蛇床子素通过减轻阿尔茨海默病大鼠模型中的神经炎症改善认知功能障碍

Osthole mitigates cognitive dysfunction and neuroinflammation in a rat model of Alzheimer's disease

目的抗炎治疗为阿尔茨海默病(AD)的治疗提供了一个潜在的靶点。蛇床子素(Ost)已被证明可以改善记忆并具有多效性保护作用,但其在AD治疗过程中的确切机制尚不清楚。方法在本研究中,作者研究Ost对β-淀粉样蛋白1-42(Aβ1-42)诱导的认知功能障碍和海马炎症反应的保护作用。采用双侧海马注射Aβ_(1-42)建立AD大鼠模型,在Aβ_(1-42)注射前7 d至注射后7 d每日给予Ost。采用Morris水迷宫(MWM)试验评估大鼠的认知功能。采用免疫组化和Western blot法检测海马神经胶质反应及Toll样受体4(TLR4)、肿瘤坏死因子受体相关因子6(TRAF6)和核因子-κB(NF-κB)的表达。用酶联免疫吸附试验(ELISA)测定促炎细胞因子的产生。结果Ost治疗显著改善了AD大鼠模型海马中Aβ_(1-42)毒性诱导的认知障碍,减轻了胶质细胞的激活,降低了炎症细胞因子的释放(P<0.01)。经Ost处理后,Aβ_(1-42)诱导的TLR4、TRAF6和NF-κB表达的明显降低(P<0.01)。结论Ost通过抑制TLR4/NF-κB信号通路而减轻Aβ_(1-42)诱导的神经炎症,可能是一种很有前途的治疗药物。

Objective Anti-inflammatory therapy provides a potential target for treatment of Alzheimer's disease(AD).Osthole(Ost)has been shown to preserve memory and have pleiotropic protective effects,but its exact mechanism during AD treatment is obscure.Methods In the present study,we investigated the protective effects of Ost on cognitive dysfunction and hippocampal inflammatory response induced by beta-amyloid_(1-42)(Aβ_(1-42)).The model of AD rat was established by bilateral hippocampal injection of Aβ_(1-42)and the rats were administered with Ost from7 days before to 7 days after injections.Morris water maze(MWM)test was performed to assess the cognitive function of rats.Glial response and the expression of Toll-like receptor 4(TLR4),tumor necrosis factor receptor-associated factor-6(TRAF-6)and nuclear factor-κB(NF-κB)in hippocampus were determined by immunohistochemistry and western blot.The production of proinflammatory cytokines was measured by enzyme-linked immunosorbent assay(ELISA).Results The results showed that Ost treatment significantly improved cognitive impairment induced by Aβ_(1-42)toxicity,alleviated glial activation and decreased the release of inflammatory cytokines in the hippocampus of Aβ_(1-42)-induced AD rat(P<0.01).Furthermore,the increasing expressions of TLR4,TRAF6 and NF-κB induced by Aβ_(1-42)were alleviated significantly after Ost treatment(P<0.01).Conclusion Ost administration might be a promising candidate for AD treatment via attenuating Aβ_(1-42)-induced neuroinflammation and TLR4/NF-κB signaling pathway.