Neferine alleviated corticosterone-induced depressive-like behaviors in mice via the inhibition of TNF/NF-κB pathway by binding to PPARγ.

Depression is a widespread neuropsychiatric disorder with the current therapeutic approaches achieving only suboptimal efficacy. Neferine is the main bioactive component of Nelumbinis plumula with multiple pharmacological functions. This study sought to investigate the antidepressant activity of neferine and elucidate its underlying mechanisms. Network pharmacology analysis was performed to uncover the molecular targets and pathways involved in neferine's antidepressant effects. The interaction of neferine with the core target was demonstrated by molecular docking and molecular dynamics simulation. The mouse model of depression triggered by chronic corticosterone (CORT) administration was utilized to validate the impact of neferine on core targets and pathways. We found that neferine remarkably attenuated CORT-induced depressive-like behaviors in mice. A total of 178 overlapping targets were acquired through the intersection of neferine and depression-related genes. The protein-protein interaction (PPI) network analysis revealed nine pivotal hub genes, namely AKT1, TNF, ESR1, PPARG, JUN, HIF1A, CASP3, NFKB1, and MMP9. Functional enrichment analysis indicated that these targets predominantly mapped to the TNF signaling pathway in depression. Molecular docking and molecular dynamics simulation showed that neferine has strong binding stability with PPARγ, a key molecule involved in regulating the TNF pathway. The results of animal experiments found that a PPARγ antagonist abolished neferine-induced alleviation of depressive-like behaviors. Moreover, neferine suppressed TNF/NF-κB pathway activation and attenuated neuronal loss in the hippocampus, potentially through activating PPARγ. Collectively, our study suggested that neferine produced antidepressant effects by suppressing hippocampal inflammation and neuronal loss through inhibiting the TNF/NF-κB signaling pathway. These preclinical evidence laid a foundation for further exploring the role of neferine in treating depression.