Xanthouhumol relieves stress-induced depressive-like behaviors through the Sirt1/NF-κB/NLRP3 pathway

Rationale: Depression is a complicated neuropsychiatric disorder with multifactorial etiology, involving alterations in behavior, neuroinflammatory processes, and oxidative homeostasis. Chronic stress disrupts synaptic plasticity and promotes neuroinflammation and redox imbalance, with pronounced effects in the medial prefrontal cortex (mPFC). Xanthohumol (XN), a prenylated flavonoid, has demonstrated neuroprotective properties; however, its therapeutic potential in the context of stress-induced depression has not been fully exploited. Objectives: This study aims to examine whether XN alleviates depressive-like behaviors in a chronic unpredictable mild stress (CUMS) mouse model, as well as to delve into the underlying mechanisms involving neuroinflammation, oxidative stress, synaptic function, and the Sirt1/NF-kappa B/NLRP3 signaling pathway. Methods: Male C57BL/6J mice were subjected to a 3-week CUMS protocol and administered XN at a dose of 20 mg/kg via intragastric gavage. Behavioral evaluations included the sucrose preference test, tail suspension test, and forced swim test to assess anhedonia and behavioral despair. mPFC tissues were collected for analysis of neuroinflammatory cytokines, Nissl staining, immunofluorescence, oxidative stress biomarkers, and synaptic protein expression. In addition, protein levels of Sirt1, phosphorylated NF-kappa B (phospho-NF-kappa B), total NF-kappa B, and NLRP3 in the mPFC were quantified via western blotting analysis. Results: XN treatment significantly ameliorated depressive-like behaviors and enhanced synaptic protein expression within the mPFC. XN markedly diminished the pro-inflammatory cytokines expression and attenuated oxidative stress via the activation of the Nrf2/HO-1 signaling pathway, thereby boosting the brain's antioxidant capacity. Additionally, XN upregulated the expression of Sirt1 and suppressed the NF-kappa B/NLRP3 inflammasome pathway activation. Conclusions: XN exerts antidepressant-like impact through the Sirt1/NF-kappa B/NLRP3 and Nrf2/HO-1 pathways, highlighting XN as a potentially effective therapeutic alternative for stress-induced depression.