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.

Key words: 5-O-methylvisammioside, depression-like behavior, hippocampus, major depressive disorder, microglia, network pharmacology, neuroinflammation, nuclear factor kappa B signaling pathway, PP2, Src