5-O-Methylvisammioside alleviates depression-like behaviors by inhibiting nuclear factor kappa B pathway activation via targeting SRC

Abstract Preliminary studies on emerging herbal ingredients have highlighted alternative pathways that inflammation and modulate perturbed immunity as valuable strategies for treating depression. Previous studies have shown that 5-O-methylvisammioside, a bioactive compound derived from Saposhnikoviae Radix, possesses excellent anti-inflammatory and antioxidant biological functions, exhibits a neuroprotective effect. The purpose of this study was to explore the targets and signaling pathways of 5-O-methylvisammioside in the potential treatment of major depressive disorder using a combination of network pharmacology analysis and biological experiments. The network pharmacological analysis results indicated that the proto-oncogene tyrosine-protein kinase Src and the nuclear factor kappa B signaling pathway were highly correlated with the treatment of major depressive disorder with 5-O-methylvisammioside. Further experiments indicated that 5-O-methylvisammioside significantly improved lipopolysaccharide-induced depression-like behaviors in mice, ameliorated microglial polarization in the hippocampal CA1 and CA3 regions, and inhibited Src phosphorylation and nuclear factor kappa B pathway activation. The effects of 5-O-methylvisammioside were similar to those of the Src inhibitor PP2. When 5-O-methylvisammioside was administered with PP2, no effects were observed on lipopolysaccharide-induced depression-like behaviors in mice, nuclear factor kappa B pathway proteins, and microglial polarization. These findings indicate that 5-O-methylvisammioside may exert its antidepressant potential by inhibiting Src-mediated activation of the nuclear factor kappa B signaling pathway. Therefore, 5-O-methylvisammioside might serve as a promising Chinese herbal medicine for the prevention and treatment of depression.