Neuroprotective effects of quercetin in LPS-induced depression: implications for antidepressant therapy

Cognitive dysfunction is a prevalent and debilitating symptom associated with major depressive disorder (MDD), with neuroinflammation, driven by microglial activation, serving as a critical pathological mechanism. This study explored the therapeutic potential of quercetin, a dietary bioflavonoid recognized for its anti-inflammatory properties, within a lipopolysaccharide (LPS)-induced mouse model of depression. We posited that quercetin would mitigate depressive-like behaviors and cognitive deficits by targeting the NLRP3 inflammasome pathway. Behavioral assessments demonstrated that quercetin treatment significantly alleviated LPS-induced anhedonia, as evidenced by the sucrose preference test, and reduced behavioral despair, as observed in the forced swim and tail suspension tests. Additionally, quercetin ameliorated impairments in spatial working memory and recognition memory, as indicated by performance in the Y-maze and novel object recognition/location tests. Mechanistically, quercetin inhibited the upregulation of hippocampal NLRP3 and its molecular chaperone HSP90, while concurrently reducing the levels of pro-inflammatory cytokines (IL-6, IL-1β, MCP-1, TNF-α) in both hippocampal tissue and primary microglial cultures. The present findings indicate that quercetin significantly alleviates depressive-like behaviors and related cognitive impairments by suppressing the activation of the NLRP3 inflammasome and the ensuing neuroinflammatory processes. These results underscore quercetin's dual impact on mood and cognitive function, suggesting its potential as an innovative therapeutic agent or adjunctive treatment for depression and its cognitive consequences.