Evaluation of Krebs cycle enzymes in the brain of rats after chronic administration of antidepressants

Scaini, Giselli; Santos, P.M.L.; Benedet, Joana; Rochi, Natália; Gomes, Lara M.; Borges, Lislaine S.; Rezin, Gislaine T.; Pezente, Daiana P.; Quevedo, Joao L De; Streck, Emílio L.

doi:10.1016/j.brainresbull.2010.03.006

Cited by 45 publications

(27 citation statements)

References 35 publications

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“…Thus, the increase in SDH expression after tianeptine treatment will have a beneficial impact on brain metabolism. Moreover, our data are consistent with previously published reports that chronic treatment with antidepressants, such as nortriptyline, paroxetine, or venlafaxine, enhances SDH activity in the brain [8]. In the hippocampus, chronic tianeptine treatment of our model of depression upregulated not only Krebs cycle enzymes but also proteins in the respiratory chain including SDH as well as NADH dehydrogenase iron-sulfur protein 4 [39].…”

Section: Discussionsupporting

confidence: 92%

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The effect of chronic tianeptine administration on the brain mitochondria: direct links with an animal model of depression

et al. 2016

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A growing body of evidence has focused on the impact of mitochondrial disturbances in the development of depression, but little data exist regarding the effects of chronic administration of antidepressant drugs on the brain’s mitochondrial protein profile. The aim of this study was to investigate the impact of chronic treatment with an atypical antidepressant drug—tianeptine—on the mitochondria-enriched subproteome profile in the hippocampus and the frontal cortex of 3-month-old male rats following a prenatal stress procedure. Rats that were exposed to a prenatal stress procedure displayed depressive- and anxiety-like disturbances based on the elevated plus-maze and Porsolt tests. Moreover, two-dimensional electrophoresis coupled with mass spectrometry showed structure-dependent mitoproteome changes in brains of prenatally stressed rats after chronic tianeptine administration. A component of 2-oxoglutarate and succinate flavoprotein subunit dehydrogenases, isocitrate subunit alpha, was upregulated in the hippocampus. In the frontal cortex, there was a striking increase in the expression of glutamate dehydrogenase and cytochrome bc1 complex subunit 2. These findings suggest that mitochondria are underappreciated targets for therapeutic interventions, and mitochondrial function may be crucial for the effective treatment of stress-related diseases.

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Section: Discussionsupporting

confidence: 92%

“…An improvement in mitochondrial function could represent a crucial component in the effective treatment of stress-related diseases [8]. …”

Section: Introductionmentioning

confidence: 99%

The effect of chronic tianeptine administration on the brain mitochondria: direct links with an animal model of depression

et al. 2016

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“…Furthermore, 4-methyl-2-oxopentanoate is often used to assess liver mitochondrial function and can influence glutamate synthesis in neurons [80, 81]. Several studies have implicated alterations in brain energetics in the pathogenesis of depression and effects of antidepressants [38, 82, 83]. Consistent with these observations, our results suggest a model in which subtle alterations in mitochondrial bioenergetics may contribute to the pathophysiology of depressive symptoms.…”

Section: Discussionsupporting

confidence: 87%

Altered Monoamine and Acylcarnitine Metabolites in HIV-Positive and HIV-Negative Subjects With Depression

Cassol

Misra

Morgello

et al. 2015

JAIDS Journal of Acquired Immune Deficiency Syndromes

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Background Depression is a frequent comorbidity in HIV infection that has been associated with worse treatment outcomes and increased mortality. Recent studies suggest that increased innate immune activation and tryptophan catabolism are associated with higher risk of depression in HIV infection and other chronic inflammatory diseases, but the mechanisms leading to depression remain poorly understood. Methods The severity of depressive symptoms was assessed by Beck Depression Inventory or Center for Epidemiological Studies Depression Scale. Untargeted metabolomic profiling of plasma from 104 subjects (68 HIV-positive and 36 HIV-negative) across three independent cohorts was performed using liquid or gas chromatography followed by mass spectrometry. Cytokine profiling was by Bioplex array. Bioinformatic analysis was performed in Metaboanalyst and R. Results Decreased monoamine metabolites (phenylacetate, 4-hydroxyphenylacetate) and acylcarnitines (propionylcarnitine, isobutyrylcarnitine, isovalerylcarnitine, 2-methylbutyrylcarnitine) in plasma distinguished depressed subjects from controls in HIV-positive and HIV-negative cohorts, and these alterations correlated with the severity of depressive symptoms. In HIV-positive subjects, acylcarnitines and other markers of mitochondrial function correlated inversely with tryptophan catabolism, a marker of IFN responses, suggesting inter-relationships between inflammatory pathways, tryptophan catabolism, and metabolic alterations associated with depression. Altered metabolites mapped to pathways involved in monoamine metabolism, mitochondrial function, and inflammation, suggesting a model in which complex relationships between monoamine metabolism and mitochondrial bioenergetics contribute to biological mechanisms involved in depression that may be augmented by inflammation during HIV infection. Conclusions Integrated approaches targeting inflammation, monoamine metabolism, and mitochondrial pathways may be important for prevention and treatment of depression in people with and without HIV.

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“…48 Chronic administration of different antidepressants, including SSRIs, was associated with increased levels of biomarkers for energy metabolism, such as activity of brain creatine kinase, of mitochondrial respiratory chain complexes II and IV, and of citrate synthase and succinate dehydrogenase. 17, 49, 50 Recently in an animal model significant changes in amino-acid metabolism related to energy metabolism via TCA cycle, and increased levels of glucose, glucose-6-phosphate and fructose-6-phosphate following chronic paroxetine treatment were found. 18 Additional mechanisms related to the observed changes in energy metabolism following sertraline treatment could be related to the effects of 5-HT on glucose metabolism and glycolysis.…”

Section: Discussionmentioning

confidence: 99%

Pharmacometabolomic mapping of early biochemical changes induced by sertraline and placebo

et al. 2013

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In this study, we characterized early biochemical changes associated with sertraline and placebo administration and changes associated with a reduction in depressive symptoms in patients with major depressive disorder (MDD). MDD patients received sertraline or placebo in a double-blind 4-week trial; baseline, 1 week, and 4 weeks serum samples were profiled using a gas chromatography time of flight mass spectrometry metabolomics platform. Intermediates of TCA and urea cycles, fatty acids and intermediates of lipid biosynthesis, amino acids, sugars and gut-derived metabolites were changed after 1 and 4 weeks of treatment. Some of the changes were common to the sertraline- and placebo-treated groups. Changes after 4 weeks of treatment in both groups were more extensive. Pathway analysis in the sertraline group suggested an effect of drug on ABC and solute transporters, fatty acid receptors and transporters, G signaling molecules and regulation of lipid metabolism. Correlation between biochemical changes and treatment outcomes in the sertraline group suggested a strong association with changes in levels of branched chain amino acids (BCAAs), lower BCAAs levels correlated with better treatment outcomes; pathway analysis in this group revealed that methionine and tyrosine correlated with BCAAs. Lower levels of lactic acid, higher levels of TCA/urea cycle intermediates, and 3-hydroxybutanoic acid correlated with better treatment outcomes in placebo group. Results of this study indicate that biochemical changes induced by drug continue to evolve over 4 weeks of treatment and that might explain partially delayed response. Response to drug and response to placebo share common pathways but some pathways are more affected by drug treatment. BCAAs seem to be implicated in mechanisms of recovery from a depressed state following sertraline treatment.

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Evaluation of Krebs cycle enzymes in the brain of rats after chronic administration of antidepressants

Cited by 45 publications

References 35 publications

The effect of chronic tianeptine administration on the brain mitochondria: direct links with an animal model of depression

The effect of chronic tianeptine administration on the brain mitochondria: direct links with an animal model of depression

Altered Monoamine and Acylcarnitine Metabolites in HIV-Positive and HIV-Negative Subjects With Depression

Pharmacometabolomic mapping of early biochemical changes induced by sertraline and placebo

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