Showing papers on "Monoamine oxidase B published in 2001"

Rasagiline [N-propargyl-1R(+)-aminoindan], a selective and potent inhibitor of mitochondrial monoamine oxidase B

Abstract: Rasagiline [N-propargyl-1R(+)-aminoindan], was examined for its monoamine oxidase (MAO) A and B inhibitor activities in rats together with its S(−)-enantiomer (TVP 1022) and the racemic compound (AGN-1135) and compared to selegiline (1-deprenyl). The tissues that were studied for MAO inhibition were the brain, liver and small intestine. While rasagiline and AGN1135 are highly potent selective irreversible inhibitors of MAO in vitro and in vivo, the S(−) enantiomer is relatively inactive in the tissues examined. The in vitro IC50 values for inhibition of rat brain MAO activity by rasagiline are 4.43±0.92 nM (type B), and 412±123 nM (type A). The ED50 values for ex vivo inhibition of MAO in the brain and liver by a single dose of rasagiline are 0.1±0.01, 0.042±0.0045 mg kg−1 respectively for MAO-B, and 6.48±0.81, 2.38±0.35 mg kg−1 respectively for MAO-A. Selective MAO-B inhibition in the liver and brain was maintained on chronic (21 days) oral dosage with ED50 values of 0.014±0.002 and 0.013±0.001 mg kg−1 respectively. The degree of selectivity of rasagiline for inhibition of MAO-B as opposed to MAO-A was similar to that of selegiline. Rasagiline was three to 15 times more potent than selegiline for inhibition of MAO-B in rat brain and liver in vivo on acute and chronic administration, but had similar potency in vitro. These data together with lack of tyramine sympathomimetic potentiation by rasagiline, at selective MAO-B inhibitory dosage, indicate that this inhibitor like selegiline may be a useful agent in the treatment of Parkinson's disease in either symptomatic or L-DOPA adjunct therapy, but lack of amphetamine-like metabolites could present a therapeutic advantage for rasagiline. Keywords: Monoamine oxidase (MAO) A and B, brain, liver, small intestine, selegiline (l-deprenyl), clorgyline, rasagiline, irreversible inhibitors, Parkinson's disease, dopamine Introduction The knowledge that dopamine is equally well oxidatively deaminated by monoamine oxidase (MAO) types A and B (Collins et al., 1970), the dominance of MAO-B (80%) as compared to MAO-A in the extrapyramidal regions of human brain (Collins et al., 1970; Squires, 1972; O'Carroll et al., 1983) and the absence of the ‘cheese reaction' in whole animal and isolated tissue preparations by the selective irreversible MAO-B inhibitor selegiline (deprenyl; Knoll & Magyar, 1972) led to the introduction of selegiline as an adjunct to L-DOPA therapy of Parkinson's disease (Birkmayer et al., 1975; 1977; Lees et al., 1977). Selegiline has proved to be a useful antiparkinson drug both in monotherapy (Parkinson Study Group, 1989) and as adjunct to L-DOPA therapy, and has L-DOPA sparing action (Birkmayer et al., 1977; Riederer & Rinne, 1992). Selegiline is a propargyl derivative of 1-amphetamine. It irreversibly inhibits MAO-B by binding mole per mole covalently to the N5 position of the isoalloxazine moiety of FAD, the cofactor of MAO-B (Maycock et al., 1976; Youdim, 1978). It is metabolized in vivo to 1-amphetamine and to 1-methamphetamine (Reynolds et al., 1978) and has amphetamine-like sympathomimetic actions (Simpson, 1978; Finberg et al., 1981). In this paper we report on the in vitro and acute and chronic in vivo inhibitory activity of a highly potent and selective inhibitor of MAO-B, rasagiline [N-propargyl-1R(+)-aminoindan; TVP-1012; Youdim et al., 1995; Sterling et al., 1998] with structural similarity to selegiline (Sabbagh & Youdim, 1978; Kalir et al., 1981; see Figure 1. Rasagiline has been developed as an antiparkinson drug (Youdim et al., 1995; Finberg et al., 1996; 1999) and is an analogue of selegiline, but unlike the latter is metabolized to aminoindan, which is largely devoid of amphetamine-like properties. It was isolated from the racemic form of the selective MAO-B inhibitor, AGN1135 (Sabbagh > Youdim, 1978; Kalir et al., 1981), since the latter drug was shown by us to be devoid of sympathomimetic activity and does not produce the ‘cheese reaction' in isolated tissue preparations or in vivo in rats and cats in doses selective for inhibition of MAO-B (Finberg et al., 1981; Finberg & Youdim, 1985). Figure 1 Chemical structures of rasagiline, selegiline (deprenyl) and their metabolites. Methods Animals and drug treatments Male Sprague-Dawley rats (Charles-River) were housed in wire-mesh cages at an environmental temperature of 19 – 21°C, 12 h light – dark cycle (lights on at 0700), and were fed rat chow ad libitum for the duration of the experiment.

Excessive activation of serotonin (5-HT) 1B receptors disrupts the formation of sensory maps in monoamine oxidase a and 5-ht transporter knock-out mice.

Abstract: Deficiency in the monoamine degradation enzyme monoamine oxidase A (MAOA) or prenatal exposure to the monoamine uptake inhibitor cocaine alters behavior in humans and rodents, but the mechanisms are unclear. In MAOA knock-out mice, inhibiting serotonin synthesis during development can prevent abnormal segregation of axons in the retinogeniculate and somatosensory thalamocortical systems. To investigate this effect, we crossed MAOA knock-outs with mice lacking the serotonin transporter 5-HTT or the 5-HT1B receptor, two molecules present in developing sensory projections. Segregation was abnormal in 5-HTT knock-outs and MAOA/5-HTT double knock-outs but was normalized in MAOA/5-HT1B double knock-outs and MAOA/5-HTT/5-HT1B triple knock-outs. This demonstrates that the 5-HT1B receptor is a key factor in abnormal segregation of sensory projections and suggests that serotonergic drugs represent a risk for the development of these projections. We also found that the 5-HT1B receptor has an adverse developmental impact on beam-walking behavior in MAOA knock-outs. Finally, because the 5-HT1B receptor inhibits glutamate release, our results suggest that visual and somatosensory projections must release glutamate for proper segregation.

Molecular basis of neuroprotective activities of rasagiline and the anti-Alzheimer drug TV3326 [(N-propargyl-(3R)aminoindan-5-YL)-ethyl methyl carbamate].

Abstract: Rasagiline (N-propargyl-1-(R)-aminoindan) is a selective, irreversible monoamine oxidase B (MAO B) inhibitor which has been developed as an anti-Parkinson drug. In controlled monotherapy and as adjunct to L-dopa it has shown anti-Parkinson activity. In cell culture (PC-12 and neuroblastoma SH-SY5Y cells) it exhibits neuroprotective and antiapoptotic activity against several neurotoxins (SIN-1, MPTP, 6-hydroxydopamine and N-methyl-(R)-salsolinol) and ischemia. In vivo, it reduces the sequelae of traumatic brain injury in mice and speeds their recovery. The neuroprotective activity of rasagaline does not result from MAO B inhibition, since its S-enantiomer, TVP1022, which has 1000-fold weaker MAO inhibitory activity, exhibits similar neuroprotective properties. Introduction of a carbamate moiety into the rasagiline molecule to confer cholinesterase inhibitory activity for the treatment of Alzheimer's disease, resulted in compounds TV3326 [(N-Propargyl-(3R)Aminoindan-5-YL)-Ethyl Methyl Carbamate] and its S-enantiomer TV3279 [(N-Propargyl-(3S) Aminoindan-5-YL)-Ethyl Methyl Carbamate], which retain the neuroprotective activities of rasagiline and TVP1022. They also antagonize scopolamine-induced impairments in spatial memory. In addition, TV3326 exhibits brain-selective MAO A and B inhibitory activity after chronic administration and has antidepressant-like activity in the forced swim test. This is associated with an increase in brain levels of serotonin. The antiapoptotic activity of these propargylamine-containing derivatives may be related to their ability to delay the opening of voltage-dependent anion channels (VDAC), which are part of the mitochondrial permeability transition pore. The propargylamine moiety is responsible for the increase in the mitochondrial family of Bcl-2 proteins, prevention in the fall in mitochondrial membrane potential, prevention of the activation of caspase 3, and of translocation of glycerlaldehyde-3-phosphate dehydrogenase from the cytoplasm to the nucleus. The latter processes are closely associated with neurotoxin-induced apoptosis. Rasagiline interacts with and prevents the binding of PK11195 to the pro-apoptotic peripheral benzodiazepine receptor, which together with Bcl-2, hexokinase, porin, and adenine nucleotide translocator constitutes part of the VDAC. Furthermore, rasagiline, TV3326 and TV3279 are able to influence the processing of amyloid precursor protein by activation of alpha-secretase and increasing the release of soluble alpha APP in rat PC-12 and human neuroblastoma SH-SY5Y cells and in rat and mice cortex and hippocampus. This process has been shown to involve the upregulation of PKC and MAP kinase. It is quite likely that the induction of Bcl-2 and activation of PKC by rasagiline and TV3326 is closely linked to the anti-apototic action of these drugs and their ability to process APP by activation of alpha-secretase.

Monoamine oxidases and tobacco smoking

Abstract: Although nicotine has been identified as the main ingredient in tobacco responsible for aspects of the tobacco dependence syndrome, not all of the psychopharmacological effects of smoking can be explained by nicotine alone. Accumulating preclinical and clinical evidence has demonstrated that smoking also leads to potent inhibition of both types (A and B) of monoamine oxidase (MAO). Smokers have 30-40 % lower MAOB and 20-30 % lower MAOA activity than non-smokers. Reduced MAO activity in smokers has been shown by direct measures (platelets, positron emission tomographic studies) or by indirect measures (concentration of monoamine catabolites in plasma or CSF). We examine the hypothesis that chronic habitual smoking can be better understood in the context of two pharmacological factors: nicotine and reduced MAO activity. We speculate that MAO inhibition by compounds found in either tobacco or tobacco smoke can potentiate nicotine's effects. Based on this concept, more effective anti-smoking drug strategies may be developed. As a practical consequence of tobacco smoke's MAO-inhibitory properties, comparative psychiatric research studies need to screen and control for tobacco use.

Molecular characterization of monoamine oxidases A and B

Abstract: Monoamine oxidase A and B (MAO A and B) are the major neurotransmitter-degrading enzymes in the central nervous system and in peripheral tissues. MAO A and B cDNAs from human, rat, and bovine species have been cloned and their deduced amino acid sequences compared. Comparison of A and B forms of the enzyme shows approximately 70% sequence identity, whereas comparison of the A or B forms across species reveals a higher sequence identity of 87%. Within these sequences, several functional regions have been identified that contain crucial amino acid residues participating in flavin adenine dinucleotide (FAD) or substrate binding. These include a dinucleotide-binding site, a second FAD-binding site, a fingerprint site, the FAD covalent-binding site, an active site, and the membrane-anchoring site. The specific residues that play a role in FAD or substrate binding were identified by comparing sequences in wild-type and variants of MAO with those in soluble flavoproteins of known structures. The genes that encode MAO A and B are closely aligned on the X chromosome (Xp11.23), and have identical exon-intron organization. Immunocytochemical localization studies of MAO A and B in primate brain showed distribution in distinct neurons with diverse physiological functions. A defective MAO A gene has been reported to associate with abnormal aggressive behavior. A deleterious role played by MAO B is the activation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a proneurotoxin that can cause a parkinsonian syndrome in mammals. Deprenyl, an inhibitor of MAO B, has been used for the treatment of early-stage Parkinson's disease and provides protection of neurons from age-related decay.

Monoamine oxidase B and free radical scavenging activities of natural flavonoids in Melastoma candidum D. Don.

Abstract: Monoamine oxidase type B (MAO-B) activity and free radicals are elevated in certain neurological diseases. Four natural flavonoids, quercitrin, isoquercitrin, rutin, and quercetin, were isolated for the first time from the leaves of Melastoma candidum D. Don. They exhibited an inhibitory effect on MAO-B. These potent flavonoids were purified using bioassay-guided fractionation and were separated by Diaion, Sephadex LH-20, and MCI CHP20P columns. The IC(50) values of the four potent flavonoids, quercitrin, isoquercitrin, rutin, and quercetin on monoamine oxidase were 19.06, 11.64, 3.89, and 10.89 microM and enzyme kinetics analysis revealed apparent inhibition constants (K(i)) of 21.01, 2.72, 1.83, and 7.95 microM, respectively, on the substrate, benzylamine. The four potent compounds also exhibited hydroxyl radical scavenging activity as determined using a spin trapping electron spin resonance method. This suggests that the four flavonoids from M. candidum possess both MAO-B inhibitory and free radical scavenging activities. These important properties may be used for preventing some neurodegenerative diseases in the future.

Linkage studies between attention-deficit hyperactivity disorder and the monoamine oxidase genes.

Abstract: Attention-deficit hyperactivity disorder (ADHD) is a prevalent behavioral disorder in children and the etiology of this disorder is not clear. Molecular genetic and pharmacological studies suggest the involvement of dopaminergic and noradrenergic neurotransmitter systems in ADHD, e.g., several reports have found association between ADHD and the dopamine receptor gene DRD-4, the dopamine transporter gene DAT1, and the catecholamine clearance enzyme catechol-O-methyltransferase. Monoamine oxidase (MAO) A and B genes encode enzymes that participate in the metabolism of neurotransmitters of the dopaminergic and noradrenergic systems. MAO inhibitors have been shown to be effective in the treatment of ADHD. Our previous studies showed an association between ADHD and the DXS7 locus, which is located in close vicinity to the MAO genes on chromosome X. These findings suggest that there might be linkage between ADHD and MAO genes. To test this hypothesis, we used the transmission/disequilibrium test (TDT) to test for linkage between a VNTR polymorphism at the MAOA(CA)(n) or MAOB(GT)(n) locus and DSM-III-R-diagnosed ADHD in 82 nuclear families of the Chinese population. The TDT analysis revealed linkage between ADHD and the MAOA(CA)(n) locus (chi-square = 15.25, df = 7, P 0.05). The data showed that ADHD was in linkage with the MAOA gene and suggested that MAOA might be a susceptibility factor for ADHD.

The COMT L allele modifies the association between MAOB polymorphism and PD in Taiwanese.

Abstract: Objective: Reports suggest that catechol- O -methyltransferase (COMT L/L ) (Val 158 /Met) and monoamine oxidase B (MAOB) intron 13 genotype polymorphism is associated with PD. To understand the ethnicity-specific effects of genetic polymorphism, we performed a case-control study of the association between PD susceptibility and polymorphism of MAOB and COMT, both separately and in combination, in Taiwanese. Methods: Two hundred twenty-four patients with PD and 197 controls, matched for age, sex, and birthplace, were recruited. MAOB and COMT polymorphism genotyping was performed by using PCR-based restriction fragment length polymorphism (RFLP) analyses. χ 2 , OR, and Fisher’s exact tests were used to compare differences in allelic frequencies and genotypes. Results: The MAOB G genotype ( G in men and G/G in women) was associated with a 2.07-fold increased relative risk of PD. COMT polymorphism, considered alone, showed no correlation with PD risk; however, a significant synergistic enhancement was found in PD patients harboring both the COMT L and MAOB G genotypes. Conclusions: These results suggest that, in Taiwanese, PD risk is associated with MAOB G intron 13 polymorphism, and this association is augmented in the presence of the COMT L genotype, indicating an interaction of these two dopamine-metabolizing enzymes in the pathogenesis of sporadic PD. However, the relatively low frequencies of these combined genotypes in our study necessitates confirmation with a larger sample size.

Regulation of human monoamine oxidase B gene by Sp1 and Sp3.

Abstract: The human monoamine oxidase (MAO) B plays a major role in the degradation of biogenic and dietary amines such as phenylethylamine, benzylamine, dopamine, and tyramine. We previously showed that the −246/−99 MAO B promoter region exhibited the highest activity and contained two clusters of overlapping Sp1 sites, a CACCC element and a TATA box. Here, using a series of 10 deletion constructs of the 2-kilobase pair 5′-flanking sequence, we identified additional potential regulatory elements, including activator proteins 1 and 4, CAAT, GATA, upstream stimulatory factor (USF), estrogen receptor (ER), and sex-determining region Y-box 5 (SOX5). Analysis of nine site-directed mutations of −246/−99 region reveals that both clusters of Sp1 sites contribute positively whereas the CACCC element contributes negatively to the transcriptional activity. Gel shift analysis demonstrates that in addition to Sp1, Sp3 can interact with both clusters of Sp1 sites. Cotransfection experiments show that Sp1 and its closely related family member Sp4 cantrans-activate MAO B promoter activity through the proximal cluster of Sp1 sites and its activation can be repressed by the over-expression of Sp3 and a related family member BTEB2. These results suggest that the binding to the overlapping Sp1 sites by various members of Sp family is important for the regulation of the MAO B gene expression.

Biochemical effects of the monoamine neurotoxins DSP-4 and MDMA in specific brain regions of MAO-B-deficient mice.

Abstract: Previous studies reported that drugs acting as monoamine oxidase (MAO)-B inhibitors prevented biochemical effects induced by the neurotoxins N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) and 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”). In this study, we administered DSP-4 (50 mg/kg) or MDMA (50 mg/kg ×2, 2 h apart) to MAO-B deficient mice. Monoamine content in various brain regions (cerebellum, frontal cortex, hippocampus, hypothalamus, striatum, substantia nigra) was assayed 1 week after neurotoxin administration. Injection of DSP-4 to wild-type mice caused a marked norepinephrine (NE) loss in specific brain regions. Unexpectedly, DSP-4 caused similar effects in MAO-B-deficient and in wild-type mice in all brain regions investigated. These results suggest that MAO-B is not involved in DSP-4 toxicity. In wild-types, the neurotoxin MDMA induced both serotonin (5HT) and dopamine (DA) depletion in specific brain areas. In MAO-B-deficient mice, 5HT depletion observed in wild-types did not occur. In contrast, MDMA produced a more pronounced DA loss in knockout mice compared with wild-types. The present findings, together with previous data obtained using selective enzyme inhibitors, suggest that MAO-B is not involved in the mechanism of action of DSP-4, whereas it plays opposite roles in MDMA-induced DA and 5HT depletions. Synapse 39:213–221, 2001. © 2001 Wiley-Liss, Inc.

Monoamine oxidase inhibition is unlikely to be relevant to the risks associated with phentermine and fenfluramine: a comparison with their abilities to evoke monoamine release.

Abstract: OBJECTIVE AND DESIGN: It has been proposed that the anti-obesity agent, phentermine, may act in part via inhibition of monoamine oxidase (MAO). The ability of phentermine to inhibit both MAOA and MAOB in vitro has been examined along with that of the fenfluramine isomers, a range of selective serotonin reuptake inhibitors and sibutramine and its active metabolites. RESULTS: In rat brain, harmaline and lazabemide showed potent and selective inhibition of MAOA and MAOB, their respective target enzymes, with IC50 values of 2.3 and 18 nM. In contrast, all other drugs examined were only weak inhibitors of MAOA and MAOB with IC50 values for each enzyme in the moderate to high micromolar range. For MAOA, the IC50 for phentermine was estimated to be 143 µM, that for S(+)-fenfluramine, 265 µM and that for sertraline, 31 µM. For MAOB, example IC50s were as follows: phentermine (285 µM), S(+)-fenfluramine (800 µM) and paroxetine (16 µM). Sibutramine was unable to inhibit either enzyme, even at its limit of solubility. CONCLUSION: We therefore suggest that MAO inhibition is unlikely to play a role in the pharmacodynamic properties of any of the tested drugs, including phentermine. Instead, the lack of potency of these drugs as MAO inhibitors is contrasted with their powerful ability either to inhibit the uptake of one or more monoamines (fluoxetine, paroxetine, sertraline, sibutramine's active metabolites) or to evoke the release of one or more monoamines (S(+)-fenfluramine, S(+)-norfenfluramine, phentermine). These differences in mode of action may be linked to the adverse cardiovascular events experienced with some of the releasing agents.

Monoamine oxidase activity, lipid peroxidation, and morphological changes in human hypothalamus during aging.

Abstract: Progressive gliosis of the hypothalamus during aging in humans is accompanied by activation of monoamine oxidase B activity, intensification of lipid peroxidation, and inhibition of SDH. Density of capillaries decreases. The role of monoamine oxidase B in the induction of lipid peroxidation is discussed.

Spectrometric evidence for the flavin-1-phenylcyclopropylamine inactivator adduct with monoamine oxidase N.

Abstract: 1-Phenylcyclopropylamine (1-PCPA) is shown to be an inactivator of the fungal flavoenzyme monoamine oxidase (MAO) N. Inactivation results in an increase in absorbance at 410 nm and is accompanied by the concomitant loss of the flavin absorption band at 458 nm. The spectral properties of the covalent adduct formed between the flavin cofactor of MAO N and 1-PCPA are similar to those reported for the irreversible inactivation product formed with 1-PCPA and mammalian mitochondrial monoamine oxidase B [Silverman, R. B., and Zieske, P. A. (1985) Biochemistry 24, 2128−2138]. There is a hypsochromic shift of the 410 nm band upon lowering the pH to 2, indicating that an N5-flavin adduct formed upon inactivation. Use of the fungal enzyme, MAO N, which lacks the covalent attachment to the flavin adenine dinucleotide (FAD) cofactor present in the mammalian forms MAO A and MAO B, has allowed for the isolation and further structural identification of the flavin−inactivator adduct. The incorporation of two 13C labels in...

Biochemical characteristics of liver and brain monoamine oxidase from pacu

Abstract: Monoamine oxidase (MAO) activity in the liver and brain of the pacu, Piaractus mesopotamicus was determined using a fluorescence assay with kynuramine as substrate. Apparent Michaelis constant values (20.33 μM for liver and 25.85 μM for brain) were similar in these tissues, but in terms of tissue protein MAO activity from liver was 4.5 times higher than from brain. The greater inhibitory effects of clorgyline than of deprenyl on MAO activity from liver and brain of this species suggest that pacu's MAO is a type A-like enzyme.

Comparative analysis of age-related changes in activities of monoamine oxidase-B and antioxidant defense enzymes in various structures of human brain.

Abstract: Activities of monoamine oxidase B, Cu-Zn-dependent superoxide dismutase (SOD), and catalase, and concentration of enzyme-active ceruloplasmin were measured in brain preparations from 43 humans died at the age of 21-92 years. Activity of monoamine oxidase B in the neocortex, cerebellum, basal ganglia, and stem structures increased with age, while SOD activity decreased and catalase and ceruloplasmin concentrations slightly increased. A contribution of age-related increase of cerebral monoamine oxidase activity into ontogenetic impairment of the antioxidant defense in human brain is discussed.

Oxidative stress indices in Parkinson's disease : biochemical determination.

Abstract: ABSTRUCT: Parkinson's disease (PD) is associated with progressive degeneration of melanin-containing dopamine neuron cell bodies arising in the substantia nigra pars compacta (SNpc) and projecting terminals to the striatum. The disease is best characterized biochemically as a deficiency of striatal dopamine. The mechanism of neurodegeneration remains an enigma despite a large body of investigation and several hypotheses (1-5). In the past decade much has been learned about the chemical pathology of the disease. This progress has been helped by elucidation of the mechanism of the neurotoxic actions of 6-hydroxydopamine (6-OHDA) and N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which are used to induce animal models of this disease. Thus, the most valid current hypothesis concerning the pathogenesis of idiopathic PD is progressive oxidative stress (OS), which can generate excessive reactive oxygen species (ROS) selectively in the SNpc (1-9), and subsequent biochemical abnormalities (Table 1). In addition, the ROS scavenging system may also diminish, which would exaggerate the condition leading to accumulation of ROS. In PD, it is thought that both these events occur; Table 1 gives a summary of the biochemical changes identified to date in the SNpc of PD patients. Iron, monoamine oxidase B (MAO-B), copper/zinc superoxide dismutase (Cu/Zn-SOD), and heme oxygenase (radical producing) are increased; reduced glutathione (GSH) and vitamin C (radical scavenging) are decreased. Whether OS is a primary or secondary event in PD has not been established, but when it does occur, OS can lead to a cascade of events resulting in the demise of the nigrostriatal dopaminergic neurons. One approach toward protection of such neurons is the use of radical scavengers or iron chelators as neuroprotective drugs (10). Table 1 Biochemical Alterations in Substantia Nigra of Parkinson's Disease Indicating Oxidative Stress Elevated Decreased Iron (in microglia, astrocytes, oligodendrocytes, and melanized dopamine neurons and mitochondria) GSH (GSSG unchanged); GSH/GSSG ratio decreased Mitochondrial complex I Ferritin Calcium binding protein (calbindin 28) Mitochondrial monoamine oxidase B Transferrin and transferrin receptor Lipofuscin Vitamins E and C Ubiquitin Copper Cu/Zn-superoxide dismutase Cytotoxic cytokines (TNF-a, IL-1, IL-6) Inflammatory transcription factor NFKB Heme oxygenase-1 Ratio of oxidized to reduced glutathione (GSSG/GSH) Nitric oxide Neuromelanin.

Computer modeling of oxygen containing heptylamines as monoamine oxidase inactivators

Abstract: Monoamine oxidase is a flavoenzyme that catalyzes the oxidation of amines. Primary amines are excellent substrates for MAO but primary amine analogues having an electron withdrawing group near the amino methyl methylene group are known to inactivate the enzyme. In order to investigate the proposed inductive effect, a series of amino ethers and their enzyme-adduct models were studied with Self Consistent Field theory using a semi-empirical PM3 method and an ab initio method at the MP2/6-31G∗//6-31G∗ level. According to the proposed inactivation mechanism, the stabilities of the adducts are inversely related to the enzyme reactivation rate. Therefore, we interpreted the order of enzyme reactivation rate in terms of intramolecular stabilization and stereoelectronic effects. Calculations predicted that intramolecular H-bonding interactions and CH2/O nonbonded interactions play important roles in the stability of these molecules. In enzyme-adducts, we also found out a special SCH3/N type of nonbonded interaction and negative hyperconjugation in the –SCH2NH2 fragment.