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Glen B. Baker - One of the best experts on this subject based on the ideXlab platform.
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attenuation of the effects of oxidative stress by the mao inhibiting antidepressant and carbonyl scavenger Phenelzine
Chemico-Biological Interactions, 2019Co-Authors: Glen B. Baker, Andrew Holt, Dmitriy Matveychuk, Erin M Mackenzie, Yanlin Wang, S KarAbstract:Abstract Phenelzine (β-phenylethylhydrazine) is a monoamine oxidase (MAO)-inhibiting antidepressant with anxiolytic properties. It possesses a number of important pharmacological properties which may alter the effects of oxidative stress. After conducting a comprehensive literature search, the authors of this review paper aim to provide an overview and discussion of the mechanisms by which Phenelzine may attenuate oxidative stress. It inhibits γ-aminobutyric acid (GABA) transaminase, resulting in elevated brain GABA levels, inhibits both MAO and primary amine oxidase and, due to its hydrazine-containing structure, reacts chemically to sequester a number of reactive aldehydes (e.g. acrolein and 4-hydroxy-2-nonenal) proposed to be implicated in oxidative stress in a number of neurodegenerative disorders. Phenelzine is unusual in that it is both an inhibitor of and a substrate for MAO, the latter action producing at least one active metabolite, β-phenylethylidenehydrazine (PEH). This metabolite inhibits GABA transaminase, is a very weak inhibitor of MAO but a strong inhibitor of primary amine oxidase, and sequesters aldehydes. Phenelzine may ameliorate the effects of oxidative stress by reducing formation of reactive metabolites (aldehydes, hydrogen peroxide, ammonia/ammonia derivatives) produced by the interaction of MAO with biogenic amines, by sequestering various other reactive aldehydes and by inhibiting primary amine oxidase. In PC12 cells treated with the neurotoxin MPP+, Phenelzine has been reported to reduce several adverse effects of MPP+. It has also been reported to reduce lipid peroxidative damage induced in plasma and platelet proteins by peroxynitrite. In animal models, Phenelzine has a neuroprotective effect in global ischemia and in cortical impact traumatic brain injury. Recent studies reported in the literature on the possible involvement of acrolein in spinal cord injury and multiple sclerosis indicate that Phenelzine can attenuate adverse effects of acrolein in these models. Results from studies in our laboratories on effects of Phenelzine and PEH on primary amine oxidase (which catalyzes formation of toxic aldehydes and is overexpressed in Alzheimer's disease), on sequestration of the toxic aldehyde acrolein, and on reduction of acrolein-induced toxicity in mouse cortical neurons are also reported.
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monoamine oxidase a occupancy by moclobemide and Phenelzine implications for the development of monoamine oxidase inhibitors
The International Journal of Neuropsychopharmacology, 2016Co-Authors: Glen B. Baker, Lina Chiuccariello, Robert G Cooke, Laura Miler, Robert D LevitanAbstract:Background: Monoamine oxidase inhibitors (MAOIs) are being developed for major depressive disorder, Alzheimer’s, and Parkinson’s Disease. Newer MAOIs have minimal sensitivity to tyramine, but a key limitation for optimizing their development is that standards for in vivo monoamine oxidase-A (MAO-A) occupancy in humans are not well established. The objectives were to determine the dose-occupancy relationship of moclobemide and the occupancy of Phenelzine at typical clinical dosing. Methods: Major depressive episode (MDE) subjects underwent [11C]harmine positron emission tomography scanning prior to and following 6 weeks of treatment with moclobemide or Phenelzine. Results: Mean brain MAO-A occupancies were 74.23±8.32% for moclobemide at 300–600mg daily (n = 11), 83.75±5.52% for moclobemide at 900–1200mg daily (n = 9), and 86.82±6.89% for Phenelzine at 45–60mg daily (n = 4). The regional dose-occupancy relationship of moclobemide fit a hyperbolic function [F(x) = a(x/[b + x]); F(1,18) = 5.57 to 13.32, p = 0.002 to 0.03, mean ‘a’: 88.62±2.38%, mean ‘b’: 69.88±4.36 mg]. Multivariate analyses of variance showed significantly greater occupancy of Phenelzine (45–60mg) and higher-dose moclobemide (900–1200mg) compared to lower-dose moclobemide [300–600mg; F(7,16) = 3.94, p = 0.01]. Conclusions: These findings suggest that for first-line MDE treatment, daily moclobemide doses of 300–600mg correspond to a MAO-A occupancy of 74%, whereas for treatment-resistant MDE, either Phenelzine or higher doses of moclobemide correspond to a MAO-A occupancy of at least 84%. Therefore, novel MAO inhibitor development should aim for similar thresholds. The findings provide a rationale in treatment algorithm design to raise moclobemide doses to inhibit more MAO-A sites, but suggest switching from high-dose moclobemide to Phenelzine is best justified by binding to additional targets.
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elevation of rat brain tyrosine levels by Phenelzine is mediated by its active metabolite β phenylethylidenehydrazine
Progress in Neuro-psychopharmacology & Biological Psychiatry, 2014Co-Authors: Dmitriy Matveychuk, Emerson Arcoverde Nunes, Nasir Ullah, Fahad S Aldawsari, Carlos A Velazquezmartinez, Glen B. BakerAbstract:Phenelzine, a non-selective irreversible inhibitor of monoamine oxidase (MAO), has been used in the treatment of depression and anxiety disorders for several decades. It is a unique inhibitor of MAO as it is also a substrate for MAO, with one of the metabolites being β-phenylethylidenehydrazine (PEH), and it also inhibits several transaminases (e.g. GABA transaminase) in the brain when administered i.p. to rats. Administration of either Phenelzine or PEH to rats has been reported to produce dramatic increases in rat brain levels of GABA and alanine while reducing levels of glutamine; these effects are abolished for Phenelzine, but not for PEH, when the animals are pre-treated with another MAO inhibitor, suggesting that they are mediated by the MAO-catalyzed formation of PEH from Phenelzine. In the present report, we have found that Phenelzine and E- and Z-geometric isomers of PEH significantly increased rat whole brain concentrations of L-tyrosine. In a time-response study, acute administration of Phenelzine, E-PEH and Z-PEH (30 mg/kg i.p.) elevated rat whole brain L-tyrosine levels at 3 and 6h following injection, reaching approximately 265-305% of vehicle-treated controls at 3h. To determine whether the effect on L-tyrosine is MAO-dependent, animals were pre-treated with the non-selective MAO inhibitor tranylcypromine (1mg/kg i.p.) prior to administration of Phenelzine, racemic PEH or vehicle controls. This pre-treatment reversed the effects of Phenelzine, but not of PEH, on brain L-tyrosine levels, suggesting that the tyrosine-elevating property of Phenelzine is largely the result of its active metabolite PEH. These results are discussed in relation to possible therapeutic applications of these drugs.
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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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Comparison of Phenelzine and geometric isomers of its active metabolite, β-phenylethylidenehydrazine, on rat brain levels of amino acids, biogenic amine neurotransmitters and methylamine
Journal of neural transmission (Vienna Austria : 1996), 2013Co-Authors: Dmitriy Matveychuk, Emerson Arcoverde Nunes, Nasir Ullah, Erin M Mackenzie, Carlos A. Velázquez-martínez, Glen B. BakerAbstract:Phenelzine is a monoamine oxidase (MAO) inhibitor used in treatment of depression and anxiety disorders. It also elevates brain levels of γ-aminobutyric acid (GABA) and inhibits primary amine oxidase (PrAO), an enzyme whose activity and/or expression has been reported to be increased in diabetes mellitus, Alzheimer’s disease and cardiovascular disorders. Phenelzine is not only an inhibitor of, but also a substrate for, MAO and it has been suggested that an active metabolite, namely β-phenylethylidenehydrazine (PEH), is responsible for Phenelzine’s effects on amino acids. PEH is also a strong inhibitor of PrAO but has weak effects on MAO. PEH has a double bond and can thus exist as (E)- and (Z)-geometric isomers, but to date the two isomers have not been compared with regard to their neurochemical effects. We have investigated the effects of Phenelzine, (E)- and (Z)-PEH on rat whole brain levels of amino acids, biogenic amine neurotransmitters and methylamine (an endogenous substrate of PrAO). Under the conditions used in the study, (E)- and (Z)-PEH appear to be equivalent in their neurochemical properties. Both PEH isomers and Phenelzine produced marked increases in rat brain levels of GABA and alanine while decreasing brain levels of glutamine. Phenelzine increased brain levels of biogenic amine neurotransmitters (noradrenaline, dopamine and serotonin), whereas neither PEH isomer altered levels of these neurotransmitters to a considerable extent. All three drugs significantly increased rat brain levels of methylamine, with (E)- and (Z)-PEH causing a greater increase than Phenelzine. These results are discussed in relation to the possible therapeutic applications of these drugs.
Christian Carpene - One of the best experts on this subject based on the ideXlab platform.
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oral Phenelzine treatment mitigates metabolic disturbances in mice fed a high fat diet
Journal of Pharmacology and Experimental Therapeutics, 2019Co-Authors: Josep Mercader, Saioa Gomezzorita, Alice Chaplin, Sophie Le Gonidec, Agustin G Sabater, Pauline Decaunes, Fermin I Milagro, Christian CarpeneAbstract:Novel mechanisms and health benefits have been recently suggested for the antidepressant drug Phenelzine (PHE), known as a nonselective monoamine oxidase inhibitor. They include an antilipogenic action that could have an impact on excessive fat accumulation and obesity-related metabolic alterations. We evaluated the metabolic effects of an oral PHE treatment on mice fed a high-fat diet (HFD). Eleven-week-old male C57BL/6 mice were fed a HFD and either a 0.028% PHE solution (HFD + PHE) or water to drink for 11 weeks. PHE attenuated the increase in body weight and adiposity without affecting food consumption. Energy efficiency was lower in HFD + PHE mice. Lipid content was reduced in subcutaneous fat pads, liver, and skeletal muscle. In white adipose tissue (WAT), PHE reduced sterol regulatory element-binding protein-1c and phosphoenolpyruvate carboxykinase mRNA levels, inhibited amine-induced lipogenesis, and did not increase lipolysis. Moreover, HFD + PHE mice presented diminished levels of hydrogen peroxide release in subcutaneous WAT and reduced expression of leukocyte transmigration markers and proinflammatory cytokines in visceral WAT and liver. PHE reduced the circulating levels of glycerol, triacylglycerols, high-density lipoprotein cholesterol, and insulin. Insulin resistance was reduced, without affecting glucose levels and glucose tolerance. In contrast, PHE increased rectal temperature and slightly increased energy expenditure. The mitigation of HFD-induced metabolic disturbances points toward a promising role for PHE in obesity treatment and encourages further research on its mechanisms of action. SIGNIFICANCE STATEMENT Phenelzine reduces body fat, markers of oxidative stress, inflammation, and insulin resistance in high-fat diet mice. Semicarbazide-sensitive amine oxidase, monoamine oxidase, phosphoenolpyruvate carboxykinase, and sterol regulatory element-binding protein-1c are involved in the metabolic effects of Phenelzine. Phenelzine could be potentially used for the treatment of obesity-related complications.
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metabolic effects of oral Phenelzine treatment on high sucrose drinking mice
International Journal of Molecular Sciences, 2018Co-Authors: Christian Carpene, Saioa Gomezzorita, Alice Chaplin, Josep MercaderAbstract:Phenelzine has been suggested to have an antiobesity effect by inhibiting de novo lipogenesis, which led us to investigate the metabolic effects of oral chronic Phenelzine treatment in high-sucrose-drinking mice. Sucrose-drinking mice presented higher body weight gain and adiposity versus controls. Phenelzine addition did not decrease such parameters, even though fat pad lipid content and weights were not different from controls. In visceral adipocytes, Phenelzine did not impair insulin-stimulated de novo lipogenesis and had no effect on lipolysis. However, Phenelzine reduced the mRNA levels of glucose transporters 1 and 4 and phosphoenolpyruvate carboxykinase in inguinal white adipose tissue (iWAT), and altered circulating levels of free fatty acids (FFA) and glycerol. Interestingly, glycemia was restored in Phenelzine-treated mice, which also had higher insulinaemia. Phenelzine-treated mice presented higher rectal temperature, which was associated to reduced mRNA levels of uncoupling protein 1 in brown adipose tissue. Furthermore, unlike sucrose-drinking mice, hepatic malondialdehyde levels were not altered. In conclusion, although de novo lipogenesis was not inhibited by Phenelzine, the data suggest that the ability to re-esterify FFA is impaired in iWAT. Moreover, the effects on glucose homeostasis and oxidative stress suggest that Phenelzine could alleviate obesity-related alterations and deserves further investigation in obesity models.
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body fat reduction without cardiovascular changes in mice after oral treatment with the mao inhibitor Phenelzine
British Journal of Pharmacology, 2018Co-Authors: Christian Carpene, Josep Mercader, Sophie Le Gonidec, Stephane Schaak, Jeanne Mialetperez, Alexia Zakaroffgirard, Jean GalitzkyAbstract:Background and purpose Phenelzine is an antidepressant drug known to increase the risk of hypertensive crisis when dietary tyramine is not restricted. However, this MAO inhibitor inhibits other enzymes not limited to the nervous system. Here we investigated if its antiadipogenic and antilipogenic effects in cultured adipocytes could contribute to decreased body fat in vivo, without unwanted hypertensive or cardiovascular effects. Experimental approach Mice were fed a standard chow and given 0.028% Phenelzine in drinking water for 12 weeks. Body composition was determined by NMR. Cardiovascular dysfunction was assessed by heart rate variability analyses and by evaluation of cardiac oxidative stress markers. MAO activity, hydrogen peroxide release and triacylglycerol turnover were assayed in white adipose tissue (WAT), alongside determination of glucose and lipid circulating levels. Key results Phenelzine-treated mice exhibited lower body fat content, subcutaneous WAT mass and lipid content in skeletal muscles than control, without decreased body weight gain or food consumption. A modest alteration of cardiac sympathovagal balance occurred without depressed aconitase activity. In WAT, Phenelzine impaired the lipogenic but not the antilipolytic actions of insulin, MAO activity and hydrogen peroxide release. Phenelzine treatment lowered non-fasting blood glucose and phosphoenolpyruvate carboxykinase expression. In vitro, high doses of Phenelzine decreased both lipolytic and lipogenic responses in mouse adipocytes. Conclusion and implications As Phenelzine reduced body fat content without affecting cardiovascular function in mice, it may be of benefit in the treatment of obesity-associated complications, with the precautions of use recommended for antidepressant therapy.
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combination of low dose of the anti adipogenic agents resveratrol and Phenelzine in drinking water is not sufficient to prevent obesity in very high fat diet fed mice
European Journal of Nutrition, 2014Co-Authors: Christian Carpene, Saioa Gomezzorita, Josep Mercader, R Gupta, Sandra Gres, Chloe Rancoule, T Cadoudal, A Gomez, C Bertrand, Zsuzsa IffiusolteszAbstract:Resveratrol inhibits lipid accumulation but suffers from limited bioavailability. The anti-depressive agent Phenelzine limits adipogenesis in various models of cultured preadipocytes, and this hydrazine derivative also inhibits de novo lipogenesis in mature adipocytes. It was therefore tested whether resveratrol effects on adiposity reduction and glucose tolerance improvement could be reinforced by co-administration with Phenelzine. Mice fed a very-high-fat diet (VHFD, 60 % calories as fat) were subjected to drinking solution containing low dose of resveratrol (0.003 %) and/or 0.02 % Phenelzine for 12 weeks. Body fat content, glucose tolerance, food and water consumption were checked during treatment while fat depot mass was determined at the end of supplementation. Direct influence of the agents on lipogenesis and glucose uptake was tested in adipocytes. Epididymal fat depots were reduced in mice drinking Phenelzine alone or with resveratrol. No limitation of body weight gain or body fat content was observed in the groups drinking resveratrol or Phenelzine, separately or in combination. The altered glucose tolerance and the increased fat body composition of VHFD-fed mice were not reversed by resveratrol and/or Phenelzine. Such lack of potentiation between resveratrol and Phenelzine prompted us to verify in vitro their direct effects on mouse adipocytes. Both molecules inhibited de novo lipogenesis, but did not potentiate each other at 10 or 100 μM. Only resveratrol inhibited hexose uptake in a manner that was not improved by Phenelzine. Phenelzine has no interest to be combined with low doses of resveratrol for treating/preventing obesity, when considering the VHFD mouse model.
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The amine oxidase inhibitor Phenelzine limits lipogenesis in adipocytes without inhibiting insulin action on glucose uptake
Journal of Neural Transmission, 2013Co-Authors: Christian Carpene, Sandra Gres, Simon RascalouAbstract:The antidepressant Phenelzine is a monoamine oxidase inhibitor known to inhibit various other enzymes, among them semicarbazide-sensitive amine oxidase (currently named primary amine oxidase: SSAO/PrAO), absent from neurones but abundant in adipocytes. It has been reported that Phenelzine inhibits adipocyte differentiation of cultured preadipocytes. To further explore the involved mechanisms, our aim was to study in vitro the acute effects of Phenelzine on de novo lipogenesis in mature fat cells. Therefore, glucose uptake and incorporation into lipid were measured in mouse adipocytes in response to Phenelzine, other hydrazine-based SSAO/PrAO-inhibitors, and reference agents. None of the inhibitors was able to impair the sevenfold activation of 2-deoxyglucose uptake induced by insulin. Phenelzine did not hamper the effect of lower doses of insulin. However, insulin-stimulated glucose incorporation into lipids was dose-dependently inhibited by Phenelzine and pentamidine, but not by semicarbazide or BTT2052. In contrast, all these SSAO/PrAO inhibitors abolished the transport and lipogenesis stimulation induced by benzylamine. These data indicate that Phenelzine does not inhibit glucose transport, the first step of lipogenesis, but inhibits at 100 μM the intracellular triacylglycerol assembly, consistently with its long-term anti-adipogenic effect and such rapid action was not found with all the hydrazine derivatives tested. Therefore, the alterations of body weight control consecutive to the use of this antidepressant drug might be not only related to central effects on food intake/energy expenditure, but could also depend on its direct action in adipocytes. Nonetheless, Phenelzine antilipogenic action is not merely dependent on SSAO/PrAO inhibition.
Josep Mercader - One of the best experts on this subject based on the ideXlab platform.
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oral Phenelzine treatment mitigates metabolic disturbances in mice fed a high fat diet
Journal of Pharmacology and Experimental Therapeutics, 2019Co-Authors: Josep Mercader, Saioa Gomezzorita, Alice Chaplin, Sophie Le Gonidec, Agustin G Sabater, Pauline Decaunes, Fermin I Milagro, Christian CarpeneAbstract:Novel mechanisms and health benefits have been recently suggested for the antidepressant drug Phenelzine (PHE), known as a nonselective monoamine oxidase inhibitor. They include an antilipogenic action that could have an impact on excessive fat accumulation and obesity-related metabolic alterations. We evaluated the metabolic effects of an oral PHE treatment on mice fed a high-fat diet (HFD). Eleven-week-old male C57BL/6 mice were fed a HFD and either a 0.028% PHE solution (HFD + PHE) or water to drink for 11 weeks. PHE attenuated the increase in body weight and adiposity without affecting food consumption. Energy efficiency was lower in HFD + PHE mice. Lipid content was reduced in subcutaneous fat pads, liver, and skeletal muscle. In white adipose tissue (WAT), PHE reduced sterol regulatory element-binding protein-1c and phosphoenolpyruvate carboxykinase mRNA levels, inhibited amine-induced lipogenesis, and did not increase lipolysis. Moreover, HFD + PHE mice presented diminished levels of hydrogen peroxide release in subcutaneous WAT and reduced expression of leukocyte transmigration markers and proinflammatory cytokines in visceral WAT and liver. PHE reduced the circulating levels of glycerol, triacylglycerols, high-density lipoprotein cholesterol, and insulin. Insulin resistance was reduced, without affecting glucose levels and glucose tolerance. In contrast, PHE increased rectal temperature and slightly increased energy expenditure. The mitigation of HFD-induced metabolic disturbances points toward a promising role for PHE in obesity treatment and encourages further research on its mechanisms of action. SIGNIFICANCE STATEMENT Phenelzine reduces body fat, markers of oxidative stress, inflammation, and insulin resistance in high-fat diet mice. Semicarbazide-sensitive amine oxidase, monoamine oxidase, phosphoenolpyruvate carboxykinase, and sterol regulatory element-binding protein-1c are involved in the metabolic effects of Phenelzine. Phenelzine could be potentially used for the treatment of obesity-related complications.
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metabolic effects of oral Phenelzine treatment on high sucrose drinking mice
International Journal of Molecular Sciences, 2018Co-Authors: Christian Carpene, Saioa Gomezzorita, Alice Chaplin, Josep MercaderAbstract:Phenelzine has been suggested to have an antiobesity effect by inhibiting de novo lipogenesis, which led us to investigate the metabolic effects of oral chronic Phenelzine treatment in high-sucrose-drinking mice. Sucrose-drinking mice presented higher body weight gain and adiposity versus controls. Phenelzine addition did not decrease such parameters, even though fat pad lipid content and weights were not different from controls. In visceral adipocytes, Phenelzine did not impair insulin-stimulated de novo lipogenesis and had no effect on lipolysis. However, Phenelzine reduced the mRNA levels of glucose transporters 1 and 4 and phosphoenolpyruvate carboxykinase in inguinal white adipose tissue (iWAT), and altered circulating levels of free fatty acids (FFA) and glycerol. Interestingly, glycemia was restored in Phenelzine-treated mice, which also had higher insulinaemia. Phenelzine-treated mice presented higher rectal temperature, which was associated to reduced mRNA levels of uncoupling protein 1 in brown adipose tissue. Furthermore, unlike sucrose-drinking mice, hepatic malondialdehyde levels were not altered. In conclusion, although de novo lipogenesis was not inhibited by Phenelzine, the data suggest that the ability to re-esterify FFA is impaired in iWAT. Moreover, the effects on glucose homeostasis and oxidative stress suggest that Phenelzine could alleviate obesity-related alterations and deserves further investigation in obesity models.
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body fat reduction without cardiovascular changes in mice after oral treatment with the mao inhibitor Phenelzine
British Journal of Pharmacology, 2018Co-Authors: Christian Carpene, Josep Mercader, Sophie Le Gonidec, Stephane Schaak, Jeanne Mialetperez, Alexia Zakaroffgirard, Jean GalitzkyAbstract:Background and purpose Phenelzine is an antidepressant drug known to increase the risk of hypertensive crisis when dietary tyramine is not restricted. However, this MAO inhibitor inhibits other enzymes not limited to the nervous system. Here we investigated if its antiadipogenic and antilipogenic effects in cultured adipocytes could contribute to decreased body fat in vivo, without unwanted hypertensive or cardiovascular effects. Experimental approach Mice were fed a standard chow and given 0.028% Phenelzine in drinking water for 12 weeks. Body composition was determined by NMR. Cardiovascular dysfunction was assessed by heart rate variability analyses and by evaluation of cardiac oxidative stress markers. MAO activity, hydrogen peroxide release and triacylglycerol turnover were assayed in white adipose tissue (WAT), alongside determination of glucose and lipid circulating levels. Key results Phenelzine-treated mice exhibited lower body fat content, subcutaneous WAT mass and lipid content in skeletal muscles than control, without decreased body weight gain or food consumption. A modest alteration of cardiac sympathovagal balance occurred without depressed aconitase activity. In WAT, Phenelzine impaired the lipogenic but not the antilipolytic actions of insulin, MAO activity and hydrogen peroxide release. Phenelzine treatment lowered non-fasting blood glucose and phosphoenolpyruvate carboxykinase expression. In vitro, high doses of Phenelzine decreased both lipolytic and lipogenic responses in mouse adipocytes. Conclusion and implications As Phenelzine reduced body fat content without affecting cardiovascular function in mice, it may be of benefit in the treatment of obesity-associated complications, with the precautions of use recommended for antidepressant therapy.
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combination of low dose of the anti adipogenic agents resveratrol and Phenelzine in drinking water is not sufficient to prevent obesity in very high fat diet fed mice
European Journal of Nutrition, 2014Co-Authors: Christian Carpene, Saioa Gomezzorita, Josep Mercader, R Gupta, Sandra Gres, Chloe Rancoule, T Cadoudal, A Gomez, C Bertrand, Zsuzsa IffiusolteszAbstract:Resveratrol inhibits lipid accumulation but suffers from limited bioavailability. The anti-depressive agent Phenelzine limits adipogenesis in various models of cultured preadipocytes, and this hydrazine derivative also inhibits de novo lipogenesis in mature adipocytes. It was therefore tested whether resveratrol effects on adiposity reduction and glucose tolerance improvement could be reinforced by co-administration with Phenelzine. Mice fed a very-high-fat diet (VHFD, 60 % calories as fat) were subjected to drinking solution containing low dose of resveratrol (0.003 %) and/or 0.02 % Phenelzine for 12 weeks. Body fat content, glucose tolerance, food and water consumption were checked during treatment while fat depot mass was determined at the end of supplementation. Direct influence of the agents on lipogenesis and glucose uptake was tested in adipocytes. Epididymal fat depots were reduced in mice drinking Phenelzine alone or with resveratrol. No limitation of body weight gain or body fat content was observed in the groups drinking resveratrol or Phenelzine, separately or in combination. The altered glucose tolerance and the increased fat body composition of VHFD-fed mice were not reversed by resveratrol and/or Phenelzine. Such lack of potentiation between resveratrol and Phenelzine prompted us to verify in vitro their direct effects on mouse adipocytes. Both molecules inhibited de novo lipogenesis, but did not potentiate each other at 10 or 100 μM. Only resveratrol inhibited hexose uptake in a manner that was not improved by Phenelzine. Phenelzine has no interest to be combined with low doses of resveratrol for treating/preventing obesity, when considering the VHFD mouse model.
Jonathan W. Stewart - One of the best experts on this subject based on the ideXlab platform.
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treating dsm iv depression with atypical features
The Journal of Clinical Psychiatry, 2007Co-Authors: Jonathan W. Stewart, Michael E ThaseAbstract:Depression with atypical features is characterized by mood reactivity and 2 or more symptoms of vegetative reversal (including overeating, oversleeping, severe fatigue or leaden paralysis, and a history of rejection sensitivity). Another important feature of atypical depression is its preferential response to monoamine oxidase inhibitor (MAOI) treatment, especially Phenelzine, relative to tricyclic antidepressants (TCAs). The efficacy of newer agents relative to MAOIs and TCAs is unclear. This presentation reviews currently available treatments for DSM-IV depression with atypical features, focusing specifically on placebo-controlled trials. Although Phenelzine shows the most efficacy in this population, treatment with TCAs, selective serotonin reuptake inhibitors, cognitive-behavioral therapy, MAOIs other than Phenelzine, and other agents are discussed. Following this presentation is a discussion on the treatment of depression with atypical features by experts in this subject area.
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treating depression with atypical features
The Journal of Clinical Psychiatry, 2007Co-Authors: Jonathan W. StewartAbstract:Depression with atypical features was first recognized in a subset of patients with depression who preferentially responded to the monoamine oxidase inhibitor (MAOI) Phenelzine, in contrast to patients with melancholic depression. This article reviews the history of approaches in treating depression with atypical features. Initial studies in the early 1980s focused on Phenelzine, but an unfavorable adverse effect profile limits its clinical use. Despite such difficulties, Phenelzine remains the gold standard in eliciting high response rates in nearly two thirds of patients with atypical depression. Searches for agents with improved safety profiles led to studies of tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), chromium, and cognitive therapy approaches. Of these, TCAs showed inferior efficacy to MAOIs but also had cumbersome adverse effects. SSRIs have reported efficacy, but a lack of direct comparative studies limits clinical decision making. Cognitive strategies have shown promise, but demonstrating efficacy in comparison with an MAOI and placebo is limited to a single study. Despite advances in agents for melancholic depression, treatment for atypical depression remains dependent upon older agents for the greatest efficacy.
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Prophylactic efficacy of Phenelzine and imipramine in chronic atypical depression: likelihood of recurrence on discontinuation after 6 months' remission.
The American journal of psychiatry, 1997Co-Authors: Jonathan W. Stewart, E Tricamo, Patrick J McgrathAbstract:Objective: Demonstration of antidepressant efficacy beyond 6 months has infrequently been addressed, and no long-term efficacy data exist for patients with chronic atypical depression. Method: Sixty patients with atypical depression (according to Columbia University criteria) of at least 2 years’ duration and who had improved with imipramine or Phenelzine were stabilized for 6 months and then randomly continued the same medication or placebo for 6 months. Results: Several baseline differences suggested that patients who entered the discontinuation trial on a regimen of Phenelzine were more chronically depressed than the imipramine-treated patients. Survival analysis showed a marked advantage for Phenelzine relative to placebo. In addition, patients switched to placebo from Phenelzine experienced a recurrence of depressive symptoms significantly more often than patients switched to placebo from imipramine. Patients maintained with imipramine did not have lower relapse rates than those switched from imipramine to placebo. Recurrence rates were 23% for patients maintained on a regimen of Phenelzine, 41% for those maintained on a regimen of imipramine, 47% for those switched from imipramine to placebo, and 87% for placebo-treated patients originally treated with Phenelzine. Conclusions: Patients with chronic atypical depression are at high risk of recurrence if Phenelzine is withdrawn 6 months after initial improvement. Similar findings were not demonstrated for imipramine; this replicates acute trials demonstrating imipramine’s relative ineffectiveness in patients with atypical depression. Differences in recurrence rates after the switch to placebo from Phenelzine and imipramine could be due to the two drugs’ different mechanisms of action or to baseline differences in the two populations. (Am J Psychiatry 1997; 154:31‐36)
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columbia atypical depression a subgroup of depressives with better response to maoi than to tricyclic antidepressants or placebo
The British journal of psychiatry. Supplement, 1993Co-Authors: Jonathan W. Stewart, Patrick J Mcgrath, E Tricamo, Judith G Rabkin, Katja Ocepekwelikson, Edward V Nunes, Wilma Harrison, Donald F KleinAbstract:We summarise a series of studies using a MAOI to help establish the validity of a subgroup of depressives referred to as atypical depressives. Patients with reactive mood meeting DSM-III criteria for depressive illness who had associated atypical features (which include hyperphagia, hypersomnolence, leaden paralysis, and rejection sensitivity) were randomised to imipramine, Phenelzine and placebo. Non-responders were crossed over, and in all there were over 400 patient trials. Phenelzine consistently was found to be superior to imipramine. Only in trials which included patients lacking atypical, vegetative symptoms was imipramine found to equal Phenelzine. We conclude that the researcher and the clinician should consider the relevance of the atypical depressive syndrome.
R T Coutts - One of the best experts on this subject based on the ideXlab platform.
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the antidepressant drug Phenelzine produces antianxiety effects in the plus maze and increases in rat brain gaba
Psychopharmacology, 1996Co-Authors: Teresa Paslawski, Glen B. Baker, Dallas Treit, Monica George, R T CouttsAbstract:Research on the effects of antidepressant/antipanic drugs in animal models of anxiety has yielded equivocal results, even after chronic drug regimens. In contrast, we found that the antidepressant/antipanic drug Phenelzine, given acutely, produced a clear anxiolytic effect in the elevated plus-maze, a widely-used animal model of “anxiety” that is primarily sensitive to benzodiazepine-type anxiolytics (e.g., diazepam). Furthernore, the effective dose of Phenelzine (15 mg/kg) administered to rats was associated with more than a 2-fold increase in whole brain levels of γ-aminobutyric acid (GABA), whereas an ineffective dose of Phenelzine (5.1 mg/kg) did not significantly change GABA levels. TheN-acetylated metabolite of Phenelzine,N2-acetylPhenelzine, produced neither an anxiolytic effect in the elevated plus-maze nor a significant change in whole-brain levels of GABA. However, both Phenelzine andN2-acetylPhenelzine potently inhibited monoamine oxidase inhibitors such as Phenelzine in the treatment of depression in humans. These results suggest that the mechanism whereby Phenelzine produces anxiolytic effects in the plus-maze model is unique to a facilitatory action on brain levels of GABA, in contrast to classical benzodiazepines, which produce anxiolytic effects by enhancing the affinity of the GABAA-receptor for GABA.
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effects of the antidepressant Phenelzine on brain levels of γ aminobutyric acid gaba
Journal of Affective Disorders, 1991Co-Authors: Glen B. Baker, James T F Wong, Jupita M Yeung, R T CouttsAbstract:Time- and dose-response studies were carried out on the effects of the monoamine oxidase-inhibiting antidepressant and antipanic drug Phenelzine on GABA levels in rat whole brain. At a dose of 15 mg/kg i.p., Phenelzine significantly elevated GABA levels at all time intervals studied (1, 2, 4, 8, 16, and 24 h). A further investigation indicated that this was a dose-dependent effect. The possible importance of GABA in the etiology and pharmacotherapy of depression and panic disorder is discussed.