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Glen B. Baker - One of the best experts on this subject based on the ideXlab platform.
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brain GABA and alanine: A
2013Co-Authors: Kathryn G. Todd, Glen B. BakerAbstract:effects of the Monoamine Oxidase Inhibitor phenelzine o
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neurochemical effects of the Monoamine Oxidase Inhibitor phenelzine on brain gaba and alanine a comparison with vigabatrin
Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, 2008Co-Authors: Kathryn G. Todd, Glen B. BakerAbstract:PURPOSE. To compare phenelzine (PLZ), an antidepressant drug with anxiolytic properties which inhibits Monoamine Oxidase (MAO) but also elevates rat brain levels of the amino acids ?-aminobutyric acid (GABA) and alanine (ALA), with vigabatrin (VIG), an anticonvulsant which elevates brain GABA by inhibition of GABA transaminase (GABA-T), with regard to their actions on brain levels of GABA and ALA and on activities of MAO, GABA-T and ALA transaminase (ALA-T). METHODS. Male rats were administered PLZ (10 mg/kg) or VIG (1,000 mg/kg) i.p., and the rats were euthanized 4 hours later and the brains removed for analysis of levels of GABA and ALA (by electron capture gas chromatography after derivatization) and activities of MAO, GABA-T and ALA-T (radiochemical assays). RESULTS. Both PLZ and VIG inhibited GABA-T and elevated GABA levels. Only PLZ inhibited MAO and ALA-T and elevated ALA levels. The effects of PLZ on both amino acids and their transaminases were blocked by pre-treatment with the MAO Inhibitor tranylcypromine. This pretreament had no effect on the inhibition of GABA-T or the elevation of brain GABA levels produced by VIG. CONCLUSIONS. At the doses studied, PLZ was as effective as VIG at elevating brain GABA levels, but, unlike VIG, also inhibited MAO and ALA-T (and increased brain ALA levels). Pretreatment of rats with the MAO Inhibitor tranylcypromine prevented the increase in brain GABA and ALA levels with PLZ, but did not block the effect of VIG on GABA. These observations with tranylcypromine and PLZ support the hypothesis that an active metabolite of PLZ produced by the actions of MAO on this drug plays a major role in its GABA- and ALA-elevating actions.
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Inhibitory effects of the Monoamine Oxidase Inhibitor tranylcypromine on the cytochrome p450 enzymes cyp2c19 cyp2c9 and cyp2d6
Cellular and Molecular Neurobiology, 2004Co-Authors: Mahnaz Salsali, Andrew Holt, Glen B. BakerAbstract: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.
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Effects of age and of chronic antidepressant treatment on [^3H]tryptamine and [^3H]dihydroalprenolol binding to rat cortical membranes
Cellular and Molecular Neurobiology, 1993Co-Authors: Darrell D. Mousseau, David J. Mcmanus, Glen B. Baker, Augusto V. Juorio, William G. Dewhurst, Andrew J. GreenshawAbstract:1. The effects of age and of chronic antidepressant treatment on [^3H]tryptamine and [^3H]dihydroalprenolol binding site density were measured in brain cortical membranes from male Sprague-Dawley rats. 2. The density but not the affinity of [^3H]tryptamine binding sites was increased in 18-month-old rats relative to 3-month-old rats. Neither the density nor the affinity of [^3H]dihydroalprenolol binding sites was affected by age. 3. Chronic administration (28 days s.c. via Alzet osmotic minipumps) of tricyclic antidepressant drugs (daily doses: imipramine·HCl, 30 mg kg^−1; desipramine·HCl, 10 mg kg^−1; clomipramine·HCl, 10 mg kg^−1) resulted in decreases in [^3H]dihydroalprenolol binding site density but no changes in [^3H]tryptamine binding site density; no changes in affinity of either site were observed. 4. Chronic administration (s.c. via Alzet osmotic minipumps) of Monoamine Oxidase Inhibitor antidepressant drugs (daily doses: tranylcypromine·HCl, 0.5 and 1.0 mg kg^−1; phenelzine sulfate, 5 and 10 mg kg^−1, each for 28 days; clorgyline·HCl, 1.0 mg kg^−1; (−)-deprenyl·HCl, 1.0 mg kg^−1, each for 14 days) resulted in decreases in [^3H]tryptamine binding site density, without any effects on the affinity of this site. In addition, each of these Monoamine Oxidase Inhibitors except (−)-deprenyl resulted in a decrease in [^3H]dihydroalprenolol binding site density. No affinity changes were observed. 5. These data indicate that the [^3H]tryptamine binding site exhibits physiological changes with aging and is differentially sensitive to the actions of tricyclic antidepressants and Monoamine Oxidase Inhibitor antidepressants, respectively.
Khashayar Dashtipour - One of the best experts on this subject based on the ideXlab platform.
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comprehensive review of rasagiline a second generation Monoamine Oxidase Inhibitor for the treatment of parkinson s disease
Clinical Therapeutics, 2007Co-Authors: Jack J Chen, David M Swope, Khashayar DashtipourAbstract:Background: Inhibitors of Monoamine Oxidase (MAO) with selectivity and specificity for MAO type B (MAO-B) prolong the duration of action of both endogenously and exogenously derived dopamine. Rasagiline [N-propargyl-l(R)-aminoindan] is a second-generation propargylamine pharmacophore that selectively and irreversibly inhibits brain MAO-B and is specifically designed for the treatment of Parkinson's disease (PD). Objective: The aim of this study was to review the pharmacology, tolerability, and clinical efficacy of rasagiline in the treatment of PD. Methods: MEDLINE (1966-April 2007), the Cochrane Database of Systematic Reviews, and International Pharmaceutical Abstracts (1970-April 2007) were searched for original research and review articles published in English. The search terms were Monoamine Oxidase, neuroprotection, Parkinson disease, propargylamine, rasagiline, and selegiline. The reference lists of articles were also consulted, as was information provided by the manufacturer of rasagiline. Results: Data from 63 clinical and laboratory studies were analyzed. Based on the results from those studies, we concluded that rasagiline PO QD, at the therapeutic dosage range of 0.5 to 1 rag/d, is effective and well tolerated and completely, selectively, and specifically inhibited MAO-B. Pharmacologically, rasagiline was found to be ≤10-fold more potent than selegiline and was not metabolized to amphetamine derivatives. Rasagiline was effective both as monotherapy in early PD and as adjunctive treatment in patients with advancing PD and motor fluctuations. As monotherapy, rasagiline provided modest yet clinically meaningful benefit. A randomized, double-blind, placebo-controlled study found that, after 26 weeks of treatment, the adjusted effect size for total Unified Parkinson's Disease Rating Scale score was –4.20 (95% CI, -5.66 to -2.73) for rasagiline 1 mg/d versus placebo (P < 0.001). Preliminary long-term data from an open-label study suggest a sustained therapeutic advantage when rasagiline is initiated early (before the need for dopaminergic agents) rather than later. In patients with more advanced disease who received treatment with dopaminergic agents, rasagiline and entacapone were associated with reductions of “off” time significantly greater than placebo (-1.18 and -1.2 vs 0.4 hour; both, P ≤ 0.001). Rasagiline was well tolerated in younger (aged <;70 years) and older (aged ≥70 years) patients with early or advanced PD. Pharmacologically, rasagiline has the potential to augment the vasopressor effects of diet-derived tyramine (ie, the “cheese reaction”). However, clinical challenge studies of tyramine have found this unlikely to occur even with ingestion of supraphysiologic amounts of tyramine. In experimental models, rasagiline has been found to have neuroprotective properties that may be independent of MAO-B inhibition. Conclusions: Based on this review, rasagiline has been found to be well tolerated and effective in the treatment of early PD and as adjunctive treatment in motor fluctuations. Whether rasagiline is associated with clinically significant neuroprotection (ie, disease modification) in PD is the subject of ongoing clinical trials.
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comprehensive review of rasagiline a second generation Monoamine Oxidase Inhibitor for the treatment of parkinson s disease
Clinical Therapeutics, 2007Co-Authors: Jack J Chen, David M Swope, Khashayar DashtipourAbstract:Background Inhibitors of Monoamine Oxidase (MAO) with selectivity and specificity for MAO type B (MAO-B) prolong the duration of action of both endogenously and exogenously derived dopamine. Rasagiline [N-propargyl-l(R)-aminoindan] is a second-generation propargylamine pharmacophore that selectively and irreversibly inhibits brain MAO-B and is specifically designed for the treatment of Parkinson's disease (PD). Objective The aim of this study was to review the pharmacology, tolerability, and clinical efficacy of rasagiline in the treatment of PD. Methods MEDLINE (1966-April 2007), the Cochrane Database of Systematic Reviews, and International Pharmaceutical Abstracts (1970-April 2007) were searched for original research and review articles published in English. The search terms were Monoamine Oxidase, neuroprotection, Parkinson disease, propargylamine, rasagiline, and selegiline. The reference lists of articles were also consulted, as was information provided by the manufacturer of rasagiline. Results Data from 63 clinical and laboratory studies were analyzed. Based on the results from those studies, we concluded that rasagiline PO QD, at the therapeutic dosage range of 0.5 to 1 rag/d, is effective and well tolerated and completely, selectively, and specifically inhibited MAO-B. Pharmacologically, rasagiline was found to be or =70 years) patients with early or advanced PD. Pharmacologically, rasagiline has the potential to augment the vasopressor effects of diet-derived tyramine (ie, the "cheese reaction"). However, clinical challenge studies of tyramine have found this unlikely to occur even with ingestion of supraphysiologic amounts of tyramine. In experimental models, rasagiline has been found to have neuroprotective properties that may be independent of MAO-B inhibition. Conclusions Based on this review, rasagiline has been found to be well tolerated and effective in the treatment of early PD and as adjunctive treatment in motor fluctuations. Whether rasagiline is associated with clinically significant neuroprotection (ie, disease modification) in PD is the subject of ongoing clinical trials.
Robert Gully - One of the best experts on this subject based on the ideXlab platform.
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phenelzine vs atenolol in social phobia a placebo controlled comparison
Archives of General Psychiatry, 1992Co-Authors: Michael R Liebowitz, Raphael Campeas, Franklin R Schneier, Jack M. Gorman, Abby J. Fyer, Eric Hollander, Julie A. Hatterer, Laslo Papp, Sharon O Davies, Robert GullyAbstract:Seventy-four patients who met DSM-III criteria for social phobia completed 8 weeks of double-blind, randomly assigned treatment with the Monoamine Oxidase Inhibitor phenelzine sulfate, the cardioselective β-adrenergic blocker atenolol, or placebo. The overall response rates were 64% for phenelzine, 30% for atenolol, and 23% for placebo. Phenelzine was widely superior to both atenolol and placebo on independent rater analyses and, to a lesser extent, on self-report, with no significant differences between atenolol and placebo. At the end of 16 weeks, phenelzine was still significantly superior to placebo, while atenolol showed an intermediate response that did not differ significantly from either of the other treatments. Patients with generalized social phobia constituted 76% of the sample, and they were preferentially responsive to phenelzine. The small size of the discrete social phobic sample precluded separate outcome analyses for this subtype. Overall, the findings support the responsivity of social phobia to Monoamine Oxidase Inhibitors.
Moussa B H Youdim - One of the best experts on this subject based on the ideXlab platform.
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the novel cholinesterase Monoamine Oxidase Inhibitor and antioxidant ladostigil confers neuroprotection in neuroblastoma cells and aged rats
Journal of Molecular Neuroscience, 2009Co-Authors: Orit Baram, Orly Weinreb, Tamar Amit, Moussa B H YoudimAbstract:The current therapeutic advance in which future drugs are designed to possess varied pharmacological properties and act on multiple targets has stimulated the development of the multimodal drug, ladostigil (TV3326; (N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate). Ladostigil combines neuroprotective effects with Monoamine Oxidase (MAO)-A and MAO-B and cholinesterase (ChE) Inhibitory activities in a single molecule, as a potential treatment for Alzheimer’s disease (AD) and Lewy body disease. In the present study, we demonstrate that ladostigil (10−6–10 μM) dose-dependently increased cell viability, associated with increased activity of catalase and glutathione reductase and decrease of intracellular reactive oxygen species production in a cytotoxic model of human SH-SY5Y neuroblastoma cells exposed to hydrogen peroxide (H2O2). In addition, ladostigil significantly upregulated mRNA levels of several antioxidant enzymes (catalase, NAD(P)H quinone oxidoreductase 1 and peroxiredoxin 1) in both H2O2-treated SH-SY5Y cells, as well as in the high-density human SK-N-SH neuroblastoma cultured apoptotic models. In vivo chronic treatment with ladostigil (1 mg/kg per os per day for 30 days) markedly upregulated mRNA expression levels of various enzymes involved in metabolism and oxidation processes in aged rat hippocampus. In addition to its unique combination of ChE and MAO enzyme inhibition, these results indicate that ladostigil displays neuroprotective activity against oxidative stress-induced cell apoptosis, which might be valuable for aging and age-associated neurodegenerative diseases.
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attenuation of mptp induced dopaminergic neurotoxicity by tv3326 a cholinesterase Monoamine Oxidase Inhibitor
Journal of Neurochemistry, 2004Co-Authors: Yotam Sagi, Marta Weinstock, Moussa B H YoudimAbstract:(R)-[(N-propargyl-(3R) aminoindan-5-yl) ethyl methyl carbamate] (TV3326) is a novel cholinesterase and brain-selective Monoamine Oxidase (MAO)-A/-B Inhibitor. It was developed for the treatment of dementia co-morbid with extra pyramidal disorders (parkinsonism), and depression. On chronic treatment in mice it attenuated striatal dopamine depletion induced by MPTP and prevented the reduction in striatal tyrosine hydroxylase activity, like selective B and non-selective MAO Inhibitors. TV3326 preferentially inhibits MAO-B in the striatum and hippocampus, and the degree of MAO-B inhibition correlates with the prevention of MPTP-induced dopamine depletion. Complete inhibition of MAO-B is not necessary for full protection from MPTP neurotoxicity. Unlike that seen after treatment with other MAO-A and -B Inhibitors, recovery of striatal and hippocampal MAO-A and -B activities from inhibition by TV3326 did not show first-order kinetics. This has been attributed to the generation of a number of metabolites by TV3326 that cause differential inhibition of these enzymes. Inhibition of brain MAO-A and -B by TV3326 resulted in significant elevations of dopamine, noradrenaline and serotonin in the striatum and hippocampus. This may explain its antidepressant-like activity, resembling that of moclobemide in the forced-swim test in rats.
Francesc Artigas - One of the best experts on this subject based on the ideXlab platform.
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the 5 ht1a antagonist way 100635 selectively potentiates the presynaptic effects of serotonergic antidepressants in rat brain
Neuroscience Letters, 1996Co-Authors: Luz Romero, Ildefonso Hervas, Francesc ArtigasAbstract:The increases in extracellular serotonin (5-hydroxytryptamine; 5-HT) produced by some antidepressent drugs in forebrain are attenuated by the activation of somatodendritic 5-HT1A autoreceptors by the excess 5-HT induced by these agents in the midbrain raphe. Using microdialysis, we have examined the effects of the selective 5-HT1A antagonist WAY-100635 in rats pretreated with the selective 5-HT reuptake Inhibitors (SSRIs) citalopram, fluoxetine, fluvoxamine, the tricyclic antidepressants clomipramine and desipramine and the Monoamine Oxidase Inhibitor phenelzine. WAY-100635 markedly potentiated the increases in 5-HT produced by the SSRIs, clomipramine and phenelzine but it did not alter that produced by desipramine. These results indicate that the effects of serotonergic antidepressant drugs (but not those of desipramine, which mainly blocks noradrenaline reuptake) can be potentiated by 5-HT1A autoreceptor blockade.
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effects of single and chronic treatment with tranylcypromine on extracellular serotonin in rat brain
European Journal of Pharmacology, 1994Co-Authors: Andreu Ferrer, Francesc ArtigasAbstract:Abstract We have examined the effects of tranylcypromine, a Monoamine Oxidase Inhibitor used as antidepressant, on the tissue and extracellular concentration of serotonin (5-hydroxytryptamine, 5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in frontal cortex and dorsal raphe nucleus using microdialysis in conscious rats. Single treatment with tranylcypromine sulphate (0.5, 3 and 15 mg/kg, i.p.) dose dependently elevated dialysate 5-HT in both areas but more markedly in the DRN. Extracellular and tissue 5-HT concentrations were affected by the drug in a different manner. The former increased sharply when tissue 5-HT reached a plateau. This may have reflected saturation of intracellular stores and overflow of the amine. In contrast, tissue and extracellular 5-HIAA concentrations - that indicate metabolic effects of tranylcypromine - were affected similarly. A 2-week treatment with 0.5 mg/kg · day of tranylcypromine sulphate increased basal extracellular 5-HT in frontal cortex and dorsal raphe nucleus (ca. 220%) whereas a further injection of 0.5 mg/kg was without effect in both areas. Thus, chronic, but not acute, treatment with low doses of tranylcypromine increases extracellular 5-HT concentration, suggesting that clinical effects of this Monoamine Oxidase Inhibitor are related to its capacity to enhance serotonergic transmission.