【摘要】 目的：观察淫羊藿苷对阿尔茨海默病（AD）模型大鼠海马区Toll样受体4 (TLR4)/髓样分化因子88 (MyD88)/核因子κB p65 (NF-κB p65)信号通路的影响。方法：将60只SD大鼠随机分为假手术组、模型组、阳性对照组（0.25 mg/kg盐酸多奈哌齐）、淫羊藿苷低、中、高剂量组（30.00、60.00、120.00 mg/kg）。除假手术组外，其余大鼠均注射Aβ25-35建立AD模型。治疗4周后，采用Morris水迷宫测试空间学习能力；试剂盒检测海马组织超氧化物歧化酶（SOD）、过氧化氢酶（CAT）和丙二醛（MDA）活性；酶联免疫吸附法检测海马组织炎症因子[肿瘤坏死因子-α (TNF-α)、白细胞介素-1β (IL-1β)和白细胞介素-6 (IL-6)]和神经递质[乙酰胆碱酯酶（AchE）、乙酰胆碱（Ach）、胆碱乙酰转移酶（ChAT）]水平；苏木精-伊红（HE）染色观察大鼠海马区神经元病理情况；Western blot检测海马组织TLR4、MyD88、NF-κB p65、剪切化半胱氨酸天冬氨酸蛋白激酶-3 (C-Caspase3)、B-淋巴细胞瘤基因-2 (Bcl-2)、Bcl-2相关X蛋白（Bax）蛋白表达。结果：与假手术组比较，模型组大鼠Morris水迷宫逃避潜伏期增加（P<0.05），穿越平台次数、原平台象限停留时间减少（P<0.05）；模型组大鼠海马组织Ach、ChAT、SOD、CAT水平及Bcl-2蛋白表达显著降低（P<0.05）,AchE、MDA、TNF-α、IL-1β、IL-6水平及Bax、C-Caspase-3、TLR4、MyD88、NF-κB p65蛋白表达显著升高（P<0.05）；模型组大鼠海马CA1区可见神经元排列紊乱、神经元细胞结构疏松、核固缩、有空泡结构形成。与模型组比较，阳性对照组及淫羊藿苷中、高剂量组大鼠在Morris水迷宫中的逃避潜伏期减少（P<0.05），原平台象限停留时间和穿越平台次数增加（P<0.05）；海马组织Ach、ChAT、SOD、CAT水平及Bcl-2蛋白表达显著升高（P<0.05）,AchE、MDA、TNF-α、IL-1β、IL-6水平及Bax、C-Caspase-3、TLR4、MyD88、NF-κB p65蛋白表达显著降低（P<0.05）。给药后，各给药组大鼠海马CA1区神经元损伤有不同程度的改善。结论：淫羊藿苷可通过调节TLR4/MyD88/NF-κB p65信号通路，减轻大鼠海马氧化应激和炎症反应，抑制神经元细胞凋亡，从而缓解AD。更多还原

【Abstract】 Objective:To observe the effect of icariin on toll-like receptor 4(TLR4)/myeloid differentiation factor 88(MyD88)/nuclear factor kappa-light-chain-enhancer of activated B(NF-κB p65) signaling pathway in hippocampus in rat models of Alzheimers disease(AD). Methods:A total of 60 SD rats were randomly divided into the sham operation group,the model group,the positive control group(0.25 mg/kg Donepezil Hydrochloride),and the icariin groups of low dosage,medium dosage and high dosage(30.00,60.00 and120.00 mg/kg respectively). Except the rats in the sham operation group,all rats were injected with Aβ25-35to establish AD models. After four-week treatment, Morris water maze was used to test the spatial learning ability; the activities of superoxide dismutase(SOD) and catalase(CAT), and malondialdehyde(MDA) in hippocampus were detected with the kit; enzyme-linked immunosorbent assay was used to measure the levels of inflammatory factors [tumor necrosis factor(TNF-α), interleukin-1β(IL-1β),interleukin-6(IL-6)] and neurotransmitters [acetylcholinesterase(AchE), acetylcholine(Ach), choline acetyltransferase(ChAT)] in hippocampus; Hematoxylin and Eosin(HE) staining was used to observe the pathological changes of hippocampal neurons in rats; Western blot was used to detect the protein expressions of TLR4, MyD88, NF-κB p65, cleaved cysteinyl aspartate specific proteinase-3(CCaspase3),and B-cell lymphoma-2[Bcl-2,Bcl-2-associated X protein(Bax)] in hippocampus. Results:The escape latency in Morris water maze of rats in the model group was prolonged when compared with that in the sham operation group(P<0.05),and the number of platform crossings and the time spent in the original platform quadrant in the model group were decreased(P<0.05). The levels of Ach,ChAT,SOD and CAT in hippocampus and the protein expression of Bcl-2 in rats in the model group were significantly decreased when compared with those in the sham operation group,and the levels of AchE,MDA,TNF-α,IL-β and IL-6,and the protein expressions of Bax,C-Caspase-3,TLR4,MyD88 and NF-κB p65were significantly increased(P<0.05). In the CA1 region of the hippocampus in rat models, there were disordered arrangement of neurons, loose neuronal cell structure, karyopyknosis of neurons, and the formation of vesicles. The escape latency in Morris water maze of rats in the positive control group,and the icariin groups of medium dosage and high dosage was shortened when compared with that in the model group(P<0.05),and the number of platform crossings and the time spent in the original platform quadrant in the model group were increased(P<0.05). The levels of Ach,ChAT,SOD and CAT in hippocampus and the protein expression of Bcl-2 in rats in the positive control group, and the icariin groups of medium dosage and high dosage were significantly increased when compared with those in the model group,and the levels of AchE,MDA,TNF-α,IL-β and IL-6,and the protein expressions of Bax,C-Caspase-3,TLR4, MyD88 and NF-κB p65 were significantly decreased(P<0.05). After administration, neuronal damage in the CA1 region of the hippocampus was improved to various degrees in rats of each administration group. Conclusion:Icariin can regulate TLR4/MyD88/NF-κB p65 signaling pathway to relieve oxidative stress and inflammatory responses in hippocampus of rats and inhibit neuronal apoptosis,thus alleviates AD.更多还原