1H NMR-based metabolic profiling reveals the effects of fluoxetine on lipid and amino acid metabolism in astrocytes.

Shunjie Bai,Jingjing Zhou,Weihua Shao,Pengfei Cheng,Liang Fang,Jia Yu,Meiling Liu,Wen Huang,Yuying Fu,Chanjuan Zhou,Xinfa Wang,Peng Xie

doi:10.3390/ijms16048490

Abstract

Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), is a prescribed and effective antidepressant and generally used for the treatment of depression. Previous studies have revealed that the antidepressant mechanism of fluoxetine was related to astrocytes. However, the therapeutic mechanism underlying its mode of action in astrocytes remains largely unclear. In this study, primary astrocytes were exposed to 10 µM fluoxetine; 24 h post-treatment, a high-resolution proton nuclear magnetic resonance (1H NMR)-based metabolomic approach coupled with multivariate statistical analysis was used to characterize the metabolic variations of intracellular metabolites. The orthogonal partial least-squares discriminant analysis (OPLS-DA) score plots of the spectra demonstrated that the fluoxetine-treated astrocytes were significantly distinguished from the untreated controls. In total, 17 differential metabolites were identified to discriminate the two groups. These key metabolites were mainly involved in lipids, lipid metabolism-related molecules and amino acids. This is the first study to indicate that fluoxetine may exert antidepressant action by regulating the astrocyte’s lipid and amino acid metabolism. These findings should aid our understanding of the biological mechanisms underlying fluoxetine therapy.

Highlights

Major depressive disorder is a debilitating mental disorder affecting up to 15% of the general population and accounting for 12.3% of the global burden of disease [1,2]
Immunofluorescent staining was performed to identify the purity of astrocytes
Through a 1H NMR spectroscopy metabolomic approach coupled with OPLS-DA statistical analysis, this study revealed a set of 17 differential metabolites

Summary

Introduction

Major depressive disorder (depression) is a debilitating mental disorder affecting up to 15% of the general population and accounting for 12.3% of the global burden of disease [1,2]. Among SSRIs, fluoxetine has been approved for the treatment of depression since 1987 [5]; the cellular and molecular mechanisms underlying fluoxetine therapy remain largely unclear. Astrocytes are major cells in the central nervous system (CNS) with numerous critical functions, and recent findings have reported their critical roles in neuronal development, neurotransmission and synaptic plasticity [6,7]. Astrocytic density and size are reduced in depression [8], and the loss of glial cells in the rat prefrontal cortex is sufficient to induce depressive-like behaviors in animal experiments [3]. Fluoxetine prevents the stress-induced numerical decrease of astrocytes in the medial prefrontal cortex of rats subjected to chronic psychosocial stress [9]

Objectives

Discussion

Conclusion