LAUSR

Total saponins of Panax ginseng (TSPG) have antidepressant effects. However, the underlying antidepressant mechanism of TSPG remains not clear. This study aimed to predict the mechanism of TSPG by bioinformatics analysis and to verify it experimentally. Bioinformatics analysis showed that the antidepressant effects of TSPG may be related to inflammation, and CX3CL1/CX3CR1 may play a key mediating role. Wistar rats were exposed to chronic unpredictable mild stress (CUMS) for 6 weeks, and TSPG (50 mg/kg/d, 100 mg/kg/d) was administered throughout the modeling period. It was found that TSPG improves depressive behavior and reduces neuropathic damage in the hippocampus in rats. Meanwhile, TSPG decreased mRNA and protein expression of pro‐inflammatory cytokines and CX3CL1/CX3CR1 and inhibited P38 and JNK protein phosphorylation in the hippocampus. Rat astrocytes were employed to explore further the potential mechanism of TSPG in regulating CX3CL1/CX3CR1. The results showed that CX3CL1 small interfering RNA (siRNA‐CX3CL1) and CX3CR1 inhibitor (JMS‐17‐2) had similar effects to TSPG, that is, reduced inflammatory response, reactive oxygen species (ROS), and phosphorylation of P38 and JNK proteins, while overexpression of CX3CL1 (pcDNA‐CX3CL1) counteracted the above effects of TSPG. It is suggested that the antidepressant effect of TSPG may be achieved through inhibition of CX3CL1/CX3CR1.