PT109改善链脲佐菌素诱导的散发性阿尔茨海默病小鼠认知功能障碍的作用及机制  

PT109 Ameliorates Cognitive Impairment in the Streptozotocin-induced Sporadic Alzheimer’S Disease Mice and Its Mechanisms

作　　者：陈秋荷 涂亚林 侯加卫 陈晨 鲁俊锋 皮荣标 CHEN Qiu-he;TU Ya-lin;HOU Jia-wei;CHEN Chen;LU Jun-feng;PI Rong-biao(Department of Pharmacology&Toxicology,School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou 510006,China;School of Pharmaceutical Sciences,Guangzhou University of Chinese Medicine,Guangzhou 510006,China;Department of Pharmacology,School of Medicine,Sun Yat-sen University,Shenzhen 518107,China)

机构地区：[1]中山大学药学院药理与毒理教研室,广东广州510006 [2]广州中医药大学中药学院,广东广州510006 [3]中山大学医学院药理教研室,广东深圳518107

出　　处：《中山大学学报（医学科学版）》2021年第5期694-702,共9页Journal of Sun Yat-Sen University:Medical Sciences

基　　金：广州市科技计划项目(201801010094,201704020222)。

摘　　要：【目的】观察PT109能否改善侧脑室注射链脲佐菌素(icv-STZ)诱导的散发性AD小鼠模型的认知功能障碍并对其机制进行初步探讨。【方法】32只7周龄雄性C57BL/6小鼠分为正常组(7只)、模型组(7只)、PT109低剂量组(9只)、PT109高剂量组(9只)。将STZ于第1和3天注射入小鼠侧脑室建立散发性阿尔茨海默病小鼠模型;(3mg/kg,每个注射位点5μL)造模后,分别腹腔注射PT109(30、100 mg·kg^(-1)·d^(-1)),2周后通过Morris水迷宫和避暗实验评价小鼠学习记忆能力;随后通过免疫荧光、免疫组化、免疫印迹、高尔基染色等方法检测小胶质细胞、神经元、树突棘、磷酸化Tau蛋白等AD相关指标。【结果】行为学实验结果显示:PT109可改善icv-STZ小鼠的学习记忆障碍;免疫荧光及组化结果显示:与模型组相比,PT109减少海马区域Iba1阳性细胞数量(低剂量:P<0.001,高剂量:P<0.001),高剂量PT109增加海马和皮层区域MAP2和Tuj1阳性细胞总数量(P<0.05,P<0.01),差异具有统计学意义。高尔基染色结果显示:与模型组相比,PT109增加树突棘密度(低剂量:P<0.001,高剂量:P<0.001),差异具有统计学意义。免疫印迹实验结果表明:与模型组相比,PT109降低NLRP3(高剂量:P<0.05)、磷酸化Tau蛋白的表达水平(低剂量:P<0.05,高剂量:P<0.01),高剂量PT109提高PSD95(P<0.05)、磷酸化GSK3β(P<0.05)的表达水平,差异具有统计学差异。【结论】PT109可改善icv-STZ诱导的小鼠学习记忆障碍,可能与调节GSK3β/Tau相关通路有关。【Objective】To observe whether PT 109[5-(1,2-dithiolan-3-yl)-N-(4-(isoquinolin-5-ylamino)cyclohexyl)pentanamide]could improve the cognitive dysfunction in sporadic AD mice induced by lateral ventricular injection of streptozotocin and study the underlying mechanisms.【Methods】Thirty-two seven-week-old male C 57 BL/6 mice were randomly divided into 4 groups:control group(7 mice),model group(7 mice),PT 109 low dosage group(9 mice)and PT 109 high dosage group(9 mice).To establish the sporadic Alzheimer’s disease,these mice were injected with intracerebroventricular streptozotocin on the first and third day(3 mg/kg,5μL per injection site).Then PT 109(30,100 mg·kg^(-1)·d^(-1))was injected intraperitoneally.Two weeks later,Morris water maze and step through test were used to evaluate the effect of PT 109 on the learning and memory ability of AD mice.The AD related indexes such as microglia,neurons,dendritic spines and phosphorylated Tau protein were detected by immunofluorescence,immunohistochemistry,western blotting and Golgi staining.【Results】The behavioral experiments results showed that PT 109 could improve the learning and memory impairment.The immunofluorescence and immunohistochemistry staining results showed that compared with model group,PT 109 reduced the number of Iba 1 positive cell in hippocampus region(low dosage:P<0.001,high dosage:P<0.001)and high dosage PT 109 increased the total number of MAP 2 and Tuj 1 positive cell in hippocampus and cortex region(P<0.05,P<0.01).The Golgi staining results showed that compared with model group,PT 109 increased the density of dendritic spines(low dosage:P<0.001,high dosage:P<0.001).The western blotting results showed that compared with model group,PT 109 decreased the protein levels of NLRP 3(high dosage:P<0.05)and phosphorylated Tau protein(low dosage:P<0.05,high dosage:P<0.01),and high dosage PT 109 increased the protein levels of PSD 95(P<0.05)and phosphorylated GSK 3β(P<0.05).【Conclusion】PT 109 could improve the learning and memory impairment

关 键 词：阿尔茨海默病 链脲佐菌素 PT109 多激酶抑制剂 

分 类 号：R964[医药卫生—药理学]