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目的研究知母-黄芪散复方通过TNF-α/JNK通路改善阿尔茨海默症大鼠认知障碍的作用机制及其药效初探。方法取雄性SD大鼠50只,根据基础血糖和体质量水平随机分为5组,每组10只,即正常组,模型组,知母组,黄芪散组,知母-黄芪散组;采用腹腔注射链脲佐菌素(STZ)联合喂食高脂饲料+AlCL_3灌胃的方法建立模型,连续灌胃20周。分别在给药第8、16周时,测定空腹血糖(FPG)、总胆固醇(TC)、甘油三酯(TG)水平;结合Barnes迷宫检测大鼠的认知状况;给药20周时,测定血浆TNF-α、P-JNK、Aβ_(1-42)蛋白及INS水平,结合Morris水迷宫检测大鼠的认知能力;给药20周结束,解剖保存大鼠脑组织、海马组织作病理形态学观察。结果给药8周、16周时,与正常组比较,模型组大鼠空腹血糖(FPG)、TC、TG水平均显著性升高(P<0.05,P<0.01);与模型组比较,知母-黄芪散组可有效降低模型大鼠FPG、TC、TG水平(P<0.05);给药20周,与正常组比较,模型组大鼠血浆TNF-α、P-JNK、Aβ_(1-42)水平也明显升高(P<0.01);与模型组比较,经连续给药后,知母组,知母-黄芪散组大鼠血浆TNF-α、P-JNK、Aβ1-42水平均显著降低(P<0.05,P<0.01);行为学实验结果显示,与模型组比较,知母-黄芪散组表现出较显著的改善记忆、认知行为的作用(P<0.05,P<0.01);组织形态学结果显示,正常组大鼠海马CAI区神经元排列整齐,形态规则,着色均匀;与模型组比较,知母组可有效改善大鼠海马组织神经元形态及细胞排列形态,修复神经损伤,大鼠胰腺病理形态改变与海马CAI区神经元病理改变具有一定正相关趋势。结论知母组及知母-黄芪散组不仅降糖效果明显,并且可以通过调节TNF-α/JNK通路改善STZ+高脂饲料+AlCL_3灌胃喂养诱导实验性阿尔茨海默症大鼠认知、记忆能力。
Objective To study the mechanism of action and pharmacodynamics of Zhimu-Huangqi San on cognitive impairment in Alzheimer’s disease rats through TNF-α / JNK pathway. Methods Fifty male SD rats were randomly divided into five groups according to basal blood glucose and body weight, each group containing 10 rats, namely normal group, model group, Zhimu group, Astragalus group, Zhimu-Huangqi powder group. The model was established by intraperitoneal injection of streptozotocin (STZ) combined with high fat diet + AlCl3 orally. The rats were given gavage for 20 weeks. The levels of fasting blood glucose (FPG), total cholesterol (TC) and triglyceride (TG) were determined at the 8th and 16th weeks of administration respectively. The cognitive status of rats was detected by Barnes maze. At 20 weeks after administration, Plasma levels of TNF-α, P-JNK, Aβ 1-42 and INS were detected by Western blotting. Morris water maze was used to detect the cognitive ability of rats. At the end of 20 weeks after administration, anatomical preservation of rat brain and hippocampus Learn to observe. Results Compared with the normal group, fasting blood glucose (FPG), TC and TG levels in model group were significantly increased at 8 and 16 weeks (P <0.05, P <0.01). Compared with model group, Compared with the normal group, the levels of TNF-α, P-JNK, Aβ_ (1-) in the model group were significantly lower than those in the normal group (P <0.05) (P <0.01). Compared with the model group, the levels of TNF-α, P-JNK and Aβ 1-42 in the Anemarrhena asphodeloides, Anemarrhena astigmatism and Astragalus mongholicus groups were significantly decreased after continuous administration (P <0.05, P <0.01). The results of behavioral experiments showed that, compared with the model group, the Anemarrhena Astragalus scattered group showed significant effects of improving memory and cognitive behavior (P <0.05, P <0.01) ). The results of histomorphology showed that the neurons in hippocampal CAI of rats in normal group were arranged neatly, with regular morphology and uniform coloring. Compared with model group, Zhimu group could effectively improve the morphology and arrangement of neurons in hippocampus of rats, Nerve injury, pathological changes of rat pancreas and pathological changes of hippocampal CAI neurons have a certain positive correlation. Conclusion Zhimu group and Zhimu-Huangqi San group not only have obvious hypoglycemic effect, but also can improve the cognition of experimental Alzheimer’s disease rats by regulating the TNF-α / JNK pathway to improve STZ + high fat diet + AlCl 3 intragastric administration, Memory capacity.