Dl-3-n-butylphthalide attenuates mouse behavioral deficits to chronic social defeat stress by regulating energy metabolism via AKT/CREB signaling pathway

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.