 38, 13670-13683]. Examination of side chain analogues of phenethylamine show 3-phenylpropylamine to be oxidized 2.5-fold more slowly and bound 75-fold more tightly than phenethylamine. 4-Phenylbutylamine is not a substrate for MAO A but is a good competitive inhibitor with a K(i) value of 31 +/- 5 microM. Analysis of the effect of alkyl side chain alterations on binding affinities of a series of arylalkylamine analogues taken from this study and from the literature show a linear correlation with the Taft steric value (E(s)) of the side chain. These results suggest that the binding site for the aryl ring is identical for phenethylamine and for benzylamine analogues and that steric interactions of the alkyl side chain with the enzyme strongly contribute to the binding affinities of a series of reversible inhibitors of MAO A.

CGP 3466 protects dopaminergic neurons in lesion models of Parkinson's disease

Abstract: The propargylamine derivative CGP 3466 (dibenzo[b,f]oxepin-10-ylmethyl-methyl-prop-2-ynyl-amine) has previously been found to exhibit neurorescuing and antiapoptotic properties in several in vitro and in vivo paradigms After showing that this compound does not inhibit monoamine oxidase B and only marginally inhibits monoamine oxidase A at concentrations or doses far above those relevant for its reported neuroprotective effects, we investigated it in models considered relevant for Parkinson's disease CGP 3466 or its hydrogen maleate salt, CGP 3466B, at concentrations between 10–11 M and 10–7 M, protected rat embryonic mesencephalic dopaminergic neurons in free-floating or dispersed cell culture from death inflicted by treatment with 1-methyl-4-phenyl pyridinium ion (MPP+) as measured by different readouts such as dopamine uptake, tyrosine hydroxylase activity, and counts of tyrosine hydroxylase-positive cells Treatment of mice lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 2×30 mg/kg sc at a 72-h interval) with CGP 3466 (01 mg/kg sc) or CGP 3466B (0014 mg/kg and 014 mg/kg po) bid for 18 days partially prevented the loss of tyrosine hydroxylase-positive cells in the substantia nigra; a lower dose of CGP 3466B (00014 mg/kg po) showed a marginal effect, whereas a high dose, ie 14 mg/kg po, was ineffective, suggesting a bell-shaped dose-response relationship which has also been observed in other paradigms

The neuronal survival effects of rasagiline and deprenyl on fetal human and rat ventral mesencephalic neurones in culture.

Abstract: The neuronal survival properties of rasagiline (R(+)-N-propargyl-1-aminoindane mesylate or TVP-1012), a novel monoamine oxidase B inhibitor, have been investigated using neuronal cell cultures from fetal rat and human ventral mesencephalon. The ability of rasagiline to reduce the rate of neuronal cell loss in vitro was tested using primary neuronal cell lines and immunohistochemistry to quantify the reduction in cell death. Direct comparison was made with deprenyl, a widely used and long established monoamine oxidase B inhibitor. Rasagiline was shown to act 15-20% more effectively as a neuronal survival agent than deprenyl, increasing both the survival of the total number of neurones and selectively increasing the survival of dopaminergic neurones with no statistically significant increase in survival of GABAergic neurones.

The monoamine oxidase B gene GT repeat polymorphism and Parkinson's disease in a Chinese population.

Abstract: Monoamine oxidase B (MAOB) metabolises dopamine and activates neurotoxins known to induce parkinsonism in humans and primates. Therefore the MAOB gene (MAOB; Xp15.21–4) is a candidate gene for Parkinson’s disease (PD). Longer length dinucleotide repeat sequences in a highly polymorphic GT repeat region of intron 2 of this gene showed an association with PD in an Australian cohort. We repeated this allele-association study in a population of 176 Chinese PD patients ¶(90 men, 86 women) and 203 age-matched controls (99 men, 104 women). Genomic DNA was extracted from venous blood and the polymerase chain reaction was used to amplify the appropriate regions of the MAOB gene. The length of each (GT) repeat sequence was determined by 5% polyacrylamide denaturing gel electrophoresis. There was no significant difference in allele frequencies of the (GT) repeat allelic variation between patients and controls (χ2 = 2.48; df = 5, P < 0.75). Therefore the longer length GT repeat alleles are not associated with PD in this Chinese population. Possible reasons for the discrepancy between Chinese and Australian populations include a different interaction between this genetic factor and environmental factors in the two populations and the possibility that the long length GT repeat alleles may represent a marker mutation, genetically linked to another susceptibility allele in whites but not in Chinese. Methodological differences in the ascertainment of cases and controls in this cohort could also explain the observed differences. Further study is required to determine whether the longer length GT repeat alleles are true susceptibility alleles in PD.

Imidazoline-Binding Domains on Monoamine Oxidase B and Subpopulations of Enzyme

Abstract: A series of phenoxy-substituted methylimidazoline derivatives were synthesized and used to define the ligand recognition properties of the imidazoline-binding domain (IBD) on monoamine oxidase (MAO)-B and its role in substrate processing. The rank order of potency for selected compounds in competitive binding studies with the imidazoline [(3)H]idazoxan was different from that in enzyme activity assays, suggesting that the IBD and the site involved in enzyme inhibition are distinct. IC(50) values for inhibition of MAO-B activity by imidazoline/guanidinium ligands were one to two orders of magnitude greater than ligand concentrations that probably saturate the IBD, but were equal to the K(d) values of these ligands in competitive binding assays with the reversible MAO-B inhibitor [(3)H]Ro 19-6327. In addition, the degree of enzyme inhibition by these ligands was similar in platelet and liver, tissues exhibiting 10-fold differences in the amount of the IBD-accessible enzyme subpopulation. These data suggested that the inhibitory effect of these compounds on MAO-B activity involved a secondary interaction with the enzyme domain recognizing the inhibitor Ro 19-6327 and does not involve interaction with the IBD. Subsequent radioligand-binding studies indicated that human liver MAO-B actually existed as two distinct populations that differed in the accessibility of their IBD. The relatively small amounts of MAO-B possessing an accessible IBD ( approximately 5% in human liver) precludes determination of the functional consequences of ligand binding to the IBD. This subpopulation of MAO-B may be selectively regulated or generated in different individuals or tissues and targeted by pharmacologically active compounds in a cell type-specific manner.

The novel type B MAO inhibitor PF9601N enhances the duration of L-DOPA-induced contralateral turning in 6-hydroxydopamine lesioned rats.

Abstract: The present study examined the effect of the highly potent and selective MAO B inhibitor PF9601N on L-DOPA-induced rotational behavior in unilateral nigrostriatal 6-hydroxydopamine lesioned rats. Three doses of PF9601N (20, 40 and 60mg/kg) were administered 30 min before an injection of L-DOPA (25mg/kg), and both contralateral and ipsilateral rotational behavior was measured. In addition, we also studied the effect produced by another MAO B inhibitor, deprenyl (20mg/kg), the MAO A inhibitor, clorgyline (20mg/kg), and the dopamine reuptake inhibitor, GBR2909 (7.5 mg/kg) on L-DOPA-induced rotational behavior. The results showed that PF9601N plus L-DOPA significantly enhanced the duration of contralateral rotational behavior with respect to L-DOPA plus vehicle in a dose-related manner. At the dose of 40 and 60mg/kg, PF9601N produced significantly more overall contralateral turning than L-DOPA plus vehicle, and at the dose of 60mg/kg, PF9601N produced significantly more turning behavior than L-DOPA plus deprenyl. These results suggest that PF9601N may be used as a novel tool in the treatment of Parkinson's disease.

Amyloid-beta 25-35 peptide induces expression of monoamine oxidase B in cultured rat astrocytes

Abstract: "AIM: To investigate the effects of amyloid-beta 25-35 peptide (A beta 25-35) on monoamine oxidase (MAO) expression and activity in primary cultured rat astrocytes. METHODS: Immunocytochemistry was used to observe the morphological changes in astrocytes. Fluorescence spectrophotometry was used to measure the activity of MAO in astrocytes. The expression of MAO in astrocytes was assayed by RT-PCR. RESULTS: A beta 25-35 induced a reactive morphological change in cultured rat astrocytes which was accompanied by increased immunoreactivities for glial fibrillary acidic protein. Treatment with A beta 25-35 resulted in an elevation of MAO activity in a dose- and time-dependent manner. A beta 25-35-induced enhancement of MAO activity was of type B (MAO-B). The increase in MAO-B activity appeared to be due to an increase in the number of enzyme molecules since kinetic analysis demonstrated a 1.5 fold increase in Vmax with no change in Km. Treatment with A beta 25-35 also led to a substantial increase in MAO-B mRNA level in the astrocytes. CONCLUSION: A beta 25-35 is able to selectively induce MAO-B expression in rat astrocytes and that the upregulation of MAO-B in A beta 25-35-stimulated astrocytes may play an important role in the pathogenesis of Alzheimer's disease."

Molecular Biology of Monoamine Oxidase A and B: Their Role in the Degradation of Serotonin

Abstract: Monoamine oxidase [MAO; amine:oxygen oxidoreductase (deaminating) (flavin-containing), EC 1.4.3.4] catalyzes the oxidative deamination of various biogenic amines in the CNS and peripheral tissues. MAO is integral to the outer mitochondria1 membrane (Greenwalt and Schnaitman 1970 ) and is classified as type A and type B (Johnston 1968; Squires 1968). MAOA preferentially oxidizes serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE) and is selectively inhibited by low concentrations of the irreversible inhibitor clorgyline (Johnston 1968) and by the reversible inhibitors Ro41-1049, brofaromine and moclobemide (Da Prada et al. 1990). MAOB has a high affinity for β-phenylethylamine (PEA) and is selectively inhibited by deprenyl (Knoll and Magyar 1972), Ro19-6327 (Da Prada et al. 1990) and MDL-72145 (Bey et al. 1984). Tyramine (TA) and dopamine (DA) are common substrates for both enzymes.

Methods and compositions for treating reward deficiency syndrome

Abstract: The present invention relates to methods and compositions for treating Reward Deficiency Syndrome (RDS) using a therapeutically effective amount of a monoamine oxidase B inhibitor. The present invention also relates to compositions for treating RDS comprising selegiline in very low dose.