Showing papers on "Monoamine oxidase B published in 2010"

Structurally Designed trans-2-Phenylcyclopropylamine Derivatives Potently Inhibit Histone Demethylase LSD1/KDM1,,§

Abstract: Lysine-specific demethylase 1 (LSD1/KDM1) demethylates histone H3, in addition to tumor suppressor p53 and DNA methyltransferase 1 (Dnmt1), thus regulating eukaryotic gene expression by altering chromatin structure. Specific inhibitors of LSD1 are desired as anticancer agents, because LSD1 aberrations are associated with several cancers, and LSD1 inhibition restores the expression of abnormally silenced genes in cancerous cells. In this study, we designed and synthesized several candidate compounds to inhibit LSD1, based on the structures of LSD1 and monoamine oxidase B (MAO-B), in complex with an antidepressant tranylcypromine (2-PCPA) derivative. Compound S2101 exhibited stronger LSD1 inhibition than tranylcypromine and the known small LSD1 inhibitors in LSD1 demethylation assays, with a k(inact)/K(I) value of 4560 M(-1) s(-1). In comparison with tranylcypromine, the compound displayed weaker inhibition to the monoamine oxidases. The inhibition modes of the two 2-PCPA derivatives, 2-PFPA and S1201, were identified by determination of the inhibitor-bound LSD1 structures, which revealed the enhanced stability of the inhibitor-FAD adducts by their interactions with the surrounding LSD1 residues. These molecules are potential pharmaceutical candidates for cancer or latent virus infection, as well as research tools for LSD1-related biological investigations.

Site-activated chelators targeting acetylcholinesterase and monoamine oxidase for Alzheimer's therapy.

Abstract: Chelators have the potential to treat the underlying cause of Alzheimer's disease (AD), but their therapeutic use is hampered by their poor targeting and poor permeability to the brain and/or toxic effects. Here, we report a new strategy for designing site-activated chelators targeting both acetylcholinesterase (AChE) and monoamine oxidase (MAO). We demonstrated that our lead 2 inhibited both AChE and MAO in vitro, but with little affinity for metal (Fe, Cu, and Zn) ions. Compound 2 can be activated by inhibition of AChE to release an active chelator M30. M30 has been shown to be able to modulate amyloid precursor protein regulation and beta-amyloid reduction, suppress oxidative stress, and passivate excess metal ions (Fe, Cu, and Zn). Compound 2 was less cytotoxic and more lipophilic than the brain-permeable chelator M30. Our new strategy is relatively simple and generally produces small and simple molecules with drug-like properties; it thus holds a potential use in designing site-activated multifunctional chelators with safer and more efficacious properties for treating other metal-related diseases such as Parkinson's disease and cancer where specific elimination of metals in cancer cells is required.

Low Dosage of Rasagiline and Epigallocatechin Gallate Synergistically Restored the Nigrostriatal Axis in MPTP-Induced Parkinsonism

Abstract: Background: The anti-Parkinson monoamine oxidase B inhibitor rasagiline appears to be the first neuroprotective disease-modifying therapy in early-stage Parkinson’s disease (PD). Objective: Using a polypharmacy paradigm, we tested whether the distinct neuroprotective pharmacological profile of rasagiline would complement that of (–)-epigallocatechin-3-gallate (EGCG), the main antioxidant/iron chelator polyphenol constituent of green tea, and restore the neuronal loss and molecular targets damaged in animal parkinsonism. Methods/Results: We show by high-performance liquid chromatography, immunohistochemistry and Western blot analyses that the combination of rasagiline and EGCG, at subliminal doses which have no profound protective effect, acts synergistically to restore the nigrostriatal axis in N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. A detailed analysis revealed a complementary action of these drugs, differentially acting at MPTP-injured molecules/targets in the substantia nigra (SN): induction of brain-derived neurotrophic factor by rasagiline, increased membranal levels of the protein kinase C α-isoform by EGCG and a synergistic replenishment of their downstream effector, the serine/threonine kinase Akt/protein kinase B, suggesting that this kinase might represent one point of convergence of the distinct mechanisms of action of the drug cocktail. Conclusion: These results provide molecular evidence that activation of multiple brain targets by the combination of rasagiline and EGCG may synergistically contribute to the rescue of the dopamine neurons in the SN and replenishment of striatal dopamine. This may have important implications for rasagiline-treated PD patients who could further benefit from an adjunct administration of EGCG.

Deletion of MAOA and MAOB in a male patient causes severe developmental delay, intermittent hypotonia and stereotypical hand movements.

Abstract: Monoamine oxidases (MAO-A and MAO-B) have a key role in the degradation of amine neurotransmitters, such as dopamine, norepinephrine and serotonin. We identified an inherited 240 kb deletion on Xp11.3-p11.4, which encompasses both monoamine oxidase genes but, unlike other published reports, does not affect the adjacent Norrie disease gene (NDP). The brothers who inherited the deletion, and thus have no monoamine oxidase function, presented with severe developmental delay, intermittent hypotonia and stereotypical hand movements. The clinical features accord with published reports of larger microdeletions and selective MAO-A and MAO-B deficiencies in humans and mouse models and suggest considerable functional compensation between MAO-A and MAO-B under normal conditions.

Monoamine oxidases regulate telencephalic neural progenitors in late embryonic and early postnatal development

Abstract: Monoamine neurotransmitters play major roles in regulating a range of brain functions in adults and increasing evidence suggests roles for monoamines in brain development. Here we show that mice lacking the monoamine metabolic enzymes MAO A and MAO B (MAO AB-deficient mice) exhibit diminished proliferation of neural stem cells (NSC) in the developing telencephalon beginning in late gestation [embryonic day (E) 17.5], a deficit that persists in neonatal and adult mice. These mice showed significantly increased monoamine levels and anxiety-like behaviors as adults. Assessments of markers of intermediate progenitor cells (IPC) and mitosis showed that NSC in the subventricular zone (SVZ), but not in the ventricular zone, are reduced in MAO AB-deficient mice. A developmental time course of monoamines in frontal cortical tissues revealed increased serotonin levels as early as E14.5, and a further large increase was found between E17.5 and postnatal day 2. Administration of an inhibitor of serotonin synthesis (parachlorophenylalanine) between E14.5 and E19.5 restored the IPC numbers and SVZ thickness, suggesting the role of serotonin in the suppression of IPC proliferation. Studies of neurosphere cultures prepared from the telencephalon at different embryonic and postnatal ages showed that serotonin stimulates proliferation in wild-type, but not in MAO AB-deficient, NSC. Together, these results suggest that a MAO-dependent long-lasting alteration in the proliferation capacity of NSC occurs late in embryonic development and is mediated by serotonin. Our findings reveal novel roles for MAOs and serotonin in the regulation of IPC proliferation in the developing brain.

The New Inhibitor of Monoamine Oxidase, M30, has a Neuroprotective Effect Against Dexamethasone-Induced Brain Cell Apoptosis.

Abstract: Stress detrimentally affects the brain and body and can lead to or be accompanied by depression. Although stress and depression may contribute to each other, the exact molecular mechanism underlying the effects is unclear. However, there is a correlation between stress and an increase in glucocorticoid secretion which causes a subsequent increase in monoamine oxidase (MAO) activity during stress. Consequently, MAO inhibitors have been used as traditional antidepressant drugs. Cellular treatment with the synthetic glucocorticoid, dexamethasone (a cellular stressor), has been reported to markedly increase both MAO A and MAO B catalytic activities, as well as apoptosis. This study compares the neuroprotective abilities of M30 (a new generation inhibitor of both MAO A and MAO B) with rasagiline (Azilect®, another new MAO B inhibitor) and selegiline (Deprenyl®, a traditional MAO B inhibitor) in the prevention of dexamethasone-induced brain cell death and MAO activity in human neuroblastoma cells, SH-SY5Y. M30 demonstrated the highest inhibitory effect on MAO A; however, M30 showed the lowest inhibitory effect on MAO B enzymatic activity in comparison to rasagiline and selegiline. Although, M30 exhibited the greatest neuroprotective effect by decreasing cell death rates and apoptotic DNA damage compared to rasagiline and selegiline, these neuroprotective effects of M30 were, overall, similar to rasagiline. Summarily, M30 has a generally greater impact on neuroprotection than the MAO B inhibitors, selegiline and rasagiline. Our results suggest that M30 may have great potential in alleviating disorders involving increases in both MAO A and MAO B, such as stress-induced disorders.

The Degradation of Serotonin: Role of MAO

Abstract: The enzymatic degradation of serotonin (5-hydroxytryptamine, 5-HT) is mainly served by monoamine oxidase (MAO), a mitochondrial-bound enzyme requiring flavin adenine dinucleotide as a cofactor. MAO catalyzes the oxidative deamination of 5-HT by converting it into 5-hydroxy-3-indolacetaldehyde (5-HIAL), which is further processed into 5-hydroxy-3-indolacetic acid (5-HIAA) by aldehyde dehydrogenase. MAO also serves the degradation of other monoamine neurotransmitters, such as norepinephrine, dopamine and trace amines. Two MAO isoenzymes, named A and B, have been identified, which differ in genetic bases, transcriptional regulation, substrate preference, inhibitor affinity and regional distribution. Although MAO A exhibits the highest preference for 5-HT and catalyzes its metabolism under physiological conditions, MAO B is the only isoenzyme that has been identified in 5-HTergic neurons. This chapter reviews the evidence on the biochemistry, genetics and neurobiology of MAOs, in relationship to their functions in the regulation of 5-HTergic neurotransmission, as assessed by studies on the outcomes of their pharmacological and genetic inactivation.

Dual role of the carboxyl-terminal region of pig liver L-kynurenine 3-monooxygenase: mitochondrial-targeting signal and enzymatic activity.

Abstract: L-kynurenine 3-monooxygenase (KMO) is an NAD(P)H-dependent flavin monooxygenase that catalyses the hydroxylation of L -kynurenine to 3-hydroxykynurenine, and is localized as an oligomer in the mitochondrial outer membrane. In the human brain, KMO may play an important role in the formation of two neurotoxins, 3-hydroxykynurenine and quinolinic acid, both of which provoke severe neurodegenerative diseases. In mosquitos, it plays a role in the formation both of eye pigment and of an exflagellation-inducing factor (xanthurenic acid). Here, we present evidence that the C-terminal region of pig liver KMO plays a dual role. First, it is required for the enzymatic activity. Second, it functions as a mitochondrial targeting signal as seen in monoamine oxidase B (MAO B) or outer membrane cytochrome b 5 . The first role was shown by the comparison of the enzymatic activity of two mutants (C-terminally FLAG-tagged KMO and carboxyl-terminal truncation form, KMOΔC50) with that of the wild-type enzyme expressed in COS-7 cells. The second role was demonstrated with fluorescence microscopy by the comparison of the intracellular localization of the wild-type, three carboxyl-terminal truncated forms (AC20, AC30 and ΔC50), C-terminally FLAG-tagged wild-type and a mutant KMO, where two arginine residues, Arg461-Arg462, were replaced with Ser residues.

Association study between antipsychotic-induced restless legs syndrome and polymorphisms of monoamine oxidase genes in schizophrenia.

Abstract: Objective This study aimed to investigate whether the monoamine oxidase (MAO) A and B genes are associated with antipsychoticinduced restless legs syndrome (RLS) in schizophrenia. Methods We assessed antipsychotic-induced RLS symptoms in 190 Korean schizophrenic patients and divided the subjects into two groups: thosewith RLS symptoms (n ¼96) and thosewithout RLS symptoms (n ¼94). Genotyping was performed for thevariable number of tandem repeat (VNTR) polymorphism of the MAOA gene and A644G polymorphism of the MAOB gene. Results There was no significant difference in the genotype and allele frequencies of all polymorphisms investigated between these two groups. However, the result of global haplotype analysis showed a significant difference in haplotype frequencies between male subjects with and without RLS symptoms (p ¼0.013). The interaction between two polymorphisms had a significant effect on the RLS scores of both male (p ¼0.047) and female (p ¼0.028) patients. Conclusions These data do not suggest that the MAOA gene VNTR and MAOB gene A644G polymorphisms are associated with antipsychotic-induced RLS symptoms in schizophrenia. However, we found that the haplotype frequencies differed between the male schizophrenic patients with and without RLS symptom and the interaction between the two polymorphisms had a significant influence on the RLS scores of patients with schizophrenia. Copyright # 2010 John Wiley & Sons, Ltd. key words—restless legs syndrome; antipsychotics; schizophrenia; monoamine A and B genes; polymorphism; gene‐gene interaction

Pharmacology of Rasagiline, a New MAO-B Inhibitor Drug for the Treatment of Parkinson's Disease with Neuroprotective Potential.

Abstract: Rasagiline (Azilect) is a highly selective and potent propargylamine inhibitor of monoamine oxidase (MAO) type B. Like other similar propargylamine inhibitors, rasagiline binds covalently to the N5 nitrogen of the flavin residue of MAO, resulting in irreversible inactivation of the enzyme. Therapeutic doses of the drug which inhibit brain MAO-B by 95% or more cause minimal inhibition of MAO-A, and do not potentiate the pressor or other pharmacological effects of tyramine. Metabolic conversion of the compound in vivo is by hepatic cytochrome P450-1A2, with generation of 1-aminoindan as the major metabolite. Rasagiline possesses no amphetamine-like properties, by contrast with the related compound selegiline (Deprenyl, Jumex, Eldepryl). Although the exact distribution of MAO isoforms in different neurons and tissues is not known, dopamine behaves largely as a MAO-A substrate in vivo, but following loss of dopaminergic axonal varicosities from the striatum, metabolism by glial MAO-B becomes increasingly important. Following subchronic administration to normal rats, rasagiline increases levels of dopamine in striatal microdialysate, possibly by the build-up of β-phenylethylamine, which is an excellent substrate for MAO-B, and is an effective inhibitor of the plasma membrane dopamine transporter (DAT). Both of these mechanisms may participate in the anti-Parkinsonian effect of rasagiline in humans. Rasagiline possesses neuroprotective properties in a variety of primary neuronal preparations and neuron-like cell lines, which is not due to MAO inhibition. Recent clinical studies have also demonstrated possible neuroprotective properties of the drug in human Parkinsonian patients, as shown by a reduced rate of decline of symptoms over time.

Protective effect of N‐(2‐propynyl)‐2‐(5‐benzyloxy‐indolyl) methylamine (PF 9601N), a novel MAO‐B inhibitor, on dopamine‐lesioned PC12 cultured cells

Abstract: Oxidative stress may play a role in the pathogenesis of Parkinson's disease. We have standardised a new model of dopaminergic-cell toxicity that uses dopamine, which is able to generate free radicals, as a toxin. The effect of this catecholamine on cell viability (MTT staining) was dose-dependent, reaching 65% of cell loss at a dopamine concentration of 300 microM. In this model, the protective effect of a novel MAO-B inhibitor, N-(2-propynyl)-2-(5-benzyloxy-indolyl) methylamine (PF 9601N), was studied and compared with the effect of L-deprenyl assayed under the same experimental conditions. Whereas PF 9601N (50 microM and 100 microM) showed a significant protective effect, this was not the case with L-deprenyl. This different behaviour could be explained in terms of difference in antioxidant capacity. The toxicity induced in PC12 cells by 300 microM dopamine was partially reversed by incubating it in the presence of GBR-12909, a dopamine-transporter blocker. The results indicated that, besides the intracellular toxicity effect of dopamine, another non-specific extracellular mechanism could be involved.

Ziprasidone, monoamine oxidase inhibitors, and the serotonin syndrome.

Abstract: To the Editors:Augmenting antidepressants with second-generation antipsychotics (SGAs) is a strategy with increasing clinical and research evidence supporting its use.1,2 Because both SGAs and many antidepressants (especially selective serotonin reuptake inhibitors [SSRIs], dual action agents, and m

Effects of a Silkworm Extract on Dopamine and Monoamine Oxidase-B Activity in an MPTP-induced Parkinsons Disease Model

Abstract: The protective efficacy of a silkworm extract (SE) on N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism and its possible mechanisms were studied in C57BL/6 mice. Mice were administrated intraperitoneally with SE (20 ㎎/㎏/day) for 15 days and MPTP (10 ㎎/㎏/day) was administrated subcutaneously into the mice for the first 6 consecutive days 1 hour before SE treatment. All animals were sacrificed 24 hours after the last SE treatment. Then the parameters related to general toxicity and neurobiochemical markers, such as the dopamine level and the activities of monoamine oxidase (MAO)-B, were measured in various regions of the brain. Treatment of mice with SE effectively attenuated the MPTP-induced decline of striatal dopamine level. MAO-B activity in SE-pretreated mice was inhibited in whole brain, cerebellum and substantia nigra. These results suggest that SE plays an effective role in attenuating MPTP-induced neurotoxicity in animal model. These neuroprotective effects of SE are likely the result from the inhibitory effect on MAO-B activity in mouse brain.

Platelet monoamine oxidase activity predicts alcohol sensitivity and voluntary alcohol intake in rhesus monkeys

Abstract: Platelet monoamine oxidase B (MAO-B) has been proposed to be a biological marker for the properties of monoamine systems, with low activity being associated with vulnerability for high scores on personality traits such as sensation seeking, monotony avoidance, and impulsiveness, as well as for vulnerability for alcoholism. In the present study, platelet MAO-B activity was analysed in 78 rhesus macaques, and its relation to voluntary alcohol intake and behaviours after intravenous alcohol administration was observed. Monkeys with low platelet MAO-B activity had low levels of 5-hydroxyindole acetic acid in cerebrospinal fluid and showed excessive aggression after alcohol administration. A novel finding was that animals with low platelet MAO-B activity showed less intoxication following alcohol administration. As we have shown previously, they also voluntarily consumed more alcohol. We here replicate results from studies on both humans and non-human primates, showing the utility of platelet MAO as a marker for risk behaviours and alcohol abuse. Furthermore, we link platelet MAO activity to alcohol sensitivity.

Down-regulated GABAergic expression in the olfactory bulb layers of the mouse deficient in monoamine oxidase B and administered with amphetamine.

Abstract: This study explores primarily the role of the activity of monoamine oxidase B (MAOB) in the regulation of glutamic acid decarboxylase67 (GAD67) expression in distinct layers of main olfactory bulb (OlfB), which links the limbic system. Moreover, the response of GAD67 was investigated to amphetamine perturbation in the absence of MAOB activity. Immunocytochemical analysis was performed on OlfB sections prepared from the adult wild type (WT) and the MAOB gene-knocked-out (KO) mice after receiving repeated intraperitoneal injections (two doses per day, total seven doses) of saline or amphetamine, 5 mg/kg. The levels of the GAD67 immunoreactivity were approximate 25 and 38% lower in respective glomerular (GloL) and mitral cell layers (ML) of saline-treated KO mice than that of WT, whereas similar in the external plexiform or granule cell layers (GraL) of the KO and WT. In the GloL, the level of tyrosine hydroxylase was 39% lower in the KO mice than WT, implicating different dopamine content in the KO from WT. The amphetamine exposure down-regulated the levels of GAD67 in the WT layers by 46 to 52%, and in KO layers 65 to 71%, except ML. The GraL GAD67 level may be regulated by the activation of CREB, as the phosphorylated (p) CREB coexisted with GAD67, and the percentage of GAD67-expressing pCREB neurons was decreased by the amphetamine exposure. The data indicate that the activity of MAOB could modulate the regular and amphetamine-perturbed expression of GAD67 and pCREB. Thus, interactions are suggested among the MAOB activity, GABA content of OlfB, and olfaction.

Serotonin in Tetrahymena-How Does It Work?

Abstract: Presence, uptake and production of serotonin and its effect on the production of other hormones were studied using immunocytochemical flow cytometric method. In a serotonin (10-12 M) containing medium up to 15 min. serotonin level does not elevate in the cells, but after 30 min. there is a significant elevation which remains till 4 h. In cells starved in salt solution the elevation is higher which calls attention to the effect of (starvation) stress. Using four enzyme blockers tryptophane hydroxylase inhibitor PCPA decreased (in serotonin-containing medium) and MAO B blocker deprenyl increased serotonin content, while serotonin reuptake inhibitor fluoxetine and MAO-A blocker clorgyline were ineffective. Extremely low concentrations of serotonin (10^(-15) M in case of histamine and 10^(-18) M in case of ACTH and T3) in the milieu was sufficient for increasing hormone (ACTH, T3, histamine) levels inside the cells. In conclusion; serotonin can be taken up by the cells and can be produced by induction, as Tetrahymena has enzymes for building it up and decomposing it. For synthesizing serotonin; basic molecules from outside are not needed. Serotonin in a minute amount can induce production of different hormones.

Comparative enzymological study of catalytic properties of liver monoamine oxidases in frogs

Abstract: Comparative enzymological study of catalytical properties of monoamine oxidase (MAO) of liver of the marsh frog Rana ridibunda and common frog Rana temporaria has revealed certain features of similarity and differences between these enzymes. The MAOs from both studied biological sources show catalytic properties resembling those of the classical MAO of terrestrial vertebrates: they deaminate tyramine, tryptamine, serotonin, and benzylamine and do not deaminate histamine, have sensitivity to clorgyline, the specific inhibitor of the MAO A form, and deprenyl, the specific inhibitor of the MAO B form, and are not inhibited by 10−2 M semicarbazide. Based on data of substrate-inhibitor analysis, a suggestion is put forward about the existence of two molecular forms of the enzyme in liver of the studied frog species. Quantitative interspecies differences have been revealed between liver MAO of Rana ridibunda and Rana temporaria in values of kinetic parameters of reactions of deamination of several substrates and in sensitivity to the inhibitors, deprenyl and clorgyline. In the species Rana temporaria the MAO activity in reaction of deamination of serotonin and benzylamine were virtually identical, whereas in the species Rana ridibunda these parameters for serotonin were almost one order higher than for benzylamine. In the species Rana ridibunda, selectivity of action of deprenyl was expressed many times weaker, while selectivity of the clorgyline—one order of magnitude stronger than in the species Rana temporaria. The catalytic activities towards all studied substrates of liver MAO of both studied amphibian species were several times lower as compared with the enzyme of rat liver.