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

Abstract

<p>Wogonin exhibits notable anti-inflammatory and neuroprotective effects. Current study aimed to investigate the antidepressant potential of wogonin and its underlying mechanisms through in&nbsp;vitro and in&nbsp;vivo experiments. In&nbsp;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&nbsp;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&nbsp;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.</p>