Metabolomic profiling relates tianeptine effectiveness with hippocampal GABA, myo-inositol, cholesterol, and fatty acid metabolism restoration in socially isolated rats

Abstract

Rationale: Discovering biomarkers of major depressive disorder (MDD) can give a deeper understanding of this mood disorder and improve the ability to screen for, diagnose, and treat MDD.

Objectives: In this study, metabolomics was used in unraveling metabolite fluctuations of MDD and drug outcome by creating specific metabolomic fingerprints. We report metabolomic patterns of change of the hippocampus of adult male Wistar rats following chronic social isolation (CSIS) (6 weeks), an animal model of depression, and/or chronic tianeptine (Tian) treatment (10 mg kg^-1 per day) (lasting 3 weeks of 6-week CSIS), monitored by using comprehensive GC × GC-MS.

Results: The comparative metabolomic analysis highlighted the role of gamma aminobutyric acid (GABA), iso-allocholate, and unsaturated fatty acid metabolism alterations following the CSIS, which was corroborated with moderate to strong negative Pearson's correlation of GABA, docosahexaenoic, 9-hexadecenoic acid, 5,8,11,14-eicosatetraynoic, and arachidonic acids with immobility behavior in the forced swim test. The antidepressant effect of Tian restored GABA levels, which was absent in Tian resilient rats. Tian decreased myo-inositol and increased TCA cycle intermediates, amino acids, and cholesterol and its metabolite. As key molecules of divergence between Tian effectiveness and resilience, metabolomics revealed myo-inositol, GABA, cholesterol, and its metabolite. A significant moderate positive correlation between myo-inositol and immobility was revealed. Tian probably acted by upregulating NMDAR's and α₂ adrenergic receptors (AR) or norepinephrine transporter in both control and stressed animals.

Conclusion: Metabolomics revealed several dysregulations underlying CSIS-induced depressive-like behavior and responsiveness to Tian, predominantly converging into NMDAR-mediated glutamate and myo-inositol signalization and GABA inhibitory pathways.

Keywords: Depression; GC × GC–MS; Hippocampus; Metabolomics; Tianeptine.