Purpose: It is revealed that Xiaoyaosan could reduce glutamate level in the hippocampus of depressed rats, whose metabolism leads to the pathophysiology of depression. However, the underlying mechanism remains unclear. This study aims to explore the effect of Xiaoyaosan on glutamate metabolism, and how to regulate the excitatory injury caused by glutamate.

Methods: Rats were induced by chronic unpredictable mild stress, then divided into control, vehicle (distilled water), Xiaoyaosan, fluoxetine, vehicle (DMSO), Xiaoyaosan + Ly294002 and Ly294002 groups. Ly294002 was microinjected into the lateral ventricular catheterization at 5 mM. Xiaoyaosan (2.224 g/kg) and fluoxetine (2.0 mg/kg) were orally administered for three weeks. The open field test (OFT), forced swimming test (FST), and sucrose preference test (SPT) were used to assess depressive behavior. The glutamate and corticosterone (CORT) levels were detected by ELISA. Western blot, immunochemistry or immunofluorescence were used to detect the expressions of NR2B, MAP2, PI3K and P-AKT/Akt in the hippocampal CA1 region. The mRNA level of MAP2, NR2B and PI3K were detected by RT-qPCR.

Results: Compared to the rats in control group, body weight and food intake of CUMS rats was decreased. CUMS rats also showed depression-like behavior as well as down regulate the NR2B and PI3K/Akt signaling pathway. Xiaoyaosan treatments could increase food intake and body weight as well as improved time spent in the central area, total distance traveled in the OFT. Xiaoyaosan could also decrease the immobility time as well as increase the sucrose preference in SPT. Moreover, xiaoyaosan decreased the level of glutamate in the hippocampal CA1 region and serum CORT in CUMS rats. Furthermore, xiaoyaosan improved the expression of MAP2 as well as increased the expression of NR2B, PI3K and the P-AKT/AKT ratio in the hippocampal CA1 region in the CUMS rats.

Conclusion: Xiaoyaosan treatment can exert the antidepressant effect by rescuing hippocampal neurons loss induced by the glutamate-mediated excitotoxicity in CUMS rats. The underlying pathway maybe through NR2B and PI3K/Akt signaling pathways. These results may suggest the potential of Xiaoyaosan in preventing the development of depression.

目的：揭示逍遥散可降低抑郁大鼠海马谷氨酸水平，其代谢导致抑郁的病理生理。然而，潜在的机制仍不清楚。本研究旨在探讨逍遥散对谷氨酸代谢的影响，以及如何调节谷氨酸引起的兴奋性损伤。

方法：大鼠采用慢性不可预知的轻度应激诱导，分为对照组、载体（蒸馏水）、逍遥散、氟西汀、载体（DMSO）、逍遥散+Ly294002和Ly294002组。Ly294002 以 5 mM 显微注射到侧脑室导管中。口服逍遥散（2.224 g/kg）和氟西汀（2.0 mg/kg）三周。开放场地测试 (OFT)、强迫游泳测试 (FST) 和蔗糖偏好测试 (SPT) 用于评估抑郁行为。通过 ELISA 检测谷氨酸和皮质酮 (CORT) 水平。Western blot、免疫化学或免疫荧光检测海马CA1区NR2B、MAP2、PI3K和P-AKT/Akt的表达。通过RT-qPCR检测MAP2、NR2B和PI3K的mRNA水平。

结果：与对照组大鼠相比，CUMS大鼠的体重和摄食量均有所下降。CUMS 大鼠还表现出抑郁样行为以及下调 NR2B 和 PI3K/Akt 信号通路。逍遥散治疗可以增加食物摄入量和体重，并增加在中心区域停留的时间和在 OFT 中的总行进距离。逍遥散还可以减少静止时间并增加 SPT 中的蔗糖偏好。此外，逍遥散降低了 CUMS 大鼠海马 CA1 区谷氨酸水平和血清 CORT。此外，逍遥散提高了CUMS大鼠海马CA1区MAP2的表达，增加了NR2B、PI3K的表达和P-AKT/AKT比值。

结论：逍遥散治疗可通过挽救CUMS大鼠谷氨酸介导的兴奋性毒性引起的海马神经元丢失发挥抗抑郁作用。潜在途径可能通过 NR2B 和 PI3K/Akt 信号通路。这些结果可能表明逍遥散在预防抑郁症发展方面的潜力。