Showing papers on "Monoamine oxidase B published in 1997"
TL;DR: It is shown that targetted inactivation of MAOB in mice increases levels of PEA but not those of 5-HT, NE and DA, demonstrating a primary role forMAOB in the metabolism of P EA, which has been implicated in modulating mood and affect.
Abstract: MAOA and MAOB are key iso-enzymes that degrade biogenic and dietary amines1–5. MAOA preferentially oxidizes serotonin (5-hydroxytryptamine, or 5-HT) and nore-pinephrine (NE), whereas MAOB preferentially oxidizes β-phenylethylamine (PEA). Both forms can oxidize dopamine (DA). A mutation in MAOA results in a clinical phenotype characterized by borderline mental retardation and impaired impulse control6,7. X-chromosomal deletions which include MAOB were found in patients suffering from atypical Norrie's disease8,9, which is characterized by blindness and impaired hearing. Reduced MAOB activity has been found in type-ll alcoholism and in cigarette smokers10,11. Because most alcoholics smoke, the effects of alcohol on MAOB activity remain to be determined. Here we show that targetted inactivation of MAOB in mice increases levels of PEA but not those of 5-HT, NE and DA, demonstrating a primary role for MAOB in the metabolism of PEA. PEA has been implicated in modulating mood and affect12,13. Indeed, MAOB-deficient mice showed an increased reactivity to stress. In addition, mutant mice were resistant to the neurodegenerative effects of MPTP, a toxin that induces a condition reminiscent of Parkinson's disease.
250 citations
TL;DR: The age-related increase in brain MAO B in living subjects is consistent with postmortem reports, but the degree of increase is generally lower.
227 citations
TL;DR: It is demonstrated that MPTP N-demethylation, a detoxification pathway, is catalysed by cytochrome P450 CYP2D6 and up to 40% of the hepatic metabolism is mediated by this enzyme, indicating that 2D6-mediated detoxification will occur in target cells.
Abstract: 1. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a thermal breakdown product of synthetic 'street' heroin, is known to cause Parkinson's Disease-like symptoms in man. 2. The mechanism of action of this neurotoxin is thought to involve activation by the monoamine oxidase B system and subsequent toxicity by inhibition of neuronal mitochondrial respiration. The manifestation of toxicity will be a balance between the rate of activation of this compound versus its rate of inactivation through metabolism by enzymes such as the cytochrome P450-dependent monooxygenases. 3. In this report we demonstrate that MPTP N-demethylation, a detoxification pathway, is catalysed by cytochrome P450 CYP2D6 and up to 40% of the hepatic metabolism is mediated by this enzyme. 4. Perhaps more importantly we also demonstrate by in situ hybridization that CYP2D6 is localized in the pigmented neurons of the substantia nigra indicating that 2D6-mediated detoxification will occur in target cells. 5. These data present evidence that CYP2D6 will be a factor in susceptibility to MPTP neuronal toxicity and provide a biochemical rationale for the genetic observations linking a polymorphism at the CYP2D6 locus with susceptibility to Parkinson's.
108 citations
TL;DR: The results reported in the present communication raise the possibility that the inhibition of MAO-B by 7-NI also may contribute to the observed neuroprotection.
Abstract: The neurodegenerative properties of the parkinsonian inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are thought to result from inhibition of complex I of the mitochondrial respiratory chain by the monoamine oxidase-B (MAO-B) generated 1-methyl-4-phenylpyridinium metabolite MPP+. Treatment with 7-nitroindazole (7-NI) protects rodents and baboons against MPTP's neurotoxicity, presumably as a consequence of its inhibition of neuronal nitric oxide synthase (nNOS). The results reported in the present communication, while not in conflict with the proposed role of nNOS, raise the possibility that the inhibition of MAO-B by 7-NI also may contribute to the observed neuroprotection.
103 citations
TL;DR: In situ hybridization to visualize MAOA and MAOB mRNAs in the rat brain by using specific cDNA and oligonucleotide probes demonstrates that MAOA mRNA synthesis is wide spread in many catecholaminergic and serotonergic cell groups, whereas MAOB RNA synthesis is far more discrete and limited.
Abstract: Monoamine oxidases A and B (MAOA and MAOB) are the major catabolic isoenzymes of catecholamines and serotonin in the mammalian brain. Although the distribution of the monoamine oxidase protein has been mapped by ligand binding and immunohistochemistry, the sites of MAOA and MAOB synthesis have not been precisely determined. In this study, we used in situ hybridization to visualize MAOA and MAOB mRNA in the rat brain by using specific cDNA and oligonucleotide probes. MAOA mRNA was localized in major monoaminergic cell groups, such as the dorsal vagal complex, the C1/A1 groups, the locus ceruleus, the raphe nuclei, the substantia nigra, and the ventral tegmental area. MAOA mRNA was also found in forebrain structures, such as the cortex, the hippocampus, the thalamus, and the hypothalamus. In contrast to the distribution of MAOA mRNA, high levels of MAOB mRNA were present in only three brain regions: the area postrema, the subfornical organ, and the dorsal raphe. The in situ visualization of MAO mRNA demonstrates that MAOA mRNA synthesis is wide spread in many catecholaminergic and serotonergic cell groups, whereas MAOB mRNA synthesis is far more discrete and limited. The different expression patterns of MAOA and MAOB suggests that may also have different physiological functions.
101 citations
TL;DR: Results suggest that DRD2, but not DAT, MAOA and MAOB, might be a genetic determinant of PD in the population tested.
Abstract: We assessed the role of four candidate genes encoding proteins involved in dopaminergic transmission, the dopamine transporter (DAT), the dopamine receptor D2 (DRDB), and the main catabolic enzymes of dopamine, monoamine oxidase A (MAOA) and B (MAOB), through allelic association studies in a population of familial and sporadic Parkinson9s disease (PD). Using intronic polymorphisms of the four candidate genes, we studied the allelic distributions of the polymorphic markers in 18 affected members, one patient was chosen randomly from each PD family; 60 sporadic PD and 60 healthy unrelated control subjects were matched for sex and for country of origin. All subjects were white. To complete the study of the DRD2, we subsequently tested 40 additional sporadic PD and 40 control patients, who were recruited using a similar procedure. For DAT, MAOA, MAOB polymorphisms, similar allelic frequencies were present in familial, sporadic PD and control patients. In contrast, at the DRD2 locus, the overall allelic distribution was significantly different in the sporadic PD ( p p p
86 citations
TL;DR: The results show that the actions of dopamine and iron are essential in the induction of apoptosis and lipid peroxidation and suggest that iron is capable of increasing the cytotoxicity of dopamine merely by increasing its rate of oxidation and without intervention of the monoamine oxidase B enzyme.
Abstract: Recent studies have shown that Fez+ increases the oxidation of monoamines such as serotonin, dopamine and related toxins and that the formed oxidation products can undergo co-valent binding to free sulphydryl groups of proteins such as actin and "serotonin binding proteins" which are present in soluble brain extracts. Here we have tested the ability of ferrous iron to induce (3H)dopamine association to cytoplasmic proteins and we have established that a similar oxi- dation mechanism evidenced in vitro studies could be applied in cell culture. When PC12 cells were incubated with ferrous iron (ferrocene), the binding of (3H)dopamine to proteins was found to be two fold increased with respect to control. The iron is likely to accelerate the oxidation of dopamine to produce quinones which covalently bind to proteins and induce high-molecular protein aggregates. We evidenced that dopaminehron combination induced cell death in undifferentiated PC12 cells via an active cellular process evaluated in terms of morphological and biochemical changes indicative of apoptosis. We also demonstrated induction of lipid peroxidation when dopamine and ferrocene were present in high concentrations. Moreover, ascorbic acid diminished apoptosis but not the lipid peroxidation process. It might indicate that ferrocene and dopamine could produce oxidative stress of a different nature. These results show that the actions of dopamine and iron are essential in the induction of apoptosis and lipid peroxidation. However, there is no necessary causual link between lipid peroxidation and apoptosis. Our data also suggest that iron is capable of increasing the cytotox- icity of dopamine merely by increasing its rate of oxidation and without intervention of the monoamine oxidase B enzyme and, hence, both phenomenons may occur independently from each other in rat pheochromocytoma PC12. These obser- vations may have relevance to the understanding of the mechanism by which dopaminergic neurones are destroyed in some neurodegenerative disorders.
81 citations
TL;DR: A series of mutant enzymes in which amino acid residues that are conserved among various species but are different between the two forms of the enzyme were replaced with the corresponding amino acids of the counterpart and were engineered from the cDNAs of rat liver MAO A and B.
81 citations
Journal Article•
TL;DR: Possible implications of the effects of estrogens on MAO activity are discussed, and the regulation of MAO is multifactorial, and there is evidence that it involves estrogens.
Abstract: The enzyme monoamine oxidase (MAO) has generated considerable interest as a biological marker. The serendipitous discovery that iproniazid was a weak MAO inhibitor (MAOI) led to the development and widespread use of MAOIs as antidepressants in the early 1950s. The-discovery of the two isoenzymes of MAO has led to the development of selective MAOIs that may have a more favorable side-effect profile. The regulation of MAO is multifactorial, and there is evidence that it involves estrogens. Improvement in mood and cognition reported in women on estrogen replacement therapy may also involve changes in MAO activity. The literature in this regard is reviewed here, and possible implications of the effects of estrogens on MAO activity are discussed.
65 citations
TL;DR: The combination of MAO-A andMAO-B inhibition results in a strong increase of both dopamine, noradrenaline, and serotonin, which is the most frequent psychopathological finding in Parkinson’s disease.
Abstract: Monoamine oxidase (MAO) is the predominant enzyme implied in the catabolism of the monoamines dopamine, noradrenaline, and serotonin.1 Dopamine is a substrate for both isoforms of MAO: the extraneuronal MAO-B; and MAO-A which is found both extraneuronally and intraneuronally.2 Intraneuronal MAO-A is active for dopamine, noradrenaline, and serotonin, which have a paramount influence in the pathogenesis of depression. The combination of MAO-A and MAO-B inhibition results in a strong increase of both dopamine, noradrenaline, and serotonin. Depression is the most frequent psychopathological finding in Parkinson’s disease.
In this study we compared moclobemide monotherapy with combined therapy with moclobemide and selegeline, under tyramine restriction.
Ten patients with idiopathic Parkinson’s disease of two to 15 years in duration contributed to the study. The actions of moclobemide and selegeline were described in the informed consent. Inclusion criteria were Parkinson’s disease disability Hoehn and Yahr stages II-IV, major depression using DSM III.R criteria, mini mental state examination (MMSE) score of 21 or above, and self recorded “on-off” patient …
56 citations
TL;DR: Identification of an imidazoline binding domain on MAO-B provides a new opportunity for the potential pharmacological development of imdazoline/guanidinium compounds and also presents additional avenues for structure/function analysis of the monoamine oxidase enzymes.
Abstract: Monoamine oxidase B (MAO-B) was recently identified as a member of the family of imidazoline binding proteins. To localize the imidazoline binding domain on MAO-B, we labeled the domain with the imidazoline photoaffinity adduct [ 125 I]2-(3-azido-4-iodophenoxy)methylimidazoline in rat and human liver and visualized labeled peptides by autoradiography/sodium dodecyl sulfate-polyacrylamide gel electrophoresis after CNBr cleavage of the labeled protein. Based on species-specific fragmentation patterns and immunoprecipitation of labeled peptides, the imidazoline binding domain was localized to residues K149 to M222 of human MAO-B. The imidazoline binding domain is encompassed within a region that influences substrate processing but is distinct from primary sites of interaction for the enzyme inhibitors pargyline and lazabemide (Ro 19–6327). Radioligand binding assays and photoaffinity labeling also indicated that the various classes of compounds did not cross-compete at the different enzyme domains. Identification of an imidazoline binding domain on MAO-B provides a new opportunity for the potential pharmacological development of imidazoline/guanidinium compounds and also presents additional avenues for structure/function analysis of the monoamine oxidase enzymes.
TL;DR: The results did not support the involvement of the alleles at MAOA and MAOB in the etiology of mood disorder.
Abstract: We investigated a genetic association between mood disorders (bipolar and unipolar) and the alleles of monoamine oxidase (MAO) A and B (MAOA and MAOB). One hundred and twelve unrelated Japanese patients (60 bipolar, 52 unipolar) and 100 controls were genotyped for three markers of MAOA and for one marker of MAOB. No statistically significant difference in the distribution of the alleles existed between cases and controls. Therefore, our results did not support the involvement of the alleles at MAOA and MAOB in the etiology of mood disorder.
TL;DR: Long-term oral administration of deprenyl extended the functional life span of rats with respect to cognitive, but not motor, performance and did not cause changes in sensorimotor function or binding affinity.
TL;DR: The data suggest that, although MAO and I2BS may play a role in the development of Parkinson's disease, they are not altered in the chronic phase of this disease.
TL;DR: Dopaminergic indices were associated with ADHD symptom severity (Conners-ATRS) and noradrenergic indices with CPT performance and support a multisystem dysfunction underlying ADHD pathophysiology.
TL;DR: The results document the marked differences between nonhuman primates and rodents with respect to the relative activities and the effects of age on MAO A and B, and indicate that increased MAO is not an inevitable feature of aging.
TL;DR: Data obtained suggest that the anticonvulsant effect of isatin does not result from the inhibition of MAO A and the increase of monoamine level in the brain reported in few laboratories is apparently stipulated by a mechanism that does not involveMAO A inhibition.
TL;DR: This is the first report indicating that microglia contains COMT activity which may be increased in pathological conditions, and the elevation of COMT immunoreactivity co-localized to microglial cells, but not to astrocytes.
TL;DR: The data show the predominant expression of MAO-B in rabbit renal proximal tubule and its regulation by imidazoline ligands in intact cells, and enzyme assays showed that incubation of proximal Tubule cells with imidrazoline ligand leads to a complete, dose-dependent inhibition ofMAO activity.
Abstract: Previous studies have shown that a subpopulation of the catecholamine-degrading enzymes monoamine oxidase (MAO) A and B holds a previously unknown regulatory site, the I2-imidazoline binding site (I2BS). In the present work, we characterized the isoforms of monoamine oxidases expressed in the rabbit renal proximal tubule, defined their relationship with I2BS, and investigated the ability of I2BS ligands to inhibit enzyme activity in intact cells. Two findings indicate that MAO-B is the predominant isoform expressed in the renal proximal tubule cells: 1) Western blot performed with an anti–MAO-A/MAO-B polyclonal antiserum revealed a single 55-kDa band corresponding to MAO-B; 2) enzyme assays showed an elevated MAO-B activity ([14C]β-phenylethylamine oxidation:Vmax = 1.31 ± 0.41 nmol/min/mg protein), whereas MAO-A activity was only detectable ([14C]5-HT oxidation: Vmax = 80.3 ± 19 pmol/min/mg protein). Photoaffinity labeling with the I2BS ligand [125I]2-(3-azido-4-iodophenoxy)-methylimidazoline revealed a single 55-kDa band, which indicates that MAO-B of the renal proximal tubule cells holds the I2 imidazoline binding site. [3H]Idazoxan binding studies and enzyme assays showed that, in intact cells, I2BS ligands bind to and inhibit MAO-B. Indeed, the increase in the accessibility of intracellular compartment by cell permeabilization did not enhance [3H]idazoxan binding, which indicates that, in intact cells, intracellular I2BS are fully occupied by imidazoline ligands. In addition, enzyme assays showed that incubation of proximal tubule cells with imidazoline ligands leads to a complete, dose-dependent inhibition of MAO activity. These data show the predominant expression of MAO-B in rabbit renal proximal tubule and its regulation by imidazoline ligands in intact cells.
TL;DR: It is suggested that dopamine metabolism and subsequent ROS production may be key elements in MA‐induced neurite degeneration in dopaminergic neurons.
Abstract: In vivo administration of methamphetamine (MA) produces selective damage to dopaminergic nerve terminals, which is hypothesized to be due to release of dopamine from synaptic vesicles within the terminals, allowing the generation of reactive oxygen species (ROS) via dopamine metabolism. Hydrogen peroxide formed during this reaction can interact with free iron to form hydroxyl radicals, which can oxidize proteins, nucleic acids, and membrane lipids, leading to terminal degeneration. Elevation of activity of the dopamine-metabolizing enzyme monoamine oxidase (MAO) in nerve growth factor-treated PC12 cells resulted in a substantial rise in products of dopamine metabolism following MA treatment, including 3,4-dihydroxyphenylacetic acid and hydroperoxides, as well as an increase in lipid peroxidation and a decrease in neurite number and length compared with control cells. These latter effects could be reversed by treatment with the MAO-B specific inhibitor, deprenyl. These data suggest that dopamine metabolism and subsequent ROS production may be key elements in MA-induced neurite degeneration in dopaminergic neurons.
TL;DR: Allosteric regulation of the activity of MAO via the imidazoline binding domains may be of significance in various disease states associated with elevated enzyme expression or in which the enzyme is a therapeutic target.
TL;DR: The results may have implications for the use of central catechol-O-methyltransferase inhibitors added to routine levodopa therapy in parkinsonian patients.
TL;DR: Evidence is provided for a potential role of monoamine oxidase B inhibition in the therapeutic effects of Prozac by using the radioligand, N-(6-[18F]fluorohexyl)-N-methylpropargylamine, and binding affinity, -logIC50.
TL;DR: It is shown that L-deprenyl, a drug able to rescue neurons from potentially lethal damage, can potentiate FGF-2 induction by 8Br-cAMP in cultured astrocytes, suggesting that potentiation of neurotrophic factor expression may exert neuroprotection and therefore limit the progression of neuronal damage in several pathological situations.
Abstract: THE expression of fibroblast growth factor-2 (FGF-2, basic FGF) is up-regulated in astroglial cells by different stimuli, including glucocorticoid hormones and agents that cause an increase in cyclic AMP (cAMP) levels. In the present study we showed that L-deprenyl, a drug able to rescue neurons from potentially lethal damage, can potentiate FGF-2 induction by 8Br-cAMP in cultured astrocytes. This effect appears to be independent from its well known inhibitory activity on monoamine oxidase (MAO) type B. As astrocyte activation is an important step in response to neuronal injury, our data suggest that potentiation of neurotrophic factor expression may exert neuroprotection and therefore limit the progression of neuronal damage in several pathological situations.
TL;DR: The present data suggest that serotonin, a preferential substrate for MAOA, can be oxidized by MAOB in MAOA-deficient Tg8 mice, and the localization of MAOB-positive structures are not different between T g8 mutant and normal C3H line.
TL;DR: A significant positive correlation was found between monoamine oxidation activity and the severity of illness, which suggests that monoamine oxidase activity may be a state-dependent marker of neurodegeneration.
Abstract: Blood platelet monoamine oxidase activity, as well as other platelet enzyme activities, have been studied in several neuropsychiatric disorders in an attempt to identify biochemical markers of altered brain function. In this study, we determined both total and molecular monoamine oxidase activity in platelets derived from demented patients, which showed significantly greater enzyme activity than those of the controls. It therefore seems that the high degree of monoamine oxidase activity depends on the increased intrinsic activity of individual enzyme molecules. A significant positive correlation was found between monoamine oxidase activity and the severity of illness, which suggests that monoamine oxidase activity may be a state-dependent marker of neurodegeneration. These findings are discussed with reference to the central nervous system biochemical abnormalities of demented subjects: it may be that Alzheimer-type dementia involves some central biochemical changes that are reflected in certain peripheral tissues (e.g. platelets), or a systemic derangement that also affects the brain.
TL;DR: The results confirmed previous data regarding changes in MAO A activity in brainstem and medulla oblongata, but did not confirm the hypothesis that the increase in monamine turnover and metabolites in the brain would be the result of increased MAO activity.
Abstract: Rapid eye movement (REM) sleep deprivation increases monoaminergic (noradrenergic and serotonergic) turnover and their metabolites in whole brain of rats. This increase in metabolites may indicate increased activity of the enzymes responsible for the inactivation of monoamines. To test this hypothesis, we assayed the activity of monoamineoxidases (MAOs) A and B in hippocampus, hypothalamus, brainstem and its divisions pons and medulla oblongata in rats deprived of REM sleep for 96 h. REM sleep deprivation was carried out by the flower-pot technique. A control group remained in their home cages. MAO A was assayed by using [14C]-5-hydroxytryptamine as the substrate (50 microM final concentration) and MAO B by using [14C]-beta-phenylethylamine (2 microM final concentration). The enzymes were assayed in the mitochondrial fraction.The results obtained showed that a significant decrease in the activity of MAO A was obtained in the brainstem and an increase in medulla oblongata and no statistical differences in the activity of MAO B in brainstem, pons and medulla oblongata and MAO A in pons; there were also no differences in the activities of both MAO A and B in hippocampus and hypothalamus. Although our results confirmed previous data regarding changes in MAO A activity in brainstem and medulla oblongata, they did not confirm our hypothesis that the increase in monamine turnover and metabolites in the brain would be the result of increased MAO activity.
TL;DR: Three compounds synthesized and shown to be time-dependent, irreversible inactivators of monoamine oxidase B (MAO B) protected the enzyme from inactivation, but beta-mercaptoethanol does not, suggesting that these compounds are mechanism-based inactivator.
Abstract: Cubylcarbinylamine (1a), (4-cyclopropylcubyl)carbinylamine (1b), and (4-phenylcubyl)carbinylamine (1c) were synthesized and shown to be time-dependent, irreversible inactivators of monoamine oxidase B (MAO B). Substrate protects the enzyme from inactivation, but beta-mercaptoethanol does not, suggesting that these compounds are mechanism-based inactivators. All three compounds were also substrates for MAO B with partition ratios ranging from 152 to 536. The 4-substituted analogues were more potent inactivators than the unsubstituted analogue, indicating a benefit to 4-substitution in this class of inactivators.