TLR4 as a Therapeutic Target: Antidepressant Mechanism of Saikosaponin A in Regulating the NF-κB/BDNF Axis and Mitigating Oxidative Stress and Inflammation in vivo and in vitro

lin tan¹jiayue Li²Xinyi Tian³Xiaoli Zhong¹yiyi shan^4,5*

• ¹People’s Hospital of Deyang City, Deyang, Sichuan Province, China
• ²Northeast Agricultural University, Harbin, Heilongjiang Province, China
• ³Northwest A&F University, Xianyang, Shaanxi Province, China
• ⁴Yixing Eye Hospital, yixing, China
• ⁵Yixing People's Hospital, Yixing, Jiangsu, China

Natural plant-derived active ingredients have attracted increasing attention for their potential in the treatment of depression due to their safety and multi-target pharmacological activities. Saikosaponin A (SSA), a major bioactive saponin extracted from Bupleurum (a medicine and food homologous plant), has been reported to possess anti-inflammatory, neuroprotective, and antioxidative properties. In this study, we evaluated the antidepressant-like effects of SSA in a mouse model of chronic unpredictable mild stress (CUMS)-induced depression. Mice were subjected to CUMS and followed by daily administration of SSA (20 mg/kg, po for 6 weeks. Behavioral tests, including tail suspension test, open field test, elevated plus maze and marble burying test, indicated that SSA significantly alleviated depressive-like and anxiety-like behaviors. Histopathological analysis by H&E staining showed that SSA reduced hippocampal neuronal damage induced by chronic stress. Biochemical assays revealed that SSA normalized levels of neurotransmitters (5-HT, DA, and 5-HIAA), enhanced antioxidant enzyme activity (SOD, CAT, GSH), and suppressed neuroinflammatory cytokine production (TNF-α, IL-1β, IL-6). Mechanistically, SSA exerted its antidepressant effects by inhibiting the TLR4/NF-κB signaling pathway and upregulating BDNF expression. In PC12 cells, TLR4 overexpression attenuated SSA’s protective effects, while TLR4 silencing enhanced cellular resistance to corticosterone-induced damage. These findings suggest SSA alleviates CUMS-induced depression-like behaviors in mice by modulating neuroinflammation and oxidative stress through the TLR4/NF-κB/BDNF signaling axis, indicating its potential as a functional food-derived therapy for depression.