Showing papers on "Monoamine oxidase B published in 1999"
TL;DR: MAO A and B knock-out mice are valuable models for investigating the role of monoamines in psychoses and neurodegenerative and stress-related disorders and show increased reactivity to stress.
Abstract: Cloning of MAO (monoamine oxidase) A and B has demonstrated unequivocally that these enzymes are made up of different polypeptides, and our understanding of MAO structure, regulation, and function has been significantly advanced by studies using their cDNA. MAO A and B genes are located on the X-chromosome (Xp11.23) and comprise 15 exons with identical intron-exon organization, which suggests that they are derived from the same ancestral gene. MAO A and B knock-out mice exhibit distinct differences in neurotransmitter metabolism and behavior. MAO A knock-out mice have elevated brain levels of serotonin, norephinephrine, and dopamine and manifest aggressive behavior similar to human males with a deletion of MAO A. In contrast, MAO B knock-out mice do not exhibit aggression and only levels of phenylethylamine are increased. Mice lacking MAO B are resistant to the Parkinsongenic neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine. Both MAO A and B knock-out mice show increased reactivity to stress. These knock-out mice are valuable models for investigating the role of monoamines in psychoses and neurodegenerative and stress-related disorders.
1,119 citations
TL;DR: The neural cell most vulnerable to liver failure is the astrocyte, and altered expression of several key proteins and enzymes including monoamine oxidase B, glutamine synthetase, and the so-called peripheral-type benzodiazepine receptors are modified.
Abstract: Hepatic encephalopathy (HE) is a neuropsychiatric disorder that occurs in both acute and chronic liver failure. Although the precise pathophysiologic mechanisms responsible for HE are not completely understood, a deficit in neurotransmission rather than a primary deficit in cerebral energy metabolism appears to be involved. The neural cell most vulnerable to liver failure is the astrocyte. In acute liver failure, the astrocyte undergoes swelling resulting in increased intracranial pressure; in chronic liver failure, the astrocyte undergoes characteristic changes known as Alzheimer type II astrocytosis. In portal-systemic encephalopathy resulting from chronic liver failure, astrocytes manifest altered expression of several key proteins and enzymes including monoamine oxidase B, glutamine synthetase, and the so-called peripheral-type benzodiazepine receptors. In addition, expression of some neuronal proteins such as monoamine oxidase A and neuronal nitric oxide synthase are modified. In acute liver failure, expression of the astrocytic glutamate transporter GLT-1 is reduced, leading to increased extracellular concentrations of glutamate. Many of these changes have been attributed to a toxic effect of ammonia and/or manganese, two substances that are normally removed by the hepatobiliary route and that in liver failure accumulate in the brain. Manganese deposition in the globus pallidus in chronic liver failure results in signal hyperintensity on T1-weighted Magnetic Resonance Imaging and may be responsible for the extrapyramidal symptoms characteristic of portal-systemic encephalopathy. Other neurotransmitter systems implicated in the pathogenesis of hepatic encephalopathy include the serotonin system, where a synaptic deficit has been suggested, as well as the catecholaminergic and opioid systems. Further elucidation of the precise nature of these alterations could result in the design of novel pharmacotherapies for the prevention and treatment of hepatic encephalopathy.
276 citations
TL;DR: Two forms of monoamine oxidase have been identified on the basis of biochemical properties and, subsequently, by cloning the relevant genes, with higher affinity for 5-HT and NE and for the inhibitor clorgyline and the inhibitor deprenyl.
Abstract: Monoamine oxidase (MAO) catalyzes the oxidative deamination of a number of biogenic amines, including the key neurotransmitters serotonin (5-HT), norepinephrine (NE), and dopamine (DA) and the neuromodulator phenylethylamine (PEA). Two forms of MAO, designated “MAO A” and “MAO B,” have been identified on the basis of biochemical properties and, subsequently, by cloning the relevant genes. Of the two, MAO A exhibits a higher affinity for 5-HT and NE and for the inhibitor clorgyline (Johnston 1968), whereas MAO B has a higher affinity for PEA, benzylamine, and the inhibitor deprenyl (Knoll and Magyar 1972).
239 citations
TL;DR: Early administration of rasagiline or TVP1022 can reduce the immediate sequelae of brain injury and the mechanism of action does not appear to involve monoamine oxidase-B inhibition but could be mediated by the maintenance of cholinergic transmission in brain neurons.
142 citations
TL;DR: Results show that, in a normal cell environment, MAO can be a source of reactive oxygen species which could have a functional impact on cell functions and is proposed as a rapid and sensitive procedure to characterize the monoamine oxidase isoforms and their regulation in intact cells.
Abstract: Monoamine oxidase (MAO) A and B are mitochondrial enzymes involved in the oxidative deamination of endogenous and exogenous amines. At present, the production of H2O2 by MAO in intact cells and its functional consequences in cell function have not been extensively investigated. The aim of this study was to define whether, in intact cells, the metabolism of small amounts of MAO substrates was able to induce a detectable H2O2 production. Hydrogen peroxide production was measured using a luminol-amplified chemiluminescence assay in three cell types, rat mesangial cells, rabbit proximal tubule cells and Hep-G2 cells, containing different MAO A/MAO B ratios. Our results showed that cell incubation with tyramine (50 micromol/l) led to a time-dependent H2O2 generation which was fully inhibited by MAO A (clorgyline and RO 41-1049) and MAO B (selegiline and RO 19-6327) inhibitors. The extent of inhibition of H2O2 production by selective inhibitors was in agreement with the amount of MAO isoforms expressed in each cell type, as determined by Western blot analysis and enzyme assay. Altogether, these findings show that, in a normal cell environment, MAO can be a source of reactive oxygen species which could have a functional impact on cell functions. In addition, we propose the luminol-amplified chemiluminescence assay as a rapid and sensitive procedure to characterize the monoamine oxidase isoforms and their regulation in intact cells.
94 citations
TL;DR: The GT repeat in intron 2 of the MAOB gene is a powerful marker for PD in this large Australian cohort of people with PD.
Abstract: The monoamine oxidase B gene (MAOB; Xp1521-4) is a candidate gene for Parkinson's disease (PD) given its role in dopamine metabolism and its possible role in the activation of neurotoxins The association of MAOB polymorphisms (a [GT] repeat allelic variation in intron 2 and an A-G transition in intron 13) with Parkinson's disease (PD) was studied in an Australian cohort of 204 (male:female ratio 160) people with PD and 285 (male:female ratio 164) age- and gender-matched control subjects Genomic DNA was extracted from venous blood and 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 and a DNA fragment analyzer, while the G-A genotype was determined using 2% agarose gel electrophoresis The G-A polymorphism showed no association with PD (odds ratio [OR] = 080; p = 051; 95% confidence interval [CI] = 042-153) There was a significant difference in allele frequencies of the (GT) repeat allelic variation between patients and control subjects (chi2 = 2009; p or =188 base pairs in the intron 2 marker of the MAOB gene were significantly associated with PD (OR = 460; p<000005; 95% CI = 197-1077) The 186 base pair allele was also significantly associated with PD (OR = 185; p = 0048; 95% CI = 101-342) The GT repeat in intron 2 of the MAOB gene is a powerful marker for PD in this large Australian cohort
86 citations
Journal Article•
TL;DR: Results suggest that MAO A and B have distinctly different roles in monoamine metabolism, and these mice are valuable models for investigating the role of monoamines in psychoses and neurodegenerative and stress-related disorders.
Abstract: MAO (monoamine oxidase) A and B are key isoenzymes that degrade biogenic and dietary amines MAO A preferentially oxidizes serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE), whereas MAO B preferentially oxidizes phenylethylamine (PEA) Both forms can oxidize dopamine (DA) However, the substrate specificity overlap and the in vivo function of these two isoenzymes is not clear Recently, we have shown that MAO A and B knock-out (KO) mice exhibit distinct differences in neurotransmitter metabolism and behavior MAO A KO mice have elevated brain levels of 5-HT, NE and DA and manifest aggressive behavior similar to men with a deletion of MAO A In contrast, MAO B KO mice do not exhibit aggression and only levels of PEA are increased Both MAO A and B KO mice show increased reactivity to stress Taken together, these results suggest that MAO A and B have distinctly different roles in monoamine metabolism Further, these mice are valuable models for investigating the role of monoamines in psychoses and neurodegenerative and stress-related disorders
86 citations
TL;DR: In the authors' in vitro model, rasagiline a selective irreversible monoamine oxidase‐B (MAO‐B) inhibitor, protected nerve growth factor (NGF)‐differentiated PC12 cells from cell death under oxygen and glucose deprivation (OGD).
Abstract: In our in vitro model, rasagiline a selective irreversible monoamine oxidase-B (MAO-B) inhibitor, protected nerve growth factor (NGF)-differentiated PC12 cells from cell death under oxygen and glucose deprivation (OGD). The severity of the OGD insult, as expressed by cell death, was time-dependent. Exposure of the cells to OGD for 3 hr followed by 18 hr of reoxygenation caused about 30‐40% cell death. Under these conditions, the neuroprotective effect of rasagiline was dose-dependent: rasagiline reducing OGDinduced cell death by 68% and 80% at 100 nM and 1 µM, respectively. The neuroprotective effect of rasagiline was also observed when added after the OGD insult (55% reduction in cell death). Under rasagiline treatment, there was a lesser decrease in ATP content in cultures exposed to OGD compared with that in untreated cultures. OGD followed by reoxygenation resulted in a several fold increase in PGE2 release into the extracellular medium. Rasagiline (100 nM‐1 µM) markedly inhibited OGD-induced PGE2 release. Clorgyline, a monoamine oxidase-A (MAO-A) inhibitor, did not protect NGF-differentiated PC12 cells against OGD-induced cell death. As NGF-differentiated PC12 cells contain exclusively MAO type A, these data suggest that the neuroprotective effect of rasagiline under OGD conditions is independent of MAO inhibi
86 citations
TL;DR: A new series of molecules with structural features which determine the selectivity of MAO inhibition should provide a better understanding of the active site of monoamine oxidase and could be the starting point for the design of further selective, non‐amphetamine‐like MAO‐B inhibitors with therapeutic potential for the treatment of neurological disorders.
Abstract: 1. Previous studies with indolyl derivatives as monoamine oxidase (MAO) inhibitors have shown the relevance of the indole structure for recognition by the active site of this enzyme. We now report a new series of molecules with structural features which determine the selectivity of MAO inhibition. 2. A benzyloxy group attached at position 5 of the indole ring is critical for this selective behaviour. Amongst all of these benzyloxy-indolyl methylamines, N-(2-propynyl)-2-(5-benzyloxyindol)methylamine FA-73 was the most potent MAO-B 'suicide' inhibitor studied. 3. The Ki values for MAO-A and MAO-B were 800+/-60 and 0.75+/-0.15 nM, respectively. These data represent a selectivity value of 1066 for MAO-B, being 48 times more selective than L-deprenyl (Ki values of 376+/-0.032 and 16.8+/-0.1 nM for MAO A and MAO-B, respectively). The IC50 values for dopamine uptake in striatal synaptosomal fractions from rats were 150+/-8 microM for FA-73 and 68 +/- 10 microM for L-deprenyl whereas in human caudate tissue the IC50 values were 0.36+/-0.015 microM for FA-73 and 0.10+/-0.007 microM for L-deprenyl. Moreover, mouse brain MAO-B activity was 90% ex vivo inhibited by both compounds 1 h after 4 mg kg(-1) administration, MAO-A activity was not affected. 4. These novel molecules should provide a better understanding of the active site of monoamine oxidase and could be the starting point for the design of further selective, non-amphetamine-like MAO-B inhibitors with therapeutic potential for the treatment of neurological disorders.
78 citations
TL;DR: Preliminary results indicate that several of the MAOIs mentioned above are substrates and/or inhibitors of various cytochrome P450 (CYP) enzymes, which may result in pharmacokinetic interactions with some coadministered drugs.
Abstract: 1. The principal routes of metabolism of the following monoamine oxidase inhibitors (MAOIs) are described: phenelzine, tranylcypromine, pargyline, deprenyl, moclobemide, and brofaromine. 2. Acetylation of phenelzine appears to be a minor metabolic pathway. Phenelzine is a substrate as well as an inhibitor of MAO, and major identified metabolites of phenelzine include phenylacetic acid and p-hydroxyphenylacetic acid. Phenelzine also elevates brain GABA levels, and as yet unidentified metabolites of phenelzine may be responsible for this effect. β-Phenylethylamine is a metabolite of phenelzine, and there is indirect evidence that phenelzine may also be ring-hydroxylated and N-methylated. 3. Tranylcypromine is ring-hydroxylated and N-acetylated. There is considerable debate about whether or not it is metabolized to amphetamine, with most of studies in the literature indicating that this does not occur. 4. Pargyline and R(−)-deprenyl, both propargylamines, are N-demethylated and N-depropargylated to yield arylalkylamines (benzylamine, N-methylbenzylamine, and N-propargylbenzylamine in the case of pargyline and amphetamine, N-methylamphetamine and N-propargylamphetamine in the case of deprenyl). These metabolites may then undergo further metabolism, e.g., hydroxylation. 5. Moclobemide is biotransformed by C- and N-oxidation on the morpholine ring and by aromatic hydroxylation. An active metabolite of brofaromine is formed by O-demethylation. It has been proposed that another as yet unidentified active metabolite may also be formed in vivo.
6. Preliminary results indicate that several of the MAOIs mentioned above are substrates and/or inhibitors of various cytochrome P450 (CYP) enzymes, which may result in pharmacokinetic interactions with some coadministered drugs.
69 citations
TL;DR: The concomitant expression of monoamine oxidases and of a noradrenaline transporter in human white adipocytes supports the role of the adipose tissue in the clearance of peripheral catecholamines and suggests that adipocytes should be considered as a previously unknown potential target of drugs acting on monoamine oxidationases and norad Renaline transporters.
TL;DR: This study showed that chronic administration of a small dose of selegiline caused a marked increase in extracellular DA concentration in the striatum of primates, but not in the rodents.
TL;DR: Results indicate that monkey brain MAOs are more sensitive to antidepressant drugs than those in rodent brain.
TL;DR: It is found that none of the different repeat copies was preferentially transmitted from mothers to their children affected with bipolar disorder and a non-significant trend for patients with an ultra-rapid cycling form of illness to have a higher frequency of low-activity alleles is found.
Abstract: The genes encoding for the enzymes monoamine oxidase (MAO) A and B are good candidates to investigate bipolar affective disorder. A 30 bp repeat in the MAOA promoter was recently demonstrated to be polymorphic and to affect transcriptional activity. In a family-based association design we found that none of the different repeat copies was preferentially transmitted from mothers (n = 131) to their children affected with bipolar disorder (chi(2) = 2.75, 4 d.f., p = 0.6). Following on our previous finding of an excess of low-activity genotypes of catechol-O-methyltransferase in patients with a rapid cycling form of illness, we examined for a similar trend with MAOA alleles. In an extended sample we found a non-significant trend for patients with an ultra-rapid cycling form of illness (n = 29) to have a higher frequency of low-activity alleles compared with 92 bipolar patients with a non-rapid cycling course of illness (chi(2) = 2.37, 1 d.f., p = 0.13).
TL;DR: It is concluded that MAOB may normally regulate CBF distribution and its response to blood PEA, and PEA decreased CBF globally in KO mice with a lesser effect in WILD mice.
TL;DR: Results suggest an increased MAO-B expression in ALS and support the hypothesis that neuronal cell death in neurodegenerative diseases is triggered by astroglial reaction.
Journal Article•
Journal Article•
TL;DR: The results suggest that absence of the MAO-B gene or inhibition of the enzyme with L-deprenyl are not protective or detrimental in an animal model of acute cortical infarction.
TL;DR: The synthesis of N-(6-18F-fluorohexyl)-N-methylpropargylamine as a positron emission tomography (PET) radiotracer for monoamine oxidase B (MAO-B) and the binding of 18F-FHMP in the rat brain correlated with the general distribution of MAO- B and was displaced completely by preadministration of 10 microM (R)-deprenyl.
TL;DR: The MAOB gene is located on the X chromosome and polymorphisms within the MABO gene have been investigated for the pathogenesis of Parkinson's disease as mentioned in this paper, and inhibition of MABO with selegiline may influence the early course of PD.
Abstract: To the Editor:
Monoamine oxidase B (MAOB) has many characteristics that make it of interest in the pathogenesis of PD. It activates the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, catabolizes dopamine, and generates hydrogen peroxide. MAOB is expressed in the substantia nigra and inhibition of MAOB with selegiline may influence the early course of the disease. The MAOB gene is located on the X chromosome and PD tends to be more common in men. For these reasons, polymorphisms within the MAOB gene have been investigated for …
TL;DR: In this article, the effect of varying concentrations of estrogen on the levels of activity of monoamine oxidase A and -B in brain and in other tissues was examined, and it was found that high dose estrogen significantly decreased MAO-B activity and resulted in lesser or insignificant changes in liver (-30, +1%), kidney (-22, -11%), and uterus (-57, -35%) (p < 0.05).
Abstract: Estrogen replacement therapy is widely used in postmenopausal women. The current study examines the effect of varying concentrations of estrogen on the levels of activity of monoamine oxidase A and -B in brain and in other tissues. Adult female rats were ovariectomized and randomized to receive a subcutaneous, slow-release preparation of either placebo or one of three doses of 17-beta-estradiol (0.05, 0.5, or 5.0 mg/pellet, estimated serum levels of 20-25 pg/ml, 100-600 pg/ml, and 1-2 ng/ml, respectively). Animals were sacrificed at 3 weeks and MAO-A and -B activity was assessed in homogenates of heart, liver, lung, uterus, kidney, adrenal and small intestine using 5-hydroxytryptamine and phenylethylamine as substrates. Cortex, amygdala and hypothalamus were microdissected from frozen sections of the brain and were also assayed for MAO-A and -B activity. High dose estrogen (5 mg/pellet) significantly decreased MAO-B activity and resulted in lesser or insignificant changes in MAO-A activity, respectively in liver (-30%, +1%), kidney (-22%, -11%), and uterus (-57%, -35%) (p < 0.05). No significant changes in enzyme activity were observed in heart, adrenal, lung and small intestine. In brain, estrogen (5 mg/pellet) decreased MAO-A activity in the hypothalamus (-28%) and amygdala (-21%), with no significant change seen in MAO-B. Our results suggest that estrogen exerts a tissue-specific, differential regulation of MAO-A and -B activity.
TL;DR: Existing evidence still raises the possibility that MAO-B inhibition may confer a protective effect in PD, delaying the progression of the underlying pathology.
TL;DR: Na/K-adinosine triphosphatase (ATPase) and liver cytochrome P450 activities are greater in SAMP1 neurons than in SAMR1 neurons, which may reflect an adaptive tissue response to ROS accumulation.
Abstract: The comparative neurochemical characteristics of brain and liver membranes of senescence-accelerated mice, prone (SAMP1) and senescence-accelerated mice, resistant (SAMR1) strains were evaluated using males and females of several ages. Abnormal N-methyl-D-aspartic acid (NMDA) binding and monoamine oxidase b activity in SAMP brain membranes may promote increased accumulation of reactive oxygen species (ROS) in neurons. Na/K-adinosine triphosphatase (ATPase) and liver cytochrome P450 activities are greater in SAMP1 neurons than in SAMR1 neurons, which may reflect an adaptive tissue response to ROS accumulation.
TL;DR: Exposure to low concentrations of styrene alters MAO B activity in rat brain, suggesting that the observed changes in human platelets may reflect alterations in the nervous system.
Abstract: Previous studies have indicated that workers exposed to styrene present a decreased activity of platelet monoamine oxidase B (MAO B), suggesting that this biochemical assay may represent a biomarker for styrene-induced neurotoxicity. This study was undertaken to determine whether exposure to styrene would cause changes in MAO B activity in the target organ--the brain. Groups of rats were exposed to styrene by inhalation at concentrations of 300 ppm for 4 wk or 50 ppm for 13 wk. Both treatments caused significant decreases of MAO B activity in several brain areas, while MAO A activity was not affected. Decreases in MAO B activity were also found in brainstem of rats given styrene (400 mg/kg) or styrene oxide (100 mg/kg) by i.p. injection for 2 wk. Styrene, styrene oxide, and other styrene metabolites (mandelic acid, phenylglyoxylic acid, and styrene glycol) had no direct inhibitory effect on brain MAO B activity when tested in vitro. These results indicate that exposure to low concentrations of styrene alters MAO B activity in rat brain, suggesting that the observed changes in human platelets may reflect alterations in the nervous system.
01 Jan 1999
TL;DR: Monoamine oxidase catalyzes the oxidative deamination of a number of biogenic amines, including the key neurotransmitters serotonin, norepinephrine, and dopamine and the neuromodulator phenylethylamine.
Abstract: Monoamine oxidase (MAO) catalyzes the oxidative deamination of a number of biogenic amines, including the key neurotransmitters serotonin (5-HT), norepinephrine (NE), and dopamine (DA) and the neuromodulator phenylethylamine (PEA). Two forms of MAO, designated “MAO A” and “MAO B,” have been identified on the basis of biochemical properties and, subsequently, by cloning the relevant genes. Of the two, MAO A exhibits a higher affinity for 5-HT and NE and for the inhibitor clorgyline (Johnston 1968), whereas MAO B has a higher affinity for PEA, benzylamine, and the inhibitor deprenyl (Knoll and Magyar 1972). DA is a substrate for both MAO A and MAO B. Although most
TL;DR: Structure-activity relationships were performed on a new series of thiazole derivatives which selectively inactivate monoamine oxidase-B, purified from mitochondrial beef liver, suggesting the formation of a stable adduct between the tertiary amine function, linked to the thiazolyl derivatives and the active site of the enzyme.
Abstract: Structure-activity relationships were performed on a new series of thiazole derivatives which selectively inactivate monoamine oxidase-B (MAO-B), purified from mitochondrial beef liver. All of the synthesized and tested compounds showed non-competitive inhibition, suggesting the formation of a stable adduct between the tertiary amine function, linked to the thiazolyl derivdtives and the active site of the enzyme. The mechanism of MAO-B inhibition is discussed in terms of the Ionization Potential of the amine nitrogen atom and the conformational flexibility of the inhibitors.
Journal Article•
TL;DR: The difference in the ratio of the formed metabolites suggests the existence of preferred metabolic pathways for the enantiomers of deprenyl, and its use in the therapy of Parkinson's disease is investigated.
Abstract: The optical isomers of deprenyl have different pharmacological activities and potency. Selegiline, an (-)-isomer, is the more potent monoamine oxidase B enzyme inhibitor, and this substance is used in the therapy of Parkinson's disease. The neuroprotective and neuronal rescue effects of deprenyl, as well as the psychostimulant action of its metabolites, methamphetamine and amphetamine are also different for the enantiomers. In this study the biotransformation of deprenyl enantiomers was compared. Stereoselective dealkylation of both optical isomers was found as major metabolic alteration. The difference in the ratio of the formed metabolites suggests the existence of preferred metabolic pathways for the enantiomers.