Quercetin regulates depression-like behavior in CUMS rat models via TLR4/NF-κB κ B signaling

Background: Depression is becoming increasingly prevalent around the world, imposing a substantial burden on individuals, families, as well as society. Quercetin is known to be highly effective in treating depression. However, additional research is needed to dissect the mechanisms of its anti -depressive effects. Methods: For this study, Sprague-Dawley (SD) rats were randomized into the control, model, quercetin, or fl uoxetine group. The latter three groups were exposed to chronic unpredictable mild stress (CUMS) for 42 d. The fi rst two groups received saline solution daily via oral gavage. Meanwhile, the quercetin group was orally administered a quercetin suspension (52.08 mg/kg) every day, while the fl uoxetine group was orally administered a fl uoxetine solution (2.08 mg/kg). Here, fl uoxetine served as the positive control drug to compare the therapeutic effects of quercetin. The experimental period was 6 weeks. Depressive behaviors in rats were assessed through various physiological and behavioral measures. Additionally, pathological changes in hippocampal tissues were examined using Nissl staining. Serum cytokines were detected using an enzymelinked immunosorbent assay (ELISA), and immunohistochemistry was employed to quantify the levels and integral optical density (IOD) values of ionized calcium binding adaptor molecule -1 (Iba-1) expression in the brain. Real-time fl uorescence quantitative PCR (RT-qPCR) was utilized to evaluate the mRNA levels of inflammatory fl ammatory indicators as well as toll -like receptor 4 (TLR4), and nuclear factor -Kappa B P65 (NF -KB P65) in hippocampus. Western blot (WB) technique was employed to observe the protein levels of TLR4, NF -KB P65, and phospho-NF-KB P65 (p -NF -KB P65). Results: After 42 d of exposure to CUMS, rats exhibited a slow increase in body weight, a reduction in food intake, an abnormal preference for sugar water, and aberrant open-field fi eld behaviors. Pathological analysis revealed the disintegration, rupture, interruption, and disorganization of hippocampal neuronal cells after CUMS exposure, along with a decrease in Nissl bodies in the CA1 region. This was accompanied by the elevated expression of interleukin-113 (IL -113), tumor necrosis factor -a (TNF-a), and interleukin-6 (IL -6) in the serum and the upregulation of IL -113, IL -6, and TNF-a mRNA expression in the hippocampus. Increases in Iba-1-positive cells and the IOD values of Iba-1 were detected in hippocampal microglia. Furthermore, TLR4 and NF -KB P65 mRNA and protein levels were upregulated in hippocampal tissues. Quercetin, an antidepressant, could alleviate depression -like symptoms in rats and downregulate inflammatory fl ammatory factors associated with the TLR4/NF-KB signaling pathway in hippocampal microglia, and its therapeutic effect was comparable to fl uoxetine. Conclusion: In rat models of CUMS, quercetin may act as an antidepressant by inhibiting inflammation fl ammation in hippocampal microglia via TLR4/NF-KB signaling pathway. These results offer experimental and theoretical support for applying quercetin in the clinical management of depression.