Major depressive disorder (MDD) is a severe mental disorder associated with high rates of morbidity and mortality. Current first-line pharmacotherapies for MDD are based on enhancement of monoaminergic neurotransmission, but these antidepressants are still insufficient and produce significant side-effects. Consequently, the development of novel antidepressants and therapeutic targets is desired. Dl-3-n-butylphthalide (NBP) is a compound with proven efficacy in treating ischemic stroke, yet its therapeutic effects and mechanisms for depression remain unexplored. The aim of this study was to investigate the effect of NBP in a chronic social defeat stress model of depression and its underlying molecular mechanisms. Here, we examined depression-related behavior and performed a targeted metabolomics analysis. Real-time quantitative polymerase chain reaction and western blotting were used to examine key genes and proteins involved in energy metabolism and the AKT/cAMP response element-binding protein (CREB) signaling pathway. Our results reveal NBP attenuates stress-induced social deficits, anxiety-like behavior and despair behavior, and alters metabolite levels of glycolysis and tricarboxylic acid (TCA) cycle components. NBP affected gene expression of key enzymes of the TCA cycle, as well as protein expression of p-AKT and p-CREB. Our findings provide the first evidence showing that NBP can attenuate stress-induced behavioral deficits by modulating energy metabolism by regulating activation of the AKT/CREB signaling pathway.

中文翻译：

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Dl-3-n-丁基邻苯二甲酸酯通过调节经由AKT / CREB信号通路的能量代谢，减轻了小鼠对慢性社交衰竭应激的行为缺陷。

严重抑郁症（MDD）是与高发病率和死亡率相关的严重精神障碍。当前用于MDD的一线药物疗法是基于单胺能神经传递的增强，但是这些抗抑郁药仍然不足，并且会产生明显的副作用。因此，需要开发新的抗抑郁药和治疗靶标。Dl-3-n-丁基邻苯二甲酸酯（NBP）是一种具有治疗缺血性中风功效的化合物，但其治疗效果和抑郁机制尚待探索。这项研究的目的是调查NBP在抑郁症的慢性社会挫败应激模型中的作用及其潜在的分子机制。在这里，我们检查了与抑郁相关的行为，并进行了有针对性的代谢组学分析。实时定量聚合酶链反应和免疫印迹被用来检查参与能量代谢和AKT / cAMP反应元件结合蛋白（CREB）信号通路的关键基因和蛋白质。我们的研究结果表明，NBP减轻了压力引起的社交缺陷，焦虑样行为和绝望行为，并改变了糖酵解和三羧酸（TCA）循环成分的代谢产物水平。NBP影响了TCA周期关键酶的基因表达以及p-AKT和p-CREB的蛋白质表达。我们的发现提供了第一个证据，表明NBP可以通过调节AKT / CREB信号通路的激活来调节能量代谢，从而减轻应激诱导的行为缺陷。