Wogonin Mitigates Depression by Inhibiting TNF‐α/TNFR1/CXCL1 Signalling‐Mediated Astrocyte Activation

Wogonin exhibits notable anti-inflammatory and neuroprotective effects. Current study aimed to investigate the antidepressant potential of wogonin and its underlying mechanisms through in vitro and in vivo experiments. In vitro, wogonin attenuated lipopolysaccharide (LPS)-induced astrocyte activation. Furthermore, wogonin inhibited the TNF-α/TNFR1/CXCL1 signalling axis, as evidenced by decreased protein levels of TNF-α and CXCL1 and reduced interaction between TNF-α and its receptor TNFR1. The addition of recombinant TNF-α (r-TNF-α) blocked these inhibitory effects of wogonin. In vivo, in a chronic unpredictable mild stress (CUMS) mouse model, wogonin alleviated depression-like behaviours. Moreover, wogonin rescued CUMS-induced impairments in hippocampal synaptic plasticity, restoring post-tetanic potentiation (PTP), long-term potentiation (LTP) and mitigating neuronal damage in the CA1 region. Further analysis revealed that wogonin reduced levels of TNF-α and CXCL1 in both the hippocampal CA1 region and cerebrospinal fluid, and decreased the expression of astrocyte activation markers GFAP and C3. These effects of wogonin in vivo were reversed by co-administration of r-TNF-α and were replicated by treatment with the TNF-α inhibitor etanercept. These results demonstrate that wogonin may exert antidepressant effects by modulating the TNF-α/TNFR1/CXCL1 pathway, thereby improving neuroinflammation and astrocyte activation.