~1H Nmr Based Metabolic Profiling Reveals The Effects Of Fluoxetine On Lipid And Amino Acid Metabolism In Astrocytes

Objective:Fluoxetine, as one of the selective serotonin reuptake inhibitor (SSRI) antidepressants, is a confirmed and effective antidepressant and generally used for treatment of depression. Previous studies have revealed that the antidepressant mechanism of fluoxetine was closely related to astrocytes. However, the therapeutic mechanism underlying its mode of action remains largely unclear. The regulation of some metabolic pathways by fluoxetine was investigated in astrocytes in order to explore the pathway and mechanisms associated with the action of fluoxetine.Methods:In this study, we established a highly efficient culture approach for enrichment of purified astrocytes. The high effective concentration of fluoxetine treated astrocytes was selected by the proliferation assay. After the astrocytes were treated with fluoxetine for 24 h, a high-resolution proton nuclear magnetic resonance (’H NMR)-based metabolomic approach coupled with multivariate statistical analysis was used to characterize the metabolic variations of intracellular metabolites.Results: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 controls. Totally, 17 differential metabolites were identified to discriminate the two groups. Fluoxetine induced the increases of lipids (glyceryl of lipids, lipid, low density lipoprotein (LDL) and very low density lipoprotein (VLDL)), tyrosine and lysine; as well as the decreases of high density lipoprotein (HDL), glycoprotein, isoleucine, α, β-glucose, creatine, asparagine, methionine, ethanolamine, methylamine and trimethylamine n-oxide (TMAO). These key metabolites were mainly involved in lipid metabolism and amino acids.Conclusions:By researching the change of endogenous metabolites in the fluoxetine treated astrocytes. This study indicates that fluoxetine may exert antidepressant action by regulating the astrocyte’s lipid and amino acid metabolism, and our findings help to understand the cell biological mechanisms of fluoxetine treatment.