Glabridin Improves Depression-Like Behaviors in Mice by Modulating Neuroinflammation via MAPK/NF-κB Signaling Pathway

The incidence of depression is increasing year by year and has become a major problem threatening global public health. However, the limited efficacy of existing antidepressant drugs, accompanied by significant side effects and dependence, has prompted researchers to search for safer and more effective drugs. Recent studies have shown that neuroinflammation plays a key role in the pathological mechanisms of depression, suggesting that anti-inflammatory drugs may have potential for treating depression. Glabridin, the main active ingredient in Glycyrrhiza glabra, has significant anti-inflammatory and neuroprotective effects, but its antidepressant effects and mechanisms have not been fully elucidated. In the present study, we used a combination of network pharmacological prediction and in vivo experiments to investigate the ameliorative effect of glabridin on chronic unpredictable mild stress (CUMS)-induced depressive-like behaviours in mice and the possible molecular mechanisms. The experimental results showed that glabridin significantly ameliorated the symptoms of pleasure deficit and behavioral despair in CUMS mice, as evidenced by an increase in sucrose preference and a significant reduction in tail-hanging immobility time and forced swimming immobility time. In addition, glabridin effectively alleviated CUMS-induced neuronal damage in the hippocampal region and significantly reduced the expression of inflammatory factors, such as IL-1β, IL-6, and IL-18, suggesting that it could reduce the neuroinflammatory response. Network pharmacological analysis revealed that MAPK and NF-κB signaling pathways may be the key pathways for the antidepressant effect of glabridin. Further Western blot validation showed that glabridin inhibited the activation of the P38MAPK/NF-κB pathway in the hippocampus and reduced the phosphorylation level of related proteins. Overall, we provide evidence suggesting that the antidepressant mechanism of glabridin may be closely associated with multiple pathways, including downregulation of MAPK/NF-κB pathway activity, inhibition of inflammatory factor expression, and neurotransmitter regulation. This study offers new insights into the therapeutic potential of glabridin for treating depression.