Saikosaponin d (SSd) is a traditional Chinese medicine that has been widely used in depression treatment. Given the lack of studies demonstrating the underlying mechanism of action of SSd in depression, the presented study was conducted with aims of investigating the effect of SSd on rats with depression-like behaviors induced by unpredicted chronic mild stress (UCMS) and its underlying molecular mechanism. To investigate the effect of SSd on depression, rat models with depression-like behaviors were established through 3-week exposure to UCMS, followed by administration of 10 mg/kg fluoxetine, 0.75 mg/kg SSd, 1.50 mg/kg SSd, or 10 mg/kg caffeic acid phenethyl ester (CAPE). The depression-like behaviors of rats were evaluated by sucrose preference test, open field test, forced swimming test, and tail suspension test. Afterwards, the regulatory relationship among nuclear factor-κB (NF-κB), microRNA (miR)-155 and fibroblast growth factor 2 (FGF2) were detected by dual-luciferase reporter gene assay and ChIP. RT-qPCR and Western blot analysis was conducted to determine the expression of genes and proteins. Finally, hippocampal neurons were extracted from modeled rats and transfected with miR-155 mimic, miR-155 inhibitor, NF-κB overexpression plasmid, or siRNA against NF-κB. The results showed that the depression-like behaviors induced by UCMS in rats was successfully attenuated by SSd. In hippocampal neurons of rats treated with SSd, NF-κB was significantly downregulated while FGF2 was significantly upregulated. NF-κB targets miR-155 and negatively regulates the expression of FGF2. NF-κB knockdown resulted in reduced depression-like behaviors of rats. These findings provide evidence that SSd could ameliorate depression-like behaviors in the rats treated with UCMS by downregulating NF-κB and miR-155, and upregulating FGF2.

中文翻译：

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Saikosaponin d 下调 microRNA-155 并上调 FGF2，以通过负调节 NF-κB 来改善不可预测的慢性轻度应激诱导的大鼠抑郁样行为。

柴胡皂苷d（SSd）是一种广泛用于治疗抑郁症的中药。鉴于缺乏证明 SSd 在抑郁症中的潜在作用机制的研究，本研究旨在调查 SSd 对由不可预测的慢性轻度应激 (UCMS) 诱导的抑郁样行为大鼠的影响及其潜在分子机制. 为了研究 SSd 对抑郁症的影响，通过暴露于 UCMS 3 周建立了具有抑郁样行为的大鼠模型，然后施用 10 mg/kg 氟西汀、0.75 mg/kg SSd、1.50 mg/kg SSd 或 10 mg/kg 咖啡酸苯乙酯 (CAPE)。通过蔗糖偏好试验、旷场试验、强迫游泳试验和悬尾试验评价大鼠的抑郁样行为。然后，通过双荧光素酶报告基因检测和ChIP检测核因子-κB（NF-κB）、微小RNA（miR）-155和成纤维细胞生长因子2（FGF2）之间的调控关系。进行 RT-qPCR 和蛋白质印迹分析以确定基因和蛋白质的表达。最后，从模型大鼠中提取海马神经元，并用 miR-155 模拟物、miR-155 抑制剂、NF-κB 过表达质粒或针对 NF-κB 的 siRNA 转染。结果表明，SSd成功减轻了UCMS诱导的大鼠抑郁样行为。在用SSd处理的大鼠的海马神经元中，NF-κB显着下调而FGF2显着上调。NF-κB 靶向 miR-155 并负调节 FGF2 的表达。NF-κB 敲低导致大鼠抑郁样行为减少。