Showing papers on "Monoamine oxidase B published in 2011"
TL;DR: There is considerable laboratory evidence that MAO-B inhibitors do exert some neuroprotective properties, at least in the Parkinson’s disease models currently available, however, these models have significant limitations and caution is required in assuming that such results may easily be extrapolated to clinical trials.
Abstract: Parkinson’s disease is a disorder characterized pathologically by progressive neurodegeneration of the dopaminergic cells of the nigrostriatal pathway. Although the resulting dopamine deficiency is the cause of the typical motor features of Parkinson’s disease (bradykinesia, rigidity, tremor), additional non-motor symptoms appear at various timepoints and are the result of non-dopamine nerve degeneration. Monoamine oxidase B (MAO-B) inhibitors are used in the symptomatic treatment of Parkinson’s disease as they increase synaptic dopamine by blocking its degradation. Two MAO-B inhibitors, selegiline and rasagiline, are currently licensed in Europe and North America for the symptomatic improvement of early Parkinson’s disease and to reduce off-time in patients with more advanced Parkinson’s disease and motor fluctuations related to levodopa. A third MAO-B inhibitor (safinamide), which also combines additional non-dopaminergic properties of potential benefit to Parkinson’s disease, is currently under development in phase III clinical trials as adjuvant therapy to either a dopamine agonist or levodopa. MAO-B inhibitors have also been studied extensively for possible neuroprotective or disease-modifying actions. There is considerable laboratory evidence that MAO-B inhibitors do exert some neuroprotective properties, at least in the Parkinson’s disease models currently available. However, these models have significant limitations and caution is required in assuming that such results may easily be extrapolated to clinical trials. Rasagiline 1 mg/day has been shown to provide improved motor control in terms of Unified Parkinson’s Disease Rating Scale (UPDRS) score at 18 months in those patients with early disease who began the drug 9 months before a second group. There are a number of possible explanations for this effect that may include a disease-modifying action; however, the US FDA recently declined an application for the licence of rasagiline to be extended to cover disease modification.
111 citations
TL;DR: Molecular modeling studies have been carried out to explain the selectivity of the most active homoisoflavonoids 1h and 1l, showing hMAO-B affinity better than the selective inhibitor selegiline.
Abstract: A series of homoisoflavonoids [(E)-3-benzylidenechroman-4-ones 1a−w, 3-benzyl-4H-chromen-4-ones 2a−g, and 3-benzylchroman-4-ones 3a−e] have been synthesized and tested in vitro as inhibitors of human monoamine oxidase isoforms A and B (hMAO-A and hMAO-B). Most of the compounds were found to be potent and selective MAO-B inhibitors. In general, the (E)-3-benzylidenechroman-4-ones 1a−w showed activities in the nano- or micromolar range coupled with high selectivity against hMAO-B. The reduction of the exocyclic double bond results in compounds 3a−e selective against isoform B and active in the micromolar range. In contrast, the endocyclic migration of the double bond (compounds 2a−g) generally produces the loss of the inhibitory activity or a marked reduction in potency. (E)-3-(4-(Dimethylamino)benzylidene)chroman-4-one (1l) and (E)-5,7-dihydroxy-3-(4-hydroxybenzylidene)chroman-4-one (1h) were the most interesting compounds of the entire series of inhibitors, showing hMAO-B affinity better than the selectiv...
91 citations
TL;DR: A better understanding of the transcriptional regulation of MAO A and MAO B genes may help explain the differential tissue-specific expression of these two isoenzymes and provide insights into the molecular basis of the disorders associated with MAO dysfunction.
Abstract: Monoamine oxidase (MAO) A and MAO B are a crucial pair of isoenzymes, which oxidatively deaminate monoamine neurotransmitters and dietary amines with a production of hydrogen peroxide. These two isoenzymes have different but overlapping substrate and inhibitor specificities. MAO A and MAO B share 70% amino acid sequence identity and show different temporal and spatial expressions in both humans and mice. Abnormal MAO A or MAO B activity has been implicated in numerous neurological and psychiatric disorders. A better understanding of the transcriptional regulation of MAO A and MAO B genes may help explain the differential tissue-specific expression of these two isoenzymes and provide insights into the molecular basis of the disorders associated with MAO dysfunction. This review discusses the recent progress in the transcriptional regulation and multiple functions of MAO A and MAO B genes.
83 citations
TL;DR: Bromocriptine seems to differ from L-dopa in that it does not affect the activity of M A 0 either by a direct action or indirectly via metabolic changes.
Abstract: g pronounced reduction in brain MAO-activity, lastin for several hours. In contrast, no significant changes in brain MAO-activity were observed when bromocriptine was administered either as a single dose of 32 mg kg-1 (s.c.) or for 7 consecutive days at a dose of 10 mg kg-l (s.c.). These data do not permit the conclusion that bromocriptine affects the activity of brain MAO indirectly via metabolic changes. Therefore, bromocriptine seems to differ from L-dopa in that it does not affect the activity of M A 0 either by a direct action or indirectly via metabolic changes. November 15, 1977
62 citations
TL;DR: It is concluded that these 1,3,4-oxadiazoles derivatives are promising reversible and selective MAO-B inhibitors.
Abstract: 3-Acetyl-2,5-diaryl-2,3-dihydro-1,3,4-oxadiazoles were designed, synthesized, and tested as inhibitors against human monoamine oxidase (MAO) A and B isoforms. Several compounds, obtained as racemates, were identified as selective MAO-B inhibitors. The enantiomers of some derivatives were separated by enantioselective HPLC and tested. The R-enantiomers always showed the highest activity. Docking study and molecular dynamic simulations demonstrated the putative binding mode. We conclude that these 1,3,4-oxadiazoles derivatives are promising reversible and selective MAO-B inhibitors.
56 citations
TL;DR: It is reported that dexamethasone, a synthetic glucocorticoid hormone, stimulates MAO B (an isoform of MAOs) promoter and catalytic activities via both the fourth glucoc Corticoid response element (GRE) and simian virus 40 promoter factor 1 (Sp1) binding sites inMAO B promoter.
Abstract: Glucocorticoid steroid hormones play important roles in many neurophysiological processes such as responses to stress, behavioral adaption, and mood. One mechanism by which glucocorticoids exert functions in the brain is via the modulation of neurotransmission systems. Glucocorticoids are capable of inducing the activities of monoamine oxidases (MAOs), which degrade monoamine neurotransmitters including serotonin, norepinephrine, phenylethylamine, and dopamine. However, the molecular mechanisms for such induction are not yet fully understood. Here, we report that dexamethasone, a synthetic glucocorticoid hormone, stimulates MAO B (an isoform of MAOs) promoter and catalytic activities via both the fourth glucocorticoid response element (GRE) and simian virus 40 promoter factor 1 (Sp1) binding sites in MAO B promoter. Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation analysis demonstrated that glucocorticoid receptor binds to the fourth GRE in vitro and in vivo. Using Sp1-binding motifs as bait in a yeast one-hybrid system, we identified two novel transcriptional repressors of MAO B, E2F-associated phosphoprotein (EAPP) and R1 (RAM2/CDCA7L/JPO2), that down-regulate MAO B via MAO B core promoter, which contains Sp1 sites. EMSA suggested that EAPP and R1 competed with Sp1 for binding to the Sp1 site in vitro. Moreover, EAPP and R1 reduced Sp1-activated glucocorticoid activation of MAO B promoter. In response to dexamethasone, lower occupancy by EAPP and R1 and higher occupancy by Sp1 were shown at the natural MAO B core promoter. Together, this study uncovers for the first time the molecular mechanisms for glucocorticoid activation of MAO B gene and provides new insights into the hormonal regulation of MAO.
47 citations
TL;DR: The binding of zonisamide to purified, recombinant monoamine oxidases (MAOs) has been investigated and the 1.8 Å structure of the MAO B complex demonstrates that it binds within the substrate cavity.
Abstract: The binding of zonisamide to purified, recombinant monoamine oxidases (MAOs) has been investigated. It is a competitive inhibitor of human MAO B (Ki = 3.1 ± 0.3 μM), of rat MAO B (Ki = 2.9 ± 0.5 μM), and of zebrafish MAO (Ki = 30.8 ± 5.3 μM). No inhibition is observed with purified human or rat MAO A. The 1.8 A structure of the MAO B complex demonstrates that it binds within the substrate cavity.
45 citations
TL;DR: Although bioavailability was variable depending on the source, a healthy diet contains amounts of quercetin that might give sufficient amounts in brain to induce, by monoamine oxidase A inhibition, a small decrease in neurotransmitter breakdown.
Abstract: Inhibition of monoamine oxidase is one way to treat depression and anxiety. The information now available on the pharmacokinetics of flavonoids and of the components of tobacco prompted an exploration of whether a healthy diet (with or without smoking) provides active compounds in amounts sufficient to partially inhibit monoamine oxidase. A literature search was used to identify dietary monoamine oxidase inhibitors, the levels of these compounds in foods, the pharmacokinetics of the absorption and distribution, and tissue levels observed. An estimated daily intake and the expected tissue concentrations were compared with the measured efficacies of the compounds as inhibitors of monoamine oxidases. Norharman, harman and quercetin dietary presence, pharmacokinetics, and tissue levels were consistent with significant levels reaching neuronal monoamine oxidase from the diet or smoking; 1,2,3,4-tetrahydroisoquinoline, eugenol, 1-piperoylpiperidine, and coumarin were not. Quercetin was equipotent with norharman as a monoamine oxidase A inhibitor and its metabolite, isorhamnetin, also inhibits. Total quercetin was the highest of the compounds in the sample diet. Although bioavailability was variable depending on the source, a healthy diet contains amounts of quercetin that might give sufficient amounts in brain to induce, by monoamine oxidase A inhibition, a small decrease in neurotransmitter breakdown.
44 citations
TL;DR: The results indicate that the behaviour of the beef heart enzyme towards selective inhibitors is considerably different from that of any preparations previously studied and suggest that the classification of monoamine oxidase activities into A and B types may be only of limited usefulness.
Abstract: The activity of beef heart mitochondrial monoamine oxidase towards 5-hydroxytryptamine (5-HT) is inhibited by the selective inhibitors clorgyline, PCO [5-phenyl-3-(N-cyclopropyl)-ethylamine-1,2,4-oxidiazole] and Deprenyl with a biphasic dependence on the inhibitor concentration. The activities towards tyramine, dopamine and tryptamine were also inhibited in a biphasic manner, but the apparent proportions of the two enzyme species active on dopamine and tryptamine depended on the inhibitor used. Phenethylamine oxidation was inhibited in a monophasic manner suggesting that only a single enzyme species was responsible for the oxidation of this substrate. The biphasic response of 5-HT oxidation to inhibition by clorgyline persisted when functionally competent mitochondria were used and was unaffected by the soluble amine oxidase inhibitors semicarbazine and aminoguanidine. These results indicate that the behaviour of the beef heart enzyme towards selective inhibitors is considerably different from that of any preparations previously studied and suggest that the classification of monoamine oxidase activites into A and B types may be only of limited usefulness.
41 citations
TL;DR: Nitrogen kinetic isotope effects for the oxidation of benzylamine by recombinant human monoamine oxidase B show that cleavage of the CH bond is not concerted with rehybridization of the nitrogen atom.
Abstract: Nitrogen kinetic isotope effects for the oxidation of benzylamine and (1,1-(2)H(2))benzylamine by recombinant human monoamine oxidase B show that cleavage of the CH bond is not concerted with rehybridization of the nitrogen atom.
41 citations
TL;DR: The COMT rs4680 and MAOB rs1799836 polymorphisms may increase susceptibility to PD risk among Japanese and future studies involving larger control and case populations and better pesticide exposure histories will undoubtedly lead to a more thorough understanding of the role of the polymorphisms involved in the dopamine pathway in PD.
Abstract: Parkinson's disease (PD) is characterized by alterations in dopaminergic neurotransmission. Genetic polymorphisms involved in dopaminergic neurotransmission may influence susceptibility to PD. We investigated the relationship of catechol-O-methyltransferase (COMT), monoamine oxidase B (MAOB), dopamine receptor (DR) D2 and DRD4 polymorphisms and PD risk with special attention to the interaction with cigarette smoking among 238 patients with PD and 369 controls in a Japanese population. Subjects with the AA genotype of MAOB rs1799836 showed a significantly increased risk of PD (odds ratio (OR) = 1.70, 95% confidence interval (CI) = 1.12 - 2.58) compared with the AG and GG genotypes combined. The AA genotype of COMT rs4680 was marginally associated with an increased risk of PD (OR = 1.86, 95% CI = 0.98 - 3.50) compared with the GG genotype. The DRD2 rs1800497 and DRD4 rs1800955 polymorphisms showed no association with PD. A COMT -smoking interaction was suggested, with the combined GA and AA genotypes of rs4680 and non-smoking conferring significantly higher risk (OR = 3.97, 95% CI = 2.13 - 7.41) than the AA genotype and a history of smoking (P for interaction = 0.061). No interactions of smoking with other polymorphisms were observed. The COMT rs4680 and MAOB rs1799836 polymorphisms may increase susceptibility to PD risk among Japanese. Future studies involving larger control and case populations and better pesticide exposure histories will undoubtedly lead to a more thorough understanding of the role of the polymorphisms involved in the dopamine pathway in PD.
TL;DR: It is possible that the methanolic extract of Hyoscyamusniger seeds protects against parkinsonism in mice by means of its ability to inhibit increased ·OH generated in the mitochondria.
Abstract: Hyoscyamus species is one of the four plants used in Ayurveda for the treatment of Parkinson’s disease (PD). Since Hyoscyamusniger was found to contain negligible levels of L-DOPA, we evaluated neuroprotective potential, if any, of characterized petroleum ether and aqueous methanol extracts of its seeds in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD in mice. Air dried authenticated H. niger seeds were sequentially extracted using petroleum ether and aqueous methanol and were characterized employing HPLC-electrochemistry and LCMS. Parkinsonian mice were treated daily twice with the extracts (125–500 mg/kg, p.o.) for two days and motor functions and striatal dopamine levels were assayed. Administration of the aqueous methanol extract (containing 0.03% w/w of L-DOPA), but not petroleum ether extract, significantly attenuated motor disabilities (akinesia, catalepsy and reduced swim score) and striatal dopamine loss in MPTP treated mice. Since the extract caused significant inhibition of monoamine oxidase activity and attenuated 1-methyl-4-phenyl pyridinium (MPP+)-induced hydroxyl radical (·OH) generation in isolated mitochondria, it is possible that the methanolic extract of Hyoscyamusniger seeds protects against parkinsonism in mice by means of its ability to inhibit increased ·OH generated in the mitochondria.
TL;DR: This review focuses on rasagiline and selegiline, two medications that belong to a class of antiparkinsonian drugs called monoamine oxidase B (MAO-B) inhibitors.
Abstract: Parkinson’s disease (PD) is the second most common neurodegenerative disease and the most treatable. Treatment of PD is symptomatic and generally focuses on the replacement or augmentation of levodopa. A number of options are available for treatment, both in monotherapy of early PD and to treat complications of advanced PD. This review focuses on rasagiline and selegiline, two medications that belong to a class of antiparkinsonian drugs called monoamine oxidase B (MAO-B) inhibitors. Topics covered in the review include mechanism of action, efficacy in early and advanced PD, effects on disability, the controversy regarding disease modification, safety, and patient preference for MAO-B inhibitors.
TL;DR: The results suggest that MAOB is a susceptibility gene for schizophrenia and no significant associations were observed for the MAOA functional polymorphism with schizophrenia in Han Chinese, which support further investigation of the role of MAO genes in schizophrenia.
Abstract: Monoamine oxidases (MAOs) catalyze the metabolism of dopaminergic neurotransmitters. Polymorphisms of isoforms MAOA and MAOB have been implicated in the etiology of mental disorders such as schizophrenia. Association studies detected these polymorphisms in several populations, however the data have not been conclusive to date. Here, we investigated the association of MAOA and MAOB polymorphisms with schizophrenia in a Han Chinese population. Two functional single nucleotide polymorphisms (SNPs), rs6323 of MAOA and rs1799836 of MAOB, were selected for association analysis in 537 unrelated schizophrenia patients and 536 healthy controls. Single-locus and Haplotype associations were calculated. No differences were found in the allelic distribution of rs6323. The G allele of rs1799836 was identified as a risk factor in the development of schizophrenia (P = 0.00001). The risk haplotype rs6323T-rs1799836G was associated with schizophrenia in female patients (P = 0.0002), but the frequency difference was not significant among male groups. Our results suggest that MAOB is a susceptibility gene for schizophrenia. In contrast, no significant associations were observed for the MAOA functional polymorphism with schizophrenia in Han Chinese. These data support further investigation of the role of MAO genes in schizophrenia.
TL;DR: In this article, the authors used quantum-chemical methods to study seven possible mechanisms of monoamine oxidase (MAO) inhibition by acetylenic inhibitors, considering neutral, cationic, anionic and radical mechanisms.
TL;DR: Both monoamino oxidase (MAO) B inhibitors show attenuation of glutamatergic transmission in the hippocampus but interfere with different receptor mediated excitatory modulations at low concentrations.
Abstract: Rasagiline, a new drug developed to treat Parkinson's disease, is known to inhibit monoamine oxidase B. However, its metabolite R-(-)-aminoindan does not show this kind of activity. The present series of in vitro experiments using the rat hippocampal slice preparation deals with effects of both compounds on the pyramidal cell response after electric stimulation of the Schaffer Collaterals in comparison to selegiline, another MAO B inhibitor. Stimulation of the Schaffer Collaterals by single stimuli (SS) or theta burst stimulation (TBS) resulted in stable responses of pyramidal cells measured as population spike amplitude (about 1 mV under control SS conditions or about 2 mV after TBS). During the first series, this response was attenuated in the presence of rasagiline and aminoindan-to a lesser degree of selegiline-in a concentration dependent manner (5-50 μM) after single stimuli as well as under TBS. During oxygen/glucose deprivation for 10 min the amplitude of the population spike breaks down by 75%. The presence of rasagiline and aminoindan, but rarely the presence of selegiline, prevented this break down. Following glutamate receptor mediated enhancements of neuronal transmission in a second series of experiments very clear differences could be observed in comparison to the action of selegiline: NMDA receptor, AMPA receptor as well as metabotropic glutamate receptor mediated increases of transmission were concentration dependently (0,3 - 2 μM) antagonized by rasagiline and aminoindan, but not by selegiline. On the opposite, only selegiline attenuated k ainate receptor mediated increases of excitability. Thus, both monoamino oxidase (MAO) B inhibitors show attenuation of glutamatergic transmission in the hippocampus but interfere with different receptor mediated excitatory modulations at low concentrations. Since aminoindan does not induce MAO B inhibition, these effects must be regarded as being independent from MAO B inhibition. The results provide strong evidence for a neuroprotective activity of rasagiline and aminoindan in concert with an extended clinical indication into the direction of other diseases like Alzheimer's disease or stroke.
TL;DR: Methylene blue, 5-nitroindazole, norharman, 9-methylnorharman and menadione inhibit MAO-B in mitochondria and afford protective effects, as suggested by a reduced conversion of MPTP to neurotoxic species.
TL;DR: It is concluded that MAO increases in those regions of HD brains which are known to undergo neurodegeneration accompanied by glioses, and it remains to be seen if selective enzyme inhibitors have therapeutic utility in the treatment of HD by reducing oxidative stress locally.
TL;DR: Data show MAO A is oriented on the cytosolic face and MAO B is situated on the surface facing the intermembrane space of the mitochondrial outer membrane in rat liver, relevant to their inhibition by drugs designed to be cardioprotectants or neuroprotectants.
Abstract: TEMPO-substituted pargyline analogues differentially inhibit recombinant human monoamine oxidase A (MAO A) and B (MAO B) in intact yeast mitochondria, suggesting these membrane-bound enzymes are located on differing faces of the mitochondrial outer membrane [Upadhyay, A., and Edmondson, D. E. (2009) Biochemistry 48, 3928]. This approach is extended to the recombinant rat enzymes and to rat liver mitochondria. The differential specificities exhibited for human MAO A and MAO B by the m- and p-amido TEMPO pargylines are not as absolute with the rat enzymes. Similar patterns of reactivity are observed for rat MAO A and B in mitochondrial outer membrane preparations expressed in Pichia pastoris or isolated from rat liver. In intact yeast mitochondria, recombinant rat MAO B is inhibited by the pargyline analogue whereas MAO A activity shows no inhibition. Intact rat liver mitochondria exhibit an inhibition pattern opposite to that observed in yeast where MAO A is inhibited and MAO B activity is unaffected. Protease inactivation studies show specificity in that MAO A is sensitive to trypsin whereas MAO B is sensitive to β-chymotrypsin. In intact mitochondrial preparations, MAO A is readily inactivated in rat liver but not in yeast upon trypsin treatment and MAO B is readily inactivated by β-chymotrypsin in yeast but not in rat liver. These data show MAO A is oriented on the cytosolic face and MAO B is situated on the surface facing the intermembrane space of the mitochondrial outer membrane in rat liver. The differential mitochondrial outer membrane topology of MAO A and MAO B is relevant to their inhibition by drugs designed to be cardioprotectants or neuroprotectants.
TL;DR: Results indicate that dietary‐hordenine is unlikely to be deaminated by intestinal MAO as this is predominantly MAO‐A, and it is likely to be absorbed and could affect the sympathetic nervous system, by virtue of its action as an inhibitor of noradrenaline uptake.
Abstract: The selectivity of the naturally occurring amine, N,N-dimethyltyramine (hordenine) for monoamine oxidase (MAO) and its action upon isolated vasa deferentia of the rat was investigated. Hordenine was deaminated by rat liver MAO with a Michaelis constant of 479 microM and maximum velocity of 128 nmol (mg protein)-1 h-1 compared with 144 microM and 482 nmol (mg protein)-1 h-1 for tyramine. Studies, with selective irreversible inhibitors of MAO, showed that hordenine was a highly selective substrate for MAO-B of liver and that it was not deaminated by the MAO-A of intestinal epithelium. In contrast to tyramine, hordenine did not produce contractions of isolated vasa deferentia. However, 25 microM hordenine potentiated contractile responses of vasa, from control animals, to submaximal doses of noradrenaline and inhibited responses to tyramine. It did not alter responses, to noradrenaline, of vasa denervated by chronic pretreatment of rats with guanethidine. Therefore, it appears that hordenine acted as an inhibitor of noradrenaline uptake, in isolated vasa deferentia. These results indicate that dietary-hordenine is unlikely to be deaminated by intestinal MAO as this is predominantly MAO-A. Consequently, it is likely to be absorbed and could affect the sympathetic nervous system, by virtue of its action as an inhibitor of noradrenaline uptake.
TL;DR: These data demonstrate zMAO exhibits functional properties similar to hMAO A as well as exhibits its own unique behavior, which should be useful for studies of MAO function in zebrafish models of human disease states.
Abstract: A comparative investigation of substrate specificity and inhibitor binding properties of recombinant zebrafish (Danio rerio) monoamine oxidase (zMAO) with those of recombinant human monoamine oxidases A and B (hMAO A and hMAO B) is presented. zMAO oxidizes the neurotransmitter amines (serotonin, dopamine and tyramine) with kcat values that exceed those of hMAO A or of hMAO B. The enzyme is competitively inhibited by hMAO A selective reversible inhibitors with the exception of d-amphetamine where uncompetitive inhibition is exhibited. The enzyme is unreactive with most MAO B-specific reversible inhibitors with the exception of chlorostyrylcaffeine. zMAO catalyzes the oxidation of para-substituted benzylamine analogs exhibiting Dkcat and D(kcat/Km) values ranging from 2 to 8. Structure-activity correlations show a dependence of log kcat with the electronic factor σp with a ρ value of + 1.55 ± 0.34; a value close to that for hMAO A but not with MAO B. zMAO differs from hMAO A or hMAO B in benzylamine analog binding correlations where an electronic effect (ρ = + 1.29 ± 0.31) is observed. These data demonstrate zMAO exhibits functional properties similar to hMAO A as well as exhibits its own unique behavior. These results should be useful for studies of MAO function in zebrafish models of human disease states.
TL;DR: Compound 4c is a specific inhibitor of MAO-B with high initial brain uptake in mice and is, therefore, a candidate for further investigation in PET.
Abstract: The aim in this project was to synthesize and to study fluorine-18 labeled analogues of l-deprenyl which bind selectively to the enzyme monoamine oxidase B (MAO-B). Three fluorinated l-deprenyl analogues have been generated in multistep organic syntheses. The most promising fluorine-18 compound N-[(2S)-1-[18F]fluoro-3-phenylpropan-2-yl]-N-methylprop-2-yn-1-amine (4c) was synthesized by a one-step fluorine-18 nucleophilic substitution reaction. Autoradiography on human brain tissue sections demonstrated specific binding for compound 4c to brain regions known to have a high content of MAO-B. In addition, the corresponding nonradioactive fluorine-19 compound (13) inhibited recombinant human MAO-B with an IC50 of 170.5 ± 29 nM but did not inhibit recombinant human MAO-A (IC50 > 2000 nM), demonstrating its specificity. Biodistribution of 4c in mice showed high initial brain uptake leveling at 5.2 ± 0.04%ID/g after 2 min post injection. In conclusion, compound 4c is a specific inhibitor of MAO-B with high initi...
TL;DR: The extraction of lipids from rat liver mitochondrial membranes by 2‐butanone treatment inhibited the activity of membrane‐bound monoamine oxidase ‐A but not ‐B, consistent with the hypothesis that the mitochondrial membrane lipids, while essential for the actìvìty of the A form of the enzyme in rat liver, play a more subtle modulatory role in the activity.
Abstract: The extraction of lipids from rat liver mitochondrial membranes by 2-butanone treatment inhibited the activity of membrane-bound monoamine oxidase -A but not -B. For the -B form, the apparent Michaelis constants of the enzyme towards oxygen and the maximum molecular turnover numbers obtained when beta-phenethylamine and benzylamine were used as substrates were not significantly changed by the lipid-depletion procedure, but the values of the Michaelis constant towards benzylamine was significantly increased after lipid-depletion. The differential sensitivity of beta-phenethylamine and benzylamine oxidation to inhibition by Tris-HCl was not changed after lipid-depletion. The results are consistent with the hypothesis that the mitochondrial membrane lipids, while essential for the activity of the -A form of the enzyme in rat liver, play a more subtle modulatory role in the activity of the -B form.
TL;DR: Results indicate that deprenyl protected the rat brains against the ischemia-induced oxidative damage, an effect which might be explained through multiple mechanisms, possibly due to reduction of dopamine catabolism with a subsequent increased activity on dopaminergic D2 receptors and suppressing the action of ROS as well.
Abstract: An increasing number of reports suggest the involvement of oxidative stress in neurodegenerative diseases where the increased formation of reactive oxygen species (ROS) leads to neuronal damage and cell death. Dopamine may contribute to neurodegenerative disorders such as Parkinson's disease and ischemia/reperfusion-induced damage. Monoamine oxidase (MAO) enzyme (particularly MAO-B) is responsible for metabolizing dopamine and plays an important role in oxidative stress through altering the redox state of neuronal and glial cells. MAO participates in the generation of hydroxyl radicals during ischemia/reperfusion. This suggests the possible use of MAO inhibitors as neuroprotective agents for treating ischemic injury. The protective effect of deprenyl (N-methyl-N-(1-methyl-2-phenyl-ethyl)-prop-2-yn-1-amine, CAS 14611-51-9) (2 and 10 mg/kg), a MAO-B inhibitor, and beta-carotene (10 and 20 mg/kg), a natural antioxidant, was examined in a rat model of cerebral ischemia. Ischemia was induced in rats by bilateral carotid artery occlusion for 1 h followed by declamping for another hour. The effect of the drugs on the brain activity of lactate dehydrogenase (LDH) and some of the oxidative stress biomarkers such as brain activity of superoxide dismutase (SOD) and catalase (CAT) enzymes and brain malondialdehyde (MDA) content was determined. In addition, the content of catecholamines such as noradrenaline (NA) and dopamine (DA) was determined. Deprenyl decreased the ischemia-induced elevation of LDH activity and MDA content and normalized the SOD activity. In addition, deprenyl increased the CAT activity back to normal, and increased the noradrenaline and dopamine content in the brain of rats. Beta-carotene administration ameliorated the effect of ischemia followed by reperfusion (I/R) demonstrated as decreasing the LDH activity and MDA content and by increasing the SOD activity. The drug also increased CAT activity in the brain of rats. However, beta-carotene did not alter the NA and DA content. These results indicate that deprenyl protected the rat brains against the ischemia-induced oxidative damage, an effect which might be explained through multiple mechanisms, possibly due to reduction of dopamine catabolism with a subsequent increased activity on dopaminergic D2 receptors and suppressing the action of ROS as well.
TL;DR: Initial structure-activity relationship studies identified key areas to modify the aromatic substituted TZD compounds, and substitutions on the aromatic group and the TzD nitrogen were key areas where activity was enhanced within this group of compounds.
TL;DR: This paper reports on the monoamine oxidase inhibiting properties in virro and in vivo, of a new oxazolidin-2-one derivative with antidepressant activity in animals and potential clinical efficacy in man.
Abstract: This paper reports on the monoamine oxidase (MAO, EC 1.4.3.4.) inhibiting properties in virro and in vivo, of a new oxazolidin-2-one derivative with antidepressant activity in animals (Gouret, Mocquet & others, 1977) and potential clinical efficacy in man (Martin, 1973). A comparison has been made with clorgyline, a specific inhibitor of M A 0 A (Johnston, 1968) and (k)-deprenyl, a specific inhibitor of M A 0 B (Knoll & Magyar, 1972) (for a review see Houslay, Tipton & Youdim, 1976).
TL;DR: Healthy young males on a high protein (HP) diet showed improved cognitive function and counteract well-known dementia biomarkers such as platelet MaoB and components of the methylation cycle such as vitamin B12 and homocysteine.
Abstract: Studies investigating the impact of high meat intake on cognition have yielded contradictory results as some show improved cognitive performance, whereas others report an increase of risk factors for dementia. However, few studies were designed to directly assess the effect of a high protein (HP) diet on both cognitive performance and corresponding biochemical parameters. A randomised intervention study was conducted with 23 healthy males (aged 19–31 years) to investigate the effects of a usual (UP) versus a HP diet on cognitive function and on the platelet proteome a well-established model for neurons. The study individuals were assigned to either a UP diet (15% energy) or a HP diet (30% energy) for 3 weeks with controlled intake of food and beverages. Blood samples were taken along with measurements of cognitive functions at the beginning and at the end of the intervention period. Among 908 reproducibly studied platelet proteins only the level of monoamine oxidase B (MaoB), a neurotransmitter degrading enzyme, decreased by 26% significantly (adjusted P value < 0.05) due to the HP diet. In addition, we found a correlation (r = 0.477; P < 0.02) between the decrease of MaoB expression and the shortened reaction time (cognitive function) which is in accordance with reports that dementia patients show increased MaoB activity. Plasma vitamin B12 concentration was increased by the HP diet and correlates inversely with platelet MaoB expression (r = −0.35; P < 0.02). Healthy young males on a HP diet showed improved cognitive function and counteract well-known dementia biomarkers such as platelet MaoB and components of the methylation cycle such as vitamin B12 and homocysteine.
TL;DR: Clorgyline inhibition curves at 10 and 100 μM n‐pentylamine indicated that this substrate was deaminated by MAO‐A, ‐B and a clorgy line‐resistant amine oxidase sensitive to inhibition by semicarbazide.
Abstract: n-Pentylamine is deaminated by homogenates of rat heart. Clorgyline inhibition curves at 10 and 100 microM n-pentylamine indicated that this substrate was deaminated by MAO-A, -B and a clorgyline-resistant amine oxidase sensitive to inhibition by semicarbazide. These results have been compared with two other commonly used monoamine substrates, beta-phenethylamine and benzylamine.
TL;DR: In inhibitory studies on monoamine oxidase (MAO) of a chemical library composed of stilbene-like derivatives that have potential applications in Alzheimer's disease and dementia with Lewy bodies, the findings demonstrate that the stilBene- like scaffolds could be utilized for developing promising multifunctional, neuroprotective agents for several neurodegenerative diseases.
Abstract: The design of multifunctional, neuroprotective compounds has received increasing attention due to their perceived utility in targeting not only the diverse comorbidity of neurological disorders, but also the typically complex pathoetiological pathways leading to these disorders, including insoluble proteins associated with many human neurodegenerative diseases of aging and radical-generating enzyme actions in the brain For this purpose, herein, we present inhibitory studies on monoamine oxidase (MAO) of a chemical library composed of stilbene-like derivatives that have potential applications in Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), with the ability to modulate metal-induced amyloid-β (Aβ) aggregation and neurotoxicity in vitro and in living cells Two isoforms of MAO, MAOA and MAOB, are well-known drug targets for depression and Parkinson's disease (PD), respectively Interestingly, inhibition and binding affinity studies of MAO with our chemical series indicated that three compounds, L1-b, L2-b, and L3-b, exhibited potent and relatively selective inhibitory effects of MAOB In particular, L2-b was observed to be the most effective MAOB inhibitor in our chemical library showing a reversible and competitive inhibition Generally, compounds having a dimethylamino moiety in our chemical family showed greater MAO inhibition suggesting a structure–activity relationship Overall, our findings demonstrate that the stilbene-like scaffolds could be utilized for developing promising multifunctional, neuroprotective agents for several neurodegenerative diseases
TL;DR: Ethanol increases the TIEG2–MAO B brain cell death cascade in rat brains, suggesting that the TIeg2– MAO B pathway is a novel pathway for brain cell damage resulting from ethanol exposure, and may contribute to chronic alcohol-induced brain damage.
Abstract: Brain cell loss has been reported in subjects with alcoholism. However, the molecular mechanisms are unclear. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and monoamine oxidase B (MAO B) reportedly play a role in cellular dysfunction with regards to ethanol exposure. We have recently reported that GAPDH protein expression was increased in the brains of rats fed with ethanol. Furthermore, GAPDH interacts with the transcriptional activator, transforming growth factor-beta-inducible early gene 2 (TIEG2), to augment TIEG2-mediated MAO B activation, resulting in neuronal cell damage due to ethanol exposure. The current study investigates whether the TIEG2–MAO B cascade is also active in the brains of rats fed with ethanol. Ten ethanol-preferring rats were fed with a liquid diet containing ethanol, with increasing amounts of ethanol up to a final concentration of 6.4% representing a final diet containing 36% of calories for 28 days. Ten control rats were fed the liquid diet without ethanol. The expression of TIEG2 protein, MAO B mRNA levels, MAO B catalytic activity, and the levels of anti-apoptotic protein Bcl 2 and apoptotic protein caspase 3 were determined in the prefrontal cortex of the rats. Ethanol significantly increased protein levels of TIEG2, active caspase 3, MAO B mRNA and enzyme activity, but significantly decreased Bcl 2 protein expression compared to control rats. In summary, ethanol increases the TIEG2–MAO B brain cell death cascade in rat brains, suggesting that the TIEG2–MAO B pathway is a novel pathway for brain cell damage resulting from ethanol exposure, and may contribute to chronic alcohol-induced brain damage.