Quercetin mitigates CUMS-induced depression-like behaviors in rats by regulating argininosuccinic acid-induced astrocyte pyroptosis in the hippocampus.

Depression, or major depressive disorder, is a prevalent psychological disorder, but its underlying mechanisms remain understood, hindering effective prevention and treatment. This study investigated the protective effects of quercetin on chronic unpredictable mild stress (CUMS)-induced depressive-like behaviors and explored the underlying mechanisms using in vivo and in vitro experiments. Metabonomic analysis revealed that CUMS significantly elevated serum levels of argininosuccinic acid (ASA), which were strongly correlated with depression-like behaviors in rats, suggesting a potential role of ASA in depression pathogenesis. Intracerebral injection of ASA induced depression-like behaviors and upregulated inflammatory markers (inhibitory-κB kinase alpha [IKK-α], nuclear factor kappa b subunit p65, nod-like receptor protein 3 [NLRP3]) and pyroptosis-related proteins ( cysteine-aspartic acid protease-1 [caspase-1], Gasdermin D) in the rats' hippocampus (HPC). Quercetin treatment ameliorated CUMS-induced depressive behaviors, reduced serum ASA levels, and inhibited hippocampal inflammation and pyroptosis. In subsequent in vitro experiments with primary astrocytes isolated from the HPC of neonatal rats aged 1-3 days, reactive oxygen species, NLRP3, and caspase-1 inhibitors were used to demonstrate that quercetin, through its antioxidant and anti-inflammatory effects, could attenuate ASA-induced activation of the nuclear factor- kappa B/NLRP3 inflammatory pathway and subsequent pyroptosis, thereby protecting astrocytes. Collectively, this study suggested that ASA could induce NLRP3/caspase-1 activation via reactive oxygen species, triggering astrocyte pyroptosis and contributing to depression. Notably, quercetin can effectively alleviate stress-induced depression-like behaviors by inhibiting ASA-induced astrocyte pyroptosis and subsequent astrocyte loss in the HPC. This study provides valuable insights into the potential of quercetin as a therapeutic agent targeting cellular mechanisms in depression, offering new perspectives for treating this disorder.