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Metabolomic identification of biochemical changes induced by fluoxetine and imipramine in a chronic mild stress mouse model of depression.

Zhao J, Jung YH, Jang CG, Chun KH, Kwon SW, Lee J - Sci Rep (2015)

Bottom Line: As a result, 23 metabolites that had been differentially expressed among the control, CMS, and antidepressant-treated groups demonstrated that amino acid metabolism, energy metabolism, adenosine receptors, and neurotransmitters are commonly perturbed by drug treatment.Potential predictive markers for treatment effect were identified: myo-inositol for fluoxetine and lysine and oleic acid for imipramine.Collectively, the current study provides insights into the molecular mechanisms of the antidepressant effects of two widely used medications.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.

ABSTRACT
Metabolomics was applied to a C57BL/6N mouse model of chronic unpredictable mild stress (CMS). Such mice were treated with two antidepressants from different categories: fluoxetine and imipramine. Metabolic profiling of the hippocampus was performed using gas chromatography-mass spectrometry analysis on samples prepared under optimized conditions, followed by principal component analysis, partial least squares-discriminant analysis, and pair-wise orthogonal projections to latent structures discriminant analyses. Body weight measurement and behavior tests including an open field test and the forced swimming test were completed with the mice as a measure of the phenotypes of depression and antidepressive effects. As a result, 23 metabolites that had been differentially expressed among the control, CMS, and antidepressant-treated groups demonstrated that amino acid metabolism, energy metabolism, adenosine receptors, and neurotransmitters are commonly perturbed by drug treatment. Potential predictive markers for treatment effect were identified: myo-inositol for fluoxetine and lysine and oleic acid for imipramine. Collectively, the current study provides insights into the molecular mechanisms of the antidepressant effects of two widely used medications.

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Experimental design for the present study.
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f1: Experimental design for the present study.

Mentions: The discovery of biomarkers that indicate antidepressant treatment efficiency at an early stage is in great demand; thus, clinical specimens such as plasma and urine, which require only minimally invasive sampling, could be very informative and useful. However, the central goal of our metabolomics study was to investigate metabolic changes in the hippocampus, the brain region most associated with depression, as well as behavioral responses to depression and antidepressant treatment in order to provide detailed mechanistic insight into depression and the antidepressant effects of fluoxetine and imipramine. We hypothesized that treatment of CMS-treated mice with antidepressants of different classes would alter metabolic profiles of the hippocampus and/or stress-related behaviors in different manners. To test this hypothesis, we established four groups of C57BL/6N strain mice, which is typically used for depression-related behavior tests31 and the chronic stress mouse model3233. The groups comprised a control (unstressed) group, CMS (stressed) group, and CMS groups treated with either fluoxetine or imipramine. In parallel with body weight measurement and behavior tests including the open field test (OFT) and forced swimming test (FST), we performed a gas chromatography-mass spectrometry (GC-MS)-based metabolomics study in a CMS mouse model. The entire experimental design is displayed in Fig. 1. To our knowledge, this is the first systematic analysis comparing metabolomic changes after sub-chronic treatment with fluoxetine and imipramine.


Metabolomic identification of biochemical changes induced by fluoxetine and imipramine in a chronic mild stress mouse model of depression.

Zhao J, Jung YH, Jang CG, Chun KH, Kwon SW, Lee J - Sci Rep (2015)

Experimental design for the present study.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4352870&req=5

f1: Experimental design for the present study.
Mentions: The discovery of biomarkers that indicate antidepressant treatment efficiency at an early stage is in great demand; thus, clinical specimens such as plasma and urine, which require only minimally invasive sampling, could be very informative and useful. However, the central goal of our metabolomics study was to investigate metabolic changes in the hippocampus, the brain region most associated with depression, as well as behavioral responses to depression and antidepressant treatment in order to provide detailed mechanistic insight into depression and the antidepressant effects of fluoxetine and imipramine. We hypothesized that treatment of CMS-treated mice with antidepressants of different classes would alter metabolic profiles of the hippocampus and/or stress-related behaviors in different manners. To test this hypothesis, we established four groups of C57BL/6N strain mice, which is typically used for depression-related behavior tests31 and the chronic stress mouse model3233. The groups comprised a control (unstressed) group, CMS (stressed) group, and CMS groups treated with either fluoxetine or imipramine. In parallel with body weight measurement and behavior tests including the open field test (OFT) and forced swimming test (FST), we performed a gas chromatography-mass spectrometry (GC-MS)-based metabolomics study in a CMS mouse model. The entire experimental design is displayed in Fig. 1. To our knowledge, this is the first systematic analysis comparing metabolomic changes after sub-chronic treatment with fluoxetine and imipramine.

Bottom Line: As a result, 23 metabolites that had been differentially expressed among the control, CMS, and antidepressant-treated groups demonstrated that amino acid metabolism, energy metabolism, adenosine receptors, and neurotransmitters are commonly perturbed by drug treatment.Potential predictive markers for treatment effect were identified: myo-inositol for fluoxetine and lysine and oleic acid for imipramine.Collectively, the current study provides insights into the molecular mechanisms of the antidepressant effects of two widely used medications.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.

ABSTRACT
Metabolomics was applied to a C57BL/6N mouse model of chronic unpredictable mild stress (CMS). Such mice were treated with two antidepressants from different categories: fluoxetine and imipramine. Metabolic profiling of the hippocampus was performed using gas chromatography-mass spectrometry analysis on samples prepared under optimized conditions, followed by principal component analysis, partial least squares-discriminant analysis, and pair-wise orthogonal projections to latent structures discriminant analyses. Body weight measurement and behavior tests including an open field test and the forced swimming test were completed with the mice as a measure of the phenotypes of depression and antidepressive effects. As a result, 23 metabolites that had been differentially expressed among the control, CMS, and antidepressant-treated groups demonstrated that amino acid metabolism, energy metabolism, adenosine receptors, and neurotransmitters are commonly perturbed by drug treatment. Potential predictive markers for treatment effect were identified: myo-inositol for fluoxetine and lysine and oleic acid for imipramine. Collectively, the current study provides insights into the molecular mechanisms of the antidepressant effects of two widely used medications.

Show MeSH
Related in: MedlinePlus