Showing papers on "Monoamine oxidase B published in 2004"

Monoamine oxidase-B inhibition in Alzheimer's disease.

Abstract: Alzheimer's disease (AD) is the most common cause of dementia in late life. There is still no clear-cut consensus whether this disease involves genetic or environmental factors or both. There is a great need to find a way to delay the disease, as delaying the onset of the disease will bring a great relieve on social and medical resources. The monoamine oxidase-B (MAO-B) inhibitors were shown to be effective in treating Parkinson's disease and possibly AD, with concomitant extension of life span. This article gives a short review on MAO-B inhibitors and their mechanism for neuroprotective effects in AD.

Crystal structures of monoamine oxidase B in complex with four inhibitors of the N-propargylaminoindan class.

Abstract: Monoamine oxidase B (MAO B) is an outer mitochondrial membrane enzyme that catalyzes the oxidation of arylalkylamine neurotransmitters. The crystal structures of MAO B in complex with four of the N-propargylaminoindan class of MAO covalent inhibitors (rasagiline, N-propargyl-1(S)-aminoindan, 6-hydroxy-N-propargyl-1(R)-aminoindan, and N-methyl-N-propargyl-1(R)-aminoindan) have been determined at a resolution of better than 2.1 A. Rasagiline, 6-hydroxy-N-propargyl-1(R)-aminoindan, and N-methyl-N-propargyl-1(R)-aminoindan adopt essentially the same conformation with the extended propargyl chain covalently bound to the flavin and the indan ring located in the rear of the substrate cavity. N-Propargyl-1(S)-aminoindan binds with the indan ring in a flipped conformation with respect to the other inhibitors, which causes a slight movement of the Tyr326 side chain. Four ordered water molecules are an integral part of the active site and establish H-bond interactions to the inhibitor atoms. These structural studies may guide future drug design to improve selectivity and efficacy by introducing appropriate substituents on the rasagiline molecular scaffold.

Neuroprotection via pro-survival protein kinase C isoforms associated with Bcl-2 family members

Abstract: SPECIFIC AIMSUsing a model of serum deprivation, we investigated the molecular mechanism by which the anti-Parkinson/monoamine oxidase B (MAO-B) inhibitor drug rasagiline exerts its neuroprotective...

Monoamine oxidase expression during development and aging.

Abstract: Monoamine oxidase (MAO) isoenzymes play a major role in regulating the concentration of several bioactive amines, including serotonin and catecholamines. Both in the nervous system and in peripheral organs, MAOs can potentially modulate all the processes involving these bioactive amines. In the present article, we review some of the most significant articles published so far on changes in MAOs during development and aging. The data available on development refer mainly to the mammal brain at fetal and post-fetal stages. Very little work has been done on studying MAO ontogenesis during early development, that is, at stages prior to organogenesis, and what has been done refers to non-mammal vertebrates such as fish, amphibians and birds. MAO A and MAO B changes have been measured as values of enzymatic activity, as amount of protein or, more rarely, as amount of mRNAs. A knowledge of MAO developmental changes not only provides a basis for the investigation of factors regulating MAO expression, but can also contribute to a better understanding of the possible trophic and/or morphogenetic role of monoaminergic neurotransmitters in the developing brain. Transgenic mice lacking MAO A and rodents treated with MAO inhibitors during gestation have been very useful in this second case. The investigations of changes in MAO A and MAO B during aging in the literature refer mostly to humans, mice and rats. Interest in studies on aging is stimulated, among other things, by the observation that age-related diseases leading to neurodegenerative phenomena could be accompanied by changes in MAO activity.

(−)-Deprenyl, A Selective MAO-B Inhibitor, with Apoptotic and Anti-apoptotic Properties

Abstract: (-)-Deprenyl (selegiline) is an irreversible inhibitor of monoamine oxidase (MAO) B, which was discovered in 1962 and become the "golden standard" of MAO research. Like the other MAO-B inhibitors, it was synthesized as an antidepressant, but in a selective MAO-B inhibitory dose it does not act in depression. It is used in the treatment of Parkinson's disease. (-)-Deprenyl potentiates the effect of dopamine, it has antioxidant activity and prevents the toxicity of the dopaminergic (6-OH-dopamine; 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP)), the noradrenergic (DSP-4) and cholinergic (AF64A) neurotoxins after pre-treatment. When (-)-deprenyl was administered with levodopa in a long-term treatment of Parkinsonian patients, it induces adverse events (nausea, dizziness, confusion, hallucination, insomnia and cardiovascular changes), which could be due to dopamine potentiation in dopaminergic systems (limbic system), other than the nigrostriatal pathway. (-)-Deprenyl in much lower concentrations needed to induce MAO-B inhibition (10(-9) to 10(-13) M) potently inhibits MPTP or serum withdrawal induced apoptosis in tissue cultures of neuro-ectodermal origin (PC12, M1, M2058). The (+)-enantiomer of deprenyl lacks of this property. The anti-apoptotic activity of (-)-deprenyl can be prevented by inhibiting the metabolism of the drug with SKF-525A pre-treatment, which suggests that some of the presently unknown metabolites could be responsible for the anti-apoptotic activity. In high concentration (10(-3) M), (-)-deprenyl and its metabolites induce apoptosis in tissue cultures without serum withdrawal (biphasic action). Our findings support the view that 100, or even 1000 times lower dose of (-)-deprenyl can be offered in human therapy to protect, or slow down neuronal degeneration, than it is presently used. With low dose of the drug the dopaminergic adverse events could be avoided, while anti-apoptotic activity might be preserved.

Novel therapeutic effects of the anti-convulsant, zonisamide, on Parkinson's disease.

Abstract: We found that zonisamide (ZNS) has beneficial effects on Parkinson's disease (PD). ZNS is originally synthesized in Japan and has been used for over 10 years to treat intractable epilepsy. We administered 300 mg of ZNS to a patient with PD who incidentally had convulsive attacks. The attacks disappeared and, surprisingly, the parkinsonian symptoms improved dramatically. An open trial of ZNS (given in addition to their anti-PD drugs) in advanced PD patients clearly showed the lessening of symptoms, especially wearing-off. Although the effects gradually decreased after 1.5 years, more than 30% improvement of UPDRS total score was maintained up to 3 years. Nation-wide double-blind controlled study confirmed that the small dose (50mg/day) of ZNS improved all the cardinal symptoms of PD. As for its mechanism, we showed that ZNS increases dopamine contents in the striatum by activating dopamine synthesis and the level of mRNA of tyrosine hydroxylase (TH) prior to that of TH protein. ZNS moderately inhibits monoamine oxydase (MAO) B. It has no effects on dopamine receptors, dopamine transporter or dopamine release. ZNS has no direct effects on glutamate receptors, adenosine receptors, or serotonergic system, which have been suggested to be effective points of anti-PD drug other than dopamine system. Therefore, it is suggested that the activation of dopamine synthesis and the moderate level of MAOB inhibition are main mechanisms of ZNS effects on PD. ZNS has significant effects on T-type Ca(++) channels and oxidative stress. They may also affect the beneficial action of ZNS on PD.

Inactivation of Purified Human Recombinant Monoamine Oxidases A and B by Rasagiline and Its Analogues

Abstract: The inactivation of purified human recombinant monoamine oxidases (MAO) A and B by rasagiline [N-propargyl-1(R)-aminoindan] and four of its analogues [N-propargyl-1(S)-aminoindan (S-PAI), 6-hydroxy-N-propargyl-1(R)-aminoindan (R-HPAI), N-methyl-N-propargyl-1(R)-aminoindan (R-MPAI), and 6-(N-methyl-N-ethyl carbamoyloxy)-N-propargyl-1(R)-aminoindan (R-CPAI)] has been investigated. All compounds tested, with the exception of R-CPAI, form stoichiometric N(5) flavocyanine adducts with the FAD moiety of either enzyme. No H2O2 is produced during either MAO A or MAO B inactivation, which demonstrates that covalent addition occurs in a single turnover. Rasagiline has the highest specificity for MAO B, as demonstrated by a 100-fold higher inhibition potency (kinact/Ki) compared to MAO A, with the remaining compounds exhibiting lower isozyme specificities. MAO B and MAO A are more selective for the R-enantiomer (rasagiline) compared to the S-enantiomer (S-PAI) by 2500-fold and 17-fold, respectively. Differences in U...

Association analysis between a functional polymorphism in the monoamine oxidase A gene promoter and severe mood disorders.

Abstract: Monoamine oxidase A (MAOA) has been suggested to be involved in human behaviour and physiology due to its key role in the metabolism of several different biological amines including the neurotransmitters serotonin, norepinephrin and dopamine.Recently, a 30 bp repeat in the MAOA gene promoter (uMAOA)

Cloning, after cloning, knock-out mice, and physiological functions of MAO A and B.

Abstract: Cloning of MAO A and B has demonstrated clearly that MAO A and B are coded by different proteins with 70% amino acid identity. With the MAO A and B cDNA clones, we showed the tissue distribution and genomic structure of MAO A and B, the latter suggesting that they are derived from the same ancestral gene. The active sites, the role of cysteine residues, the three-dimensional models and the mitochondria targeting domains of both isoenzymes have been established. The transcriptional regulation of MAO A and B has been studied. MAO A KO mice showed increased levels of serotonin (5-HT), norepinephrine (NE), dopamine (DA) whereas MAO B KO mice showed increased phenylethylamine (PEA) levels only. Both MAO A and B KO mice showed increased response to stress. MAO A KO mice showed increased emotional learning and memory and aggressive behavior, but the vesicular monoamine transporter (VMAT2), 5-HT1A, 5-HT2A and 5-HT2C receptors were down regulated. 5-HT2A antagonist, ketanserin and MDL100907 were able to abolish the aggression, suggesting that the aggressive behavior may be mediated by 5-HT2A receptor. In contrast, MAO B KO mice are resistant to MPTP, a toxin which induces Parkinson's syndromes. Studies of these mice suggest that MAO A and B have distinct biochemical and physiological functions.

The FAD Binding Sites of Human Monoamine Oxidases A and B

Abstract: The structural details of the interactions of the covalent 8α-S-cysteinyl-FAD with the protein moiety in monoamine oxidase B (MAO B) based on the MAO B crystal structure are described. The dinucleotide is bound to the protein in an extended conformation with the majority of the bonds to the protein identified as hydrogen bonds with amino acid side chains, amide bonds, and water molecules. Since those amino acids interacting with the FAD are conserved in monoamine oxidase A (MAO A), it is proposed that the FAD binding site in MAO A is quite similar to that in MAO B. The redox-active isoalloxazine ring is buried in the protein without direct access to bulk solvent. An electrostatic interaction is observed between the anionic pyrophosphate moiety and Arg42. The normally flat oxidized flavin ring is in a bent, puckered conformation in the MAO B binding site which is suggested to contribute to its reactivity in catalysis. This structural information is then used to explain previous studies on flavin analog incorporation into either MAO B or into MAO A.

Perspectives on MAO-B in aging and neurological disease: where do we go from here?

Abstract: The catecholamine-oxidizing enzyme monoamine oxidase-B (MAO-B) has been hypothesized to be an important determining factor in the etiology of both normal aging and age-related neurological disorders such as Parkinson’s disease (PD). Catalysis of substrate by the enzyme produces H2O2 which is a primary originator of oxidative stress which in turn can lead to cellular damage. MAO-B increases with age as does predisposition towards PD which has also been linked to increased oxidative stress. Inhibition of MAO-B, along with supplementation of lost dopamine via L-DOPA, is one of the major antiparkinsonian therapies currently in use. In this review, we address several factors contributing to a possible role for MAO-B in normal brain aging and neurological disease and also discuss the use of MAO-B inhibitors as drug therapy for these conditions.

Inhibition of rodent brain monoamine oxidase and tyrosine hydroxylase by endogenous compounds - 1,2,3,4-tetrahydro-isoquinoline alkaloids.

Abstract: Four different noncatecholic and one catecholic tetrahydroisoquinolines (TIQs), cyclic condensation derivatives of beta-phenylethylamine and dopamine with aldehydes or keto acids, were examined for the inhibition of rat and mouse brain monoamine oxidase (MAO) and rat striatum tyrosine hydroxylase (TH) activity. Simple noncatecholic TIQs were found to act as moderate (TIQ, N-methyl-TIQ, 1-methyl-TIQ) or weak (1-benzyl-TIQ), MAO B and MAO A inhibitors. 1-Methyl-TIQ inhibited more potently MAO-A than MAO-B; the similar but more modest effect was exerted by salsolinol. Only salsolinol markedly inhibited TH activity, being competitive with the enzyme biopterin cofactor. The inhibition of MAO and TH by TIQs is discussed in relation to their ability to regulate monoamine metabolism.

The effect of monoamine oxidase B (MAOB) and catechol‐O‐methyltransferase (COMT) polymorphisms on levodopa therapy in patients with sporadic Parkinson's disease

Abstract: Objectives – The etiology of sporadic idiopathic Parkinson's disease (PD) is considered multifactorial with both genetic and environmental factors modifying the disease expression. Recent studies suggest that polymorphism in monoamine oxidase B (MAOB) and catechol-O-methyltransferase (COMT) might influence the risk and treatment of PD. The aim of the study was to evaluate the effect of MAOB and COMT genetic polymorphism on effective daily dose of levodopa applied during the first 5 years of treatment, and to find out if a relationship exists between MAOB and COMT haplotypes and motor disturbances onset in PD patients treated with levodopa preparations. Materials and methods – A total of 95 patients (40 females and 55 males) of Polish origin diagnosed with sporadic PD were enrolled into the study, and were divided into two groups. Group 1 – patients treated with doses of levodopa below 500 mg/day during the first 5 years of treatment. Group 2 – patients requiring levodopa doses exceeding 500 mg/24 h during the first 5 years of treatment. Low activity alleles of MAOB and COMT, i.e. MAOB allele A and COMTL as well as high activity ones, i.e. MAOB allele G and COMTH, were determined using PCR-RFLP method. Results – No statistically significant differences were found in MAOB and COMT allele distribution in the two groups. However, the frequency of COMTL/L homozygotes was higher in the group treated with low doses of levodopa when compared with the second group. MAOB and COMT AG-HH haplotype predominated in the group of females treated with high daily doses of levodopa when compared with AG-LL haplotype in the group of females treated with low daily doses of levodopa (<500 mg/24 h). Conclusion – The results of the study suggest that patients with COMTL/L genotype and possibly MAOB genotype A may benefit from more efficient and safer levodopa therapy.

Polymorphisms of dopamine degradation enzyme (COMT and MAO) genes and tardive dyskinesia in patients with schizophrenia

Abstract: Several lines of evidence suggest that tardive dyskinesia (TD) may be associated with altered dopaminergic neurotransmission We hypothesized that deranged dopamine degradation enzyme activities might be related to the susceptibility to TD through altered dopaminergic neurotransmission in the central nervous system In the present study, we investigated the relationship between the gene polymorphisms of three dopamine degradation enzymes and TD We genotyped the valine/methionine polymorphism of codon 108/158 in the catechol-O-methyltransferase (COMT) gene, the 30-bp repeat polymorphism in the promoter of the monoamine oxidase A (MAOA) gene, and the A/G polymorphism in intron 13 of the monoamine oxidase B (MAOB) gene in 206 Japanese patients with schizophrenia No significant difference was found in total scores on the Abnormal Involuntary Movement Scale (AIMS) among the subject groups, sorted according to the COMT, MAOA and MAOB genotypes Moreover, no significant difference was found in allele frequencies between patients with TD and patients without TD for any of the polymorphisms As both COMT and MAO genes are involved in degrading catecholamines, we also sought evidence for additive and epistatic effects, but none was observed Our data, therefore, do not support the hypothesis that polymorphisms in COMT, MAOA, and MAOB genes are involved individually or in combination in the predisposition to TD

Tobacco Leaf, Smoke and Smoking, MAO Inhibitors, Parkinson’s Disease and Neuroprotection; Are There Links?

Abstract: The potential neuroprotective properties of monoamine oxidase B (MAO-B) inhibitors have been of interest in part because of the role that this enzyme plays in the bioactivation of the parkinsonian inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Interestingly, tobacco smokers have lowered levels of brain and blood platelet MAO-B activity and a well documented lowered incidence of Parkinson's disease (PD) compared to non-smokers. This correlation has led to the intriguing question of whether there are possible relationships between smoking, MAO-B activity and PD. Recent studies have evaluated specific components of tobacco smoke for their MAO inhibiting and neuroprotective properties. This chapter summarizes the relevant literature relating to the basic questions in these areas. We have undertaken studies to identify possible inhibitors of MAO-B in the tobacco leaf and tobacco smoke and have evaluated one such compound in the MPTP PD mouse model. In this chapter we report on the results of these studies and present a discussion of potential avenues of research and their implication with respect to PD, smoking and monoamine oxidase.

Tribulin and endogenous MAO-inhibitory regulation in vivo.

Abstract: Tribulin is the name given to a family of endogenous nonpeptide substances which inhibit monoamine oxidase (MAO) and benzodiazepine binding. It is widely distributed in mammalian tissues and body fluids, and exhibit some species and tissue variations. Several components selectively inhibiting MAO A, MAO B, central and peripheral benzodiazepine binding (tribulins A, B, BZc and BZp, respectively) have been recognised. Tribulin A represents some tissue-specific metabolites of trace amines, whereas isatin is the major component of tribulin B. Tribulin content increases in brain under conditions of stress and anxiety and is reduced under sedation. Changes in tribulin content in the brain are accompanied by corresponding changes in the content of monoamines and their acidic metabolites, and also by altered susceptibility of MAO to specific mechanism-based inhibitors. This suggests that tribulin is involved in MAO inhibitory regulation in vivo.

EGb761 pretreatment reduces monoamine oxidase activity in mouse corpus striatum during 1-methyl-4-phenylpyridinium neurotoxicity

Abstract: EGb761 produces reversible inhibition of both monoamine oxidase (MAO) isoforms in the central nervous system. 1-methyl-4-phenylpyridinium (MPP+) neurotoxicity is prevented by treatment with the MAO inhibitor pargyline. We investigated EGb761's effect on striatal MAO activity during MPP+ neurotoxicity. C-57 black mice were pretreated with EGb761 (10 mg/kg) daily for 17 days followed by administration of MPP (0.72 mg/kg). MPP+ enhanced striatal MAO (30%) activity at 6 h, and EGb761 prevented this effect. MAO-B activity in striatum was enhanced (70%) 6 h after MPP+ administration and was reduced to almost normal levels in EGb761 + MPP+ group compared to MPP+ group. Pretreatment with EGb761 partially prevented (32%) the striatal dopamine-depleting effect of MPP+ and prevented the reduction in striatal tyrosine hydroxylase activity (100%). Results suggest that EGb761 supplements may be effective in reducing MAO activity as well as enhancement in dopamine metabolism, thereby preventing MPP+-neurotoxicity.

Inhibitory effects of the monoamine oxidase inhibitor tranylcypromine on the cytochrome P450 enzymes CYP2C19, CYP2C9, and CYP2D6.

Abstract: 1. The inhibitory effects of tranylcypromine, a nonselective irreversible inhibitor of monoamine oxidase (MAO), on three cytochrome P450 (CYP) enzymes, namely CYP2C9, CYP2C19, and CYP2D6, have been evaluated in vitro.

Comparative study of the effects of isatin, an endogenous MAO-inhibitor, and selegiline on bradykinesia and dopamine levels in a rat model of Parkinson's disease induced by the Japanese encephalitis virus.

Abstract: We previously reported that exogenously administered isatin, an endogenous monoamine oxidase (MAO) inhibitor, significantly increased acetylcholine (ACh) and dopamine (DA) levels in the rat striatum. Selegiline [(-)-deprenil] was developed as a MAO-B inhibitor more than 30 years ago and widely used in the treatment of Parkinson's disease. Effects of isatin or selegiline were investigated in Japanese encephalitis virus (JEV)-induced post-encephalitic parkinsonism rats by a pole test for detecting motor activity and by the determination of biogenic amine levels. Motor activity of JEV-induced rats receiving isatin (100 mg/kg per day for 1 week, i.p.) or selegiline (0.2 mg/kg per day for 1 week, i.p.) was significantly improved compared with that of untreated JEV-infected rats. Both isatin and selegiline prevented the decrease in striatal DA levels in JEV-rats. The increased turnover of DA (DOPAC/DA) induced by JEV was significantly inhibited by isatin, but not by selegiline. These results suggested that exogenously administered isatin and selegiline can improve JEV-induced parkinsonism by increasing DA concentrations in the striatum.