Ginsenoside Rd alleviates LPS-induced neuroinflammation and depressive-like behaviors via regulating TLR4-PI3K-NF-κB-JMJD3 signaling
Hongyu Chen, Jingjing Piao, Zihui Geng, Xu Han, Runxin Li, Ranji Cui, Bingjin Li
Abstract
BACKGROUND AND PURPOSE: Previous studies have highlighted a strong association between neuroinflammation and depression, and inhibiting neuroinflammation could offer a promising alternative strategy for depression treatment. Ginsenoside Rd (Rd), a major bioactive saponin from Panax ginseng, exhibits potent anti-inflammatory activity. This study aimed to evaluate the antidepressant-like effects of Rd in a lipopolysaccharide (LPS)-induced mouse model of depression and to elucidate its underlying molecular mechanisms. METHODS: Male mice were intraperitoneally injected with LPS (0.83 mg/kg) to induce depressive-like behaviors. Behavioral tests (open field test, sucrose preference test, tail suspension test, and forced swimming test) were performed to evaluate the antidepressant-like effect of Rd. Hippocampal neuronal damage was assessed by Nissl and H&E staining. Network pharmacology and transcriptomic analyses predicted potential targets and pathways, which were validated by Western blotting. Microglial activation and hippocampal cell proliferation were examined via immunofluorescence, dendritic spine density was analyzed using Golgi staining. RESULTS: Rd treatment significantly ameliorated LPS-induced depressive-like behaviors, concomitant with decreased levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) and attenuated neuronal damage in the hippocampus. These effects were associated with inhibition of the TLR4-PI3K-AKT-NF-κB signaling pathway, downregulation of the expression of jumonji domain-containing protein 3 (JMJD3), and suppression of microglial activation. Additionally, Rd reversed the LPS-induced reduction in dendritic spine density, increased the expression of postsynaptic density protein 95 (PSD-95) and synaptophysin (SYP) in the hippocampus. CONCLUSION: Our research suggests that Rd exerts antidepressant-like effects by alleviating neuroinflammation and enhancing spinogenesis, which may be associated with the modulation of the TLR4-PI3K-NF-κB-JMJD3 signaling pathway.