Showing papers on "Monoamine oxidase published in 2001"

Dopamine oxidation alters mitochondrial respiration and induces permeability transition in brain mitochondria: implications for Parkinson's disease.

Abstract: Both reactive dopamine metabolites and mitochondrial dysfunction have been implicated in the neurodegeneration of Parkinson's disease. Dopamine metabolites, dopamine quinone and reactive oxygen species, can directly alter protein function by oxidative modifications, and several mitochondrial proteins may be targets of this oxidative damage. In this study, we examined, using isolated brain mitochondria, whether dopamine oxidation products alter mitochondrial function. We found that exposure to dopamine quinone caused a large increase in mitochondrial resting state 4 respiration. This effect was prevented by GSH but not superoxide dismutase and catalase. In contrast, exposure to dopamine and monoamine oxidase-generated hydrogen peroxide resulted in a decrease in active state 3 respiration. This inhibition was prevented by both pargyline and catalase. We also examined the effects of dopamine oxidation products on the opening of the mitochondrial permeability transition pore, which has been implicated in neuronal cell death. Dopamine oxidation to dopamine quinone caused a significant increase in swelling of brain and liver mitochondria. This was inhibited by both the pore inhibitor cyclosporin A and GSH, suggesting that swelling was due to pore opening and related to dopamine quinone formation. In contrast, dopamine and endogenous monoamine oxidase had no effect on mitochondrial swelling. These findings suggest that mitochondrial dysfunction induced by products of dopamine oxidation may be involved in neurodegenerative conditions such as Parkinson's disease and methamphetamine-induced neurotoxicity.

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.

Coumarins derivatives as dual inhibitors of acetylcholinesterase and monoamine oxidase

Abstract: A set of 17 coumarin and 2 chromone derivatives with known inhibitory activity toward monoamine oxidase (MAO) A and B were tested as acetylcholinesterase (AChE) inhibitors. All compounds inhibited AChE with values in the micromolar range (3−100 μM). A kinetic study showed that most compounds acted as noncompetitive AChE inhibitors. This finding may be of interest in the context of Alzheimer's disease because recent observations suggest that MAO and AChE inhibition might decrease β-amyloid deposition.

Cell surface monoamine oxidases: enzymes in search of a function

Abstract: Ectoenzymes with a catalytically active domain outside the cell surface have the potential to regulate multiple biological processes. A distinct class of copper-containing semicarbazide-sensitive monoamine oxidases, expressed on the cell surface and in soluble forms, oxidatively deaminate primary amines. Via transient covalent enzyme–substrate intermediates, this reaction results in production of aldehydes, hydrogen peroxide and ammonium, which are all biologically active substances. The physiological functions of these enzymes have remained unknown, although they have been suggested to be involved in the metabolism of biogenic amines. Recently, new roles have been proposed for these enzymes in regulation of glucose uptake and, even more surprisingly, in leukocyte–endothelial cell interactions. The emerging functions of ectoenzymes in signalling and cell–cell adhesion suggest a novel mode of molecular control of these complex processes.

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.

Use of dopamine-beta-hydroxylase-deficient mice to determine the role of norepinephrine in the mechanism of action of antidepressant drugs.

Abstract: Norepinephrine (NE) is thought to play an important role in the pathophysiology of depression, and in the mechanism of action of antidepressant compounds. Previously, we created mice that are unable to synthesize NE and epinephrine due to targeted disruption of the dopamine-β-hydroxylase gene ( Dbh ). To specifically test the role of NE in mediating behavioral changes elicited by antidepressants, these mice were examined in the forced swim test. There was no difference in baseline immobility scores in the forced swim test between Dbh +/−mice, which have normal levels of NE, and Dbh −/− mice. However, the Dbh −/− mice failed to demonstrate antidepressant-like behavioral effects following the administration of several classes of antidepressants. These included the NE reuptake inhibitors desipramine and reboxetine, the monoamine oxidase inhibitor pargyline, and the atypical antidepressant bupropion. In addition, desipramine significantly reduced immobility in the Dbh −/− mice following pretreatment with the synthetic NE precursorl- threo -3,4-dihydroxyphenylserine, but not saline. Biochemical studies showed that there was no significant difference in the regional brain levels of NE transporter immunoreactivity or monoamine oxidase activity, the primary targets for most of the compounds examined. Taken together, these data show that the use of mice that lack endogenous NE may be an important strategy for unraveling the role of NE in tests sensitive to the effects of various psychotherapeutic agents.

Parkinson's disease--redox mechanisms.

Abstract: Parkinsons disease occurs in 1percent of people over the age of 65 when about 60percent of the dopaminergic neurons in the substantia nigra of the midbrain are lost. Dopaminergic neurons appear to die by a process of apoptosis that is induced by oxidative stress. Oxygen radicals abstract hydrogen from DNA forming DNA radicals that lead to DNA fragmentation, activation of DNA protective mechanisms, NAD depletion and apoptosis. Oxygen radicals can be formed in dopaminergic neurons by redox cycling of MPP+ , the active metabolite of MPTP. This redox cycling mechanism involves the reduction of MPP+ by a number of enzymes, especially flavin containing enzymes, some of which are found in mitochondria. Tyrosine hydroxylase is present in all dopaminergic neurons and is responsible for the synthesis of dopamine. However, tyrosine hydroxylase can form oxygen radicals in a redox mechanism involving its cofactor, tetrahydrobiopterin. Dopamine may be oxidized by monoamine oxidase to form oxygen radicals and 3,4-dihydroxyphenylacetaldehyde. This aldehyde may be oxidized by aldehyde dehydrogenase with the formation of oxygen radicals and 3,4-dihydroxyphenylacetic acid. The redox mechanisms of oxygen radical formation by MPTP, tyrosine hydroxylase, monoamine oxidase and aldehyde dehydrogenase will be discussed. Possible clinical applications of these mechanisms will be briefly presented.

Expanding the horizons of depression: beyond the monoamine hypothesis.

Abstract: The monoamine hypothesis has dominated our understanding of depression and of pharmacological approaches to its management and it has produced several generations of antidepressant agents, ranging from the monoamine oxidase inhibitors (MAOIs), through tricyclics (TCAs) and selective serotonin reuptake inhibitors (SSRIs), to the recently introduced selective noradrenaline reuptake inhibitor (NARI), reboxetine. Greater receptor selectivity has improved tolerability, but not efficacy, when newer compounds are compared with the original tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors. Essentially, the newer antidepressants have the same distinguishing feature as older ones, i.e. acute enhancement of monoaminergic neurotransmission. The monoamine hypothesis cannot conclusively link the acute biochemical action of antidepressants on monoamine levels with their delayed clinical effect of 10-14 days, nor can it explain the mode of action of antidepressants that are effective despite being very weak inhibitors of monoaminergic transmission (e.g. iprindole) or, incongruously, enhancing monoamine uptake (e.g. tianeptine). Compared with other fields of medicine, there has been a lack of progress in understanding the pathophysiology of depression and producing truly novel antidepressant agents. Other biological approaches to depression, such as overactivity of the hypothalamic-pituitary-adrenal axis, hippocampal neural plasticity in response to stress, and the link between the inflammatory response and depression, offer new approaches to finding pharmacological agents, aided by improved techniques for visualising the human brain, better animal models, and increased knowledge of human markers of depression. Copyright 2001 John Wiley & Sons, Ltd.

Monoamine oxidase inhibitors from rhizoma of Coptis chinensis.

Abstract: Three protoberberine alkaloids jatrorrhizine, berberine and palmatine were isolated from the monoamine oxidase (MAO) inhibitory fraction of the methanol extract of Coptis chinensis rhizoma. Jatrorrhizine was shown to inhibit non-competitively both MAO-A and -B from rat brain mitochondria with the IC50 values of 4 and 62 microM, respectively. Berberine only competitively inhibited MAO-A with an IC50 values of 126 microM whereas palmatine exhibited, up to 200 microM, no inhibition on any type of the enzyme. The structure-activity relationship was briefly discussed.

Coumarins with monoamine oxidase inhibitory activity and antioxidative coumarino-lignans from Hibiscus syriacus.

Abstract: A previously undescribed coumarin and a new coumarino-lignan, together with the known compounds scopoletin and cleomiscosins A, C, and D, have been isolated from the root bark of Hibiscus syriacus, and their structures were assigned on the basis of various spectral studies. The coumarin analogue and scopoletin inhibited monoamine oxidase with moderate IC(50) values. The new coumarino-lignan and cleomiscosin C showed lipid peroxidation inhibitory activity comparable to vitamin E.

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.

Amine oxidase substrates mimic several of the insulin effects on adipocyte differentiation in 3T3 F442A cells.

Abstract: We have previously reported that substrates of monoamine oxidase (MAO) and semicarbazide-sensitive amine oxidase (SSAO) exert short-term insulin-like effects in rat adipocytes, such as stimulation of glucose transport. In the present work, we studied whether these substrates could also mimic long-term actions of insulin. Adipose differentiation of 3T3 F442A cells, which is highly insulin-dependent, served as a model to test the effects of sustained administration of amine oxidase substrates. Daily treatment of confluent cells with 0.75 mM tyramine (a substrate of MAO and SSAO) or benzylamine (a substrate of SSAO) over 1 week caused the acquisition of typical adipocyte morphology. The stimulation of protein synthesis and triacylglycerol accumulation caused by tyramine or benzylamine reached one half of that promoted by insulin. This effect was insensitive to pargyline (an MAO inhibitor), but was inhibited by semicarbazide (an SSAO inhibitor) and by N-acetylcysteine (an antioxidant agent), suggesting the involvement of the H(2)O(2) generated during SSAO-dependent amine oxidation. Chronic administration of amine oxidase substrates also induced the emergence of adipose conversion markers, such as aP2, glycerol-3-phosphate dehydrogenase, the glucose transporter GLUT4, and SSAO itself. Moreover, cells treated with amines acquired the same insulin sensitivity regarding glucose transport as adipocytes classically differentiated with insulin. In all, most of the adipogenic effects of amines were additive to insulin. Our data reveal that amine oxidase substrates partially mimic the adipogenic effect of insulin in cultured preadipocytes. Furthermore, they suggest that SSAO not only represents a novel late marker of adipogenesis, but could also be directly involved in the triggering of terminal adipocyte differentiation.

Changes in endogenous monoamines in aged rats

Abstract: SUMMARY 1. It has been documented that ageing may alter endogenous neurotransmitters. However, these results are controversial. Thus, in the present study, cerebral cortex and plasma from male Wistar rats aged 8 weeks and 6, 12 or 24 months were used to investigate the changes in monoamines using electrochemical detection. 2. A marked decrease in L-dihydroxyphenylalanine (L-DOPA) was observed in aged rats. Like the decrease in dopamine (DA), levels of 5-hydroxytryptamine (5-HT) and 5-hydroxyindolacetic acid (5-HIAA), the major metabolite of 5-HT, in aged rats were decreased in the cerebral cortex and plasma. Plasma levels of noradrenaline and levels of adrenaline in the cerebral cortex were also decreased in aged rats. Moreover, levels of 3,4-dihydroxyphenylacetic acid (DOPAC), a metabolite of DA, in the cerebral cortex and plasma were reduced by ageing. The level of homovanillic acid (HVA) in all samples was markedly increased with ageing. 3. The ratio of DOPAC/DA and 5-HIAA/5-HT, being closely linked with the activity of monoamine oxidase, was increased in the cerebral cortex and plasma with ageing. The ratio of HVA/DOPAC, an index of the activity of catechol-O-methyltransferase, was also higher in the cerebral cortex and plasma of aged rats. 4. These data suggest that ageing may alter endogenous monoamines in both the brain and peripheral tissues.

Neuroprotection in the MPTP Parkinsonian C57BL/6 mouse model by a compound isolated from tobacco.

Abstract: Epidemiological evidence suggests a lower incidence of Parkinson's disease in smokers than in nonsmokers. This evidence, together with the lower levels of brain monoamine oxidase (MAO) activity in smokers and the potential neuroprotective properties of MAO inhibitors, prompted studies which led to the isolation and characterization of 2,3,6-trimethyl-1,4-naphthoquinone (TMN), an MAO-A and MAO-B inhibitor which is present in tobacco and tobacco smoke. Results of experiments reported here provide evidence that this compound protects against the MPTP-mediated depletion of neostriatal dopamine levels in the C57BL/6 mouse. These results support the hypothesis that the inhibition of MAO by constituents of tobacco smoke may be related to the decreased incidence of Parkinson's disease in smokers.

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.

Biotransformation of xenobiotics by amine oxidases.

Abstract: Although the cytochrome P450 (CYP) system ranks first in terms of catalytic versatility and the wide range of xenobiotics it detoxifies or activates to reactive intermediates, the contribution of amine oxidases and in particular of monoamine oxidases (MAOs) to the metabolism of xenobiotics is far from negligible but has been largely neglected. In this review on the involvement of amine oxidases in the metabolism of xenobiotics, the major characteristics reported for the CYP system (protein, reaction, tissue distribution, subcellular localisation, substrates, inhibitors, inducers, genetic polymorphism, impact of different physiopathological conditions on the activity, turnover) will be compared, whenever possible, with the corresponding characteristics of amine oxidases (MAOs in particular). The knowledge of the involvement of MAO-A, -B or both in the metabolism of a drug allows us to predict interactions with selective or non-selective MAO inhibitors (e.g. the metabolism of a drug deaminated by both forms of MAO is not necessarily inhibited in vivo by a selective MAO-A or -B inhibitor). If a drug is metabolized by MAOs, competitive interactions can occur with other drugs that are MAO substrates, e.g. with beta-adrenoceptor agonists and antagonists, prodrugs of dopamine, serotonin 5-HT1-receptor agonists as well as with primaquine, flurazepam and citalopram. Moreover, the knowledge of the involvement of MAOs in the metabolism of a drug may suggest possible, although not obligatory, interactions with tyramine-containing food or drink, with over the counter medicines sold to relieve the symptoms of coughs and colds (generally containing the indirectly-acting sympathomimetic amine phenylpropanolamine) or with phenylephrine-containing preparations. Finally, biotransformation by amine oxidases, as by CYP, does not always lead to detoxication but can produce toxic compounds.

Synthesis of potential antidipsotropic isoflavones: inhibitors of the mitochondrial monoamine oxidase-aldehyde dehydrogenase pathway.

Abstract: Recently we have shown that daidzin, the major active principle of an ancient herbal treatment for "alcohol addiction", suppresses ethanol intake in alcohol-preferring laboratory animals. Further, we have identified the monoamine oxidase (MAO)-aldehyde dehydrogenase (ALDH-2) pathway of the mitochondria as the potential site of action of daidzin. Daidzin analogues that potently inhibit ALDH-2 but have no or little effect on MAO are most antidipsotropic, whereas those that also inhibit MAO exhibit little, if any, antidipsotropic activity. Therefore, in the design and synthesis of more potent antidipsotropic analogues, structural features important for the inhibition of both ALDH-2 and MAO must be taken into consideration. To gain further information on the structure-activity relationships at the inhibitor binding sites of ALDH-2 and MAO, we prepared 44 analogues of daidzin and determined their potencies for ALDH-2 and MAO inhibition. Results indicate that a sufficient set of criteria for a potent antidipsotropic analogue is an isoflavone with a free 4'-OH function and a straight-chain alkyl substituent at the 7 position that has a terminal polar function such as -OH, -COOH, or -NH(2). The preferable chain lengths for the 7-O-omega-hydroxy, 7-O-omega-carboxy, and 7-O-omega-amino subsitutents are 2 or = 4, respectively. Analogues that meet these criteria have increased potency for ALDH-2 inhibition and/or decreased potency for MAO inhibition and therefore are likely to be potent antidipsotropic agents.

Platelet monoamine oxidase B and plasma beta-phenylethylamine in Parkinson's disease.

Abstract: OBJECTIVE To evaluate the correlation between changes in platelet monoamine oxidase type B (MAO-B) activity and plasma β-phenylethylamine (PEA) concentrations in patients with Parkinson9s disease and controls. METHODS Platelet MAO-B activity and plasma PEA were measured with gas chromatography-mass spectrometry (GC-MS) in patients with Parkinson9s disease treated with levodopa (12 men and 12 women) or selegiline (three men and three women), and physically healthy subjects as a control group (10 men and 10 women). RESULTS Platelet MAO-B activity was significantly higher in the Parkinson9s disease group (mean 542 (SD 318) pmol/10 7 platelets/30 min) than in the control group (mean 349 (SD 307) pmol/10 7 platelets/30 min) (p r =−0.466, p CONCLUSIONS The increase in platelet MAO-B activity and decrease in plasma PEA concentrations in patients with Parkinson9s disease may be involved in the pathophysiological processes of the disease, and these changes are reversed by treatment with selegiline.

Pathophysiological role of the serotonin system in malignant hyperthermia

Abstract: Serotonin (5-hydroxytryptamine, 5-HT) is a biogenic amine that is distributed widely in various body tissues and cell types 1 and possesses a diversity of pharmacological effects at both central and peripheral sites. 5-HT is involved in the control of temperature regulation, cardiovascular function, muscle contraction and endocrine regulation. Peripherally, 5-HT appears to play a major role in platelet homeostasis and the motility of the gastrointestinal tract. Furthermore, 5HT exerts important effects on skeletal muscles. Synthesis and metabolism 5-HT is synthesized in situ from the amino acid precursor tryptophan. The conversion of tryptophan to 5-hydroxytryptophan is mediated by a tryptophan hydroxylase. 5Hydroxytryptophan is subsequently decarboxylated to 5hydroxytryptamine. 5-HT is then metabolized by oxidative deamination by the A enzyme of monoamine oxidase in the liver; the 5-hydroxyindoleacetaldehyde formed from this process is then oxidized to 5-hydroxyindole-3-acetic acid. 5-HT is stored in intracellular vesicles until depolarization of the neurone causes the release of this neurotransmitter into the synapse. Once 5-HT is released into the synapse, its function is terminated rapidly by its presynaptic reuptake into the neurone.

Effects of harmine on dopamine output and metabolism in rat striatum: role of monoamine oxidase-A inhibition

Abstract: In vivo microdialysis was used to investigate the effects of acute injections of harmine on extracellular concentrations of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxindoleacetic acid (5-HIAA) in the striatum of awake rats. Administration of harmine in doses of 0.5, 2.5, and 10 mg/kg (i.p.) elicited a dose-dependent increase of the dopamine efflux to 152, 173, and 243% and a decrease in DOPAC to 52, 36, and 10%, and HVA to 67, 45, and 20% throughout, respectively; 5-HIAA concentrations were decreased to 81, 74, and 72% only. In contrast to D-amphetamine, which also increases dopamine release and decreases its metabolites, the stimulatory action of harmine on dopamine release in the striatum was totally abolished in the presence of tetrodotoxin (1 µM). Similar to monoamine oxidase (MAO)-A inhibitors, harmine potentiated the stimulatory effect of D-amphetamine (10 µM), infused by reverse microdialysis in the striatum, on dopamine release. Pre-treatment with the benzodiazepine receptor antagonist flumazenil (5 mg/kg, i.p.) did not modulate the effect of harmine on striatal dopamine release and metabolism. Administration of the reversible MAO-A inhibitor, moclobemide (20 mg/kg, i.p.), induced an increase in dopamine to 256% and a decrease in DOPAC, HVA, and 5-HIAA to 30, 24, and 62%, respectively, reproducing a pattern similar to that of harmine. Taken together, these results indicate that harmine affects the brain dopamine system probably by acting as a MAO-A inhibitor and not as an inverse agonist for the benzodiazepine receptors.

Dual action of octopamine on glucose transport into adipocytes: inhibition via beta3-adrenoceptor activation and stimulation via oxidation by amine oxidases.

Abstract: Octopamine, which is closely related to norepinephrine, acts as a neurotransmitter in invertebrates and is a trace amine with undefined properties in vertebrates. The octopaminergic receptors identified in insects are targets of various pesticides but are absent in vertebrates. We have established that octopamine stimulates fat cell lipolysis in mammals via activation of beta3-adrenoceptors (ARs), whereas this amine has been described elsewhere as an alpha2-AR agonist and as a substrate for monoamine oxidase (MAO) or semicarbazide-sensitive amine oxidase (SSAO). Because we have recently reported that amine oxidase substrates promote glucose transport in rat and human adipocytes, the in vitro octopamine effects on lipolysis and glucose uptake were reassessed by using adipocytes from beta3-AR-deficient mice. The lipolytic effect and the counter-regulation of insulin action on glucose transport provoked by 0.1 to 1 mM octopamine or by 1 microM beta3-AR agonists found in control animals disappeared in adipocytes from beta3-AR-deficient mice. This revealed an insulin-like effect of octopamine on glucose uptake, which was dependent on its oxidation by MAO or SSAO, as was the case for tyramine and benzylamine, devoid of beta3-adrenergic agonism. Similarly, octopamine promoted glucose transport in human adipocytes and exhibited a weaker lipolytic stimulation than in rodent adipocytes. These findings indicate that, besides its lipolytic activity, octopamine exerts, at millimolar dose, dual effect on glucose transport in adipocytes: counteracting insulin action via beta3-AR activation and stimulating basal transport via its oxidation by MAO or SSAO.