Gao Li-Na, Yan Maocai, Zhou Lirun, Wang Jian'an, Sai Chunmei, Fu Yingjie, Liu Yang, Ding Lin
College of Pharmacy, Jining Medical University, Rizhao, China.
Shandong Collaborative Innovation Center for Diagnosis, Treatment and Behavioral Interventions of Mental Disorders, Institute of Mental Health, Jining Medical University, Jining, China.
Front Pharmacol. 2021 Dec 15;12:767333. doi: 10.3389/fphar.2021.767333. eCollection 2021.
Puerarin has been reported as a potential agent for neuro-inflammatory disorders. However, there have been no reports of using puerarin for the treatment of depression based on Toll-like receptor 4 (TLR4)-mediated inflammatory injury. In this study, we evaluated the protective effects of puerarin on depression-like rats induced by a high-fat diet (HFD) combined with chronic unpredictable mild stress (CUMS). The mechanism was screened by lipidomics and molecular docking and confirmed by tests. Puerarin treatment significantly improved 1% sucrose preference and ameliorated depression-like behavior in the open-field test. The antidepressive effects of puerarin were associated with decreased pro-inflammatory cytokine production, including interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), and increased anti-inflammatory cytokine levels (IL-10) in rat hippocampal tissues and plasma. Hematoxylin-eosin (H&E), immunofluorescence staining, and Western blotting results displayed that puerarin alleviated inflammatory injury by suppressing TLR4 expression and by repairing the intestine mucus barrier enhancing the expression of claudin-1 and occludin. Non-targeted lipidomics analysis showed that the most significantly different metabolites modified by puerarin were phospholipids. Puerarin treatment-altered biomarkers were identified as PC (15:1/20:1), PE (15:1/16:1), and PI (18:2/20:1) in comparison with the HFD/CUMS group. Molecular docking modeling revealed that puerarin could bind with cytosolic phospholipase A2 (cPLA2) and cyclooxygenase-2 (COX-2), which play central roles in TLR4-mediated phospholipid metabolism. , puerarin treatment decreased the enzyme activities of cPLA2 and COX-2, resulting in lower production of prostaglandin E (PGE) in hippocampal and intestinal tissues. In conclusion, puerarin treatment reverses HFD/CUMS-induced depression-like behavior by inhibiting TLR4-mediated intestine mucus barrier dysfunction and neuro-inflammatory damages the TLR4/cPLA2/COX-2 pathway.
葛根素已被报道为一种治疗神经炎症性疾病的潜在药物。然而，尚无基于Toll样受体4（TLR4）介导的炎症损伤使用葛根素治疗抑郁症的报道。在本研究中，我们评估了葛根素对高脂饮食（HFD）联合慢性不可预测轻度应激（CUMS）诱导的抑郁样大鼠的保护作用。通过脂质组学和分子对接筛选其作用机制，并通过实验进行验证。葛根素治疗显著提高了1%蔗糖偏好，并改善了旷场试验中的抑郁样行为。葛根素的抗抑郁作用与大鼠海马组织和血浆中促炎细胞因子生成减少有关，包括白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α），以及抗炎细胞因子水平（IL-10）升高有关。苏木精-伊红（H&E）染色、免疫荧光染色和蛋白质印迹结果显示，葛根素通过抑制TLR4表达和修复肠道黏液屏障（增强紧密连接蛋白-1和闭合蛋白的表达）减轻炎症损伤。非靶向脂质组学分析表明，葛根素修饰的最显著差异代谢物是磷脂。与HFD/CUMS组相比，葛根素治疗改变的生物标志物被鉴定为PC（15:1/20:1）、PE（15:1/16:1）和PI（18:2/20:1）。分子对接模型显示，葛根素可与在TLR4介导的磷脂代谢中起核心作用的胞质磷脂酶A2（cPLA2）和环氧化酶-2（COX-2）结合。此外，葛根素治疗降低了cPLA2和COX-2的酶活性，导致海马和肠道组织中前列腺素E（PGE）生成减少。总之，葛根素治疗通过抑制TLR4介导的肠道黏液屏障功能障碍和神经炎症损伤（通过TLR4/cPLA2/COX-2途径）逆转HFD/CUMS诱导的抑郁样行为。
