Department of Molecular Biology and Endocrinology, "VINČA" Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Mike Petrovića Alasa 12-14, 11351, Vinča, Belgrade, Serbia.
Institute of Chemistry, Technology and Metallurgy, University of Belgrade, Njegoševa 12, 11000, Belgrade, Serbia.
Psychopharmacology (Berl). 2022 Sep;239(9):2955-2974. doi: 10.1007/s00213-022-06180-y. Epub 2022 Jul 1.
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.
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 per day) (lasting 3 weeks of 6-week CSIS), monitored by using comprehensive GC × GC-MS.
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 α adrenergic receptors (AR) or norepinephrine transporter in both control and stressed animals.
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.
发现重度抑郁症（MDD）的生物标志物可以更深入地了解这种情绪障碍，并提高筛查、诊断和治疗 MDD 的能力。
在这项研究中，通过创建特定的代谢组学指纹，使用代谢组学来揭示 MDD 代谢物波动和药物结果。我们报告了慢性社会隔离（CSIS）（6 周）后成年雄性 Wistar 大鼠海马代谢组学变化模式，CSIS 是一种抑郁症动物模型，以及/或慢性噻奈普汀（Tian）治疗（每天 10mg/kg）（持续 3 周 CSIS），使用综合 GC×GC-MS 进行监测。
比较代谢组学分析突出了 CSIS 后γ-氨基丁酸（GABA）、同型别胆酸和不饱和脂肪酸代谢改变的作用，这与 GABA、二十二碳六烯酸、9-十六烯酸、5,8,11,14-二十碳四烯酸和花生四烯酸与强迫游泳试验中不动行为的中度至强负 Pearson 相关得到证实。Tian 的抗抑郁作用恢复了 GABA 水平，而 Tian 有抵抗力的大鼠则没有。Tian 降低了肌醇，增加了 TCA 循环中间体、氨基酸和胆固醇及其代谢物。作为 Tian 有效性和抵抗力之间差异的关键分子，代谢组学揭示了肌醇、GABA、胆固醇及其代谢物。还揭示了肌醇与不动性之间存在显著的中度正相关。Tian 可能通过上调 NMDAR 和α肾上腺素能受体（AR）或去甲肾上腺素转运体在对照和应激动物中发挥作用。
代谢组学揭示了 CSIS 诱导的抑郁样行为和对 Tian 反应的几种失调，主要集中在 NMDAR 介导的谷氨酸和肌醇信号传导以及 GABA 抑制途径上。
