氯沙坦通过激活AMPK抑制LPS诱导的小鼠海马GFAP表达

发布时间：2018-06-02 18:37

本文选题：氯沙坦 + 脂多糖　；参考：《中国病理生理杂志》2017年09期

【摘要】：目的:探讨氯沙坦对脂多糖(LPS)诱导的星形胶质细胞活化标志物胶质纤维酸性蛋白(GFAP)表达的影响,以及其机制是否与激活腺苷酸活化蛋白激酶(AMPK)有关。方法:将成年雄性昆明小鼠分为正常对照组、LPS模型组、氯沙坦给药组及氯沙坦与compound C合用组。侧脑室注射相同剂量LPS(24μg/d,每天1次,共2次),以建立中枢神经炎症损伤模型;氯沙坦(0.5、1或5 mg·kg~(-1)·d~(-1))于LPS注射前14 d开始连续每日腹腔注射给药;AMPK抑制剂Compound C(10 mg·kg~(-1)·d~(-1))于LPS注射前2 d开始连续每日腹腔注射给药。在LPS末次注射后的第3天取各组小鼠的海马脑区组织,利用Western blot法检测GFAP、AMPK、p-AMPK、哺乳动物雷帕霉素靶蛋白(mTOR)和p-mTOR的蛋白水平。结果:2次LPS注射后可显著诱导GFAP在海马脑区的表达(P0.01),而氯沙坦可浓度依赖地抑制LPS诱导的GFAP表达,当氯沙坦剂量为5 mg·kg~(-1)·d~(-1)时可显著抑制GFAP表达(P0.05),同时,在该剂量下,氯沙坦显著提高了AMPK的磷酸化水平(P0.01),但对mTOR的磷酸化水平无明显调节作用;而AMPK抑制剂Compound C可显著逆转氯沙坦对GFAP表达及AMPK磷酸化的调节作用(P0.05)。结论:氯沙坦可抑制LPS诱导的海马GFAP表达,该作用可能与其激活AMPK有关,但并不依赖于mTOR信号通路。
[Abstract]:Aim: to investigate the effect of losartan on the expression of glial fibrillary acidic protein (GFAP), an activation marker of astrocytes induced by lipopolysaccharide (LPS), and whether the mechanism is related to the activation of adenylate activated protein kinase (AMPK). Methods: adult male Kunming mice were divided into normal control group, Losartan administration group and Losartan combined with compound C group. Intracerebroventricular injection of the same dose of LPS(24 渭 g / d, once a day, twice a day, was used to establish the model of central nervous inflammation injury. Losartan 0.5mg / kg or 5mg / kg ~ (-1) d ~ (1) Compound (10 mg 路kg ~ (-1), an AMPK inhibitor, was continuously injected intraperitoneally 14 days before LPS injection.) (2 days before LPS injection, the drug was given intraperitoneally continuously, and the drug was given intraperitoneally at 10 mg / kg of AMPK inhibitor, Compound Cam 10 mg 路kg ~ (-1) 路L ~ (-1) 路d ~ (-1) (P < 0.05). On the third day after the last injection of LPS, the hippocampal tissues of the mice in each group were collected and the protein levels of AMPKO p-AMPK, mammalian rapamycin target protein mTORand p-mTOR were detected by Western blot method. Results the expression of GFAP in hippocampal brain was significantly induced by two LPS injections, while Losartan inhibited the expression of GFAP induced by LPS in a concentration-dependent manner. Losartan significantly inhibited the expression of GFAP at a dose of 5 mg / kg ~ (-1) D ~ (-1). At the same time, Losartan could also inhibit the expression of GFAP in the hippocampus, and at the same time, Losartan could inhibit the expression of GFAP in the hippocampus in a dose-dependent manner. Losartan significantly increased the phosphorylation level of AMPK, but did not regulate the phosphorylation level of mTOR, while AMPK inhibitor Compound C significantly reversed the effect of Losartan on the expression of GFAP and the phosphorylation of AMPK. Conclusion: losartan can inhibit the expression of GFAP in hippocampus induced by LPS, which may be related to the activation of AMPK, but does not depend on mTOR signaling pathway.
【作者单位】：山西医科大学基础医学院药理教研室;
【基金】：国家自然科学基金资助项目(No.81202520) 山西省青年科技研究基金资助项目(No.2014021038-1) 山西省重点学科建设经费资助项目
【分类号】：R965

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