[Mechanism of Guben Jiannao Liquid on Alzheimer's disease by regulating autophagy based on LKB1/AMPK/mTOR pathway].

Q3 Pharmacology, Toxicology and Pharmaceutics
Jing-Fan Zhang, Qing-Hua Long, Chu-Hua Zeng, Yi-Min Chen, Zhe-Yao Xie, Yuan-Qin Cai, Xi Wang
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引用次数: 0

Abstract

This study explores the mechanism of Guben Jiannao Liquid on Alzheimer's disease(AD) by regulating autophagy based on the liver kinase B1(LKB1)/adenosine monophosphate-activated protein kinase(AMPK)/mammalian target of rapamycin(mTOR) pathway. Male SD rats were randomly divided into the blank group, model group, low-dose and high-dose groups of Guben Jiannao Liquid, and rapamycin group, with 10 rats in each group. Except for the blank group, all other groups of rats were injected bilaterally in the hippocampus with β-amyloid(Aβ)_(1-42) to establish the AD model. The low-dose(6.21 g·kg~(-1)) and high-dose(12.42 g·kg~(-1)) groups of Guben Jiannao Liquid and rapamycin group(1 mg·kg~(-1)) were given the corresponding drugs by gavage, and the blank and model groups were given an equal volume of saline by gavage for four weeks. Morris water maze was used to test the learning and memory ability of rats in each group; hematoxylin-eosin(HE) and Nissl staining were used to observe the morphological and quantitative changes of neurons and Nissl bodies in the CA1 region of rat hippocampus; immunohistochemistry was utilized to detect Aβ-positive cell expression in the CA1 region of rat hippocampus; transmission electron microscopy was employed to observe ultrastructural changes in rat hippocampal tissue, and Western blot was used to examine the protein expression levels of LKB1, p-AMPK/AMPK, p-mTOR/mTOR, Beclin1, p62, and LC3-Ⅱ in the hippocampal tissue of the rats. The results showed that compared with those in the blank group, rats in the model group had elevated evasion latency and decreased number of platform transversal and residence time in the platform quadrant. The number of neurons in the hippocampal area was reduced, and the morphology was impaired. The average integral optical density value of Aβ-positive cells was elevated; the expression levels of LKB1, p-AMPK/AMPK, Beclin1, and LC3-Ⅱ were decreased, and the expression levels of p-mTOR/mTOR and p62 were increased. Compared with those in the model group, rats in the low-dose and high-dose groups of Guben Jiannao Liquid had shorter evasion latency, higher number of platform transversal, longer residence time in the platform quadrant, increased number of neurons, decreased expression of Aβ-positive cells and average integral optical density values, and increased number of autophagic lysosomes in hippocampal tissue. The expression levels of LKB1, Beclin1, and LC3-Ⅱ were elevated in the hippocampus of rats in the low-dose group of Guben Jiannao Liquid. The expression levels of LKB1, p-AMPK/AMPK, Beclin1, and LC3-Ⅱ were elevated in the hippocampal tissue of rats in the high-dose group of Guben Jiannao Liquid, and the expression levels of p-mTOR/mTOR and p62 were decreased. The findings suggest that Guben Jiannao Liquid can improve cognitive impairment in AD rats, and its mechanism of action may be related to the activation of the LKB1/AMPK/mTOR signaling pathway and the up-regulation of autophagy level.

[固本健脑液基于LKB1/AMPK/mTOR通路调节自噬作用治疗阿尔茨海默病的机制]。
本研究通过肝激酶B1(LKB1)/腺苷单磷酸活化蛋白激酶(AMPK)/哺乳动物雷帕霉素靶蛋白(mTOR)通路调节自噬,探讨固本健脑液治疗阿尔茨海默病(AD)的机制。将雄性SD大鼠随机分为空白组、模型组、固本健脑液低、高剂量组和雷帕霉素组,每组10只。除空白组外,其余各组大鼠均在海马双侧注射β-淀粉样蛋白(Aβ)_(1-42)建立AD模型。固本健脑液低剂量组(6.21 g·kg~(-1))、高剂量组(12.42 g·kg~(-1))和雷帕霉素组(1 mg·kg~(-1))灌胃相应药物,空白组和模型组灌胃等体积生理盐水4周。采用Morris水迷宫法检测各组大鼠学习记忆能力;采用苏木精-伊红(HE)和尼氏染色法观察大鼠海马CA1区神经元和尼氏小体的形态学和定量变化;免疫组化检测大鼠海马CA1区a β阳性细胞表达;透射电镜观察大鼠海马组织超微结构变化,Western blot检测大鼠海马组织中LKB1、p-AMPK/AMPK、p-mTOR/mTOR、Beclin1、p62、LC3-Ⅱ蛋白表达水平。结果显示,与空白组相比,模型组大鼠逃避潜伏期升高,平台横贯次数减少,平台象限停留时间减少;海马区神经元数量减少,形态受损。a β阳性细胞的平均积分光密度值升高;LKB1、p-AMPK/AMPK、Beclin1、LC3-Ⅱ表达水平降低,p-mTOR/mTOR、p62表达水平升高。与模型组比较,固本健脑液低、高剂量组大鼠逃避潜伏期缩短,平台横移次数增多,平台象限停留时间延长,神经元数量增加,a β阳性细胞表达和平均积分光密度值降低,海马组织自噬溶酶体数量增加。固本健脑液低剂量组大鼠海马组织中LKB1、Beclin1、LC3-Ⅱ表达水平升高。骨本健脑液高剂量组大鼠海马组织中LKB1、p-AMPK/AMPK、Beclin1、LC3-Ⅱ表达水平升高,p-mTOR/mTOR、p62表达水平降低。提示固本健脑液可改善AD大鼠认知功能障碍,其作用机制可能与激活LKB1/AMPK/mTOR信号通路,上调自噬水平有关。
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来源期刊
Zhongguo Zhongyao Zazhi
Zhongguo Zhongyao Zazhi Pharmacology, Toxicology and Pharmaceutics-Pharmacology, Toxicology and Pharmaceutics (all)
CiteScore
1.50
自引率
0.00%
发文量
581
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