Effect of Guilu Erxiangao on Alzheimer's Disease and Its Mechanism Based on Kidney-brain Correlation

QI Xiao-ming; LIU Xiao-qin; SU Xiao-juan; XIONG Chao; HAO Yong-xi; LI Gang-jing; MENG Xiang-long; ZHANG Shuo-sheng

doi:10.13422/j.cnki.syfjx.20220612

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Effect of Guilu Erxiangao on Alzheimer's Disease and Its Mechanism Based on Kidney-brain Correlation

更新时间：2023-05-17

- Effect of Guilu Erxiangao on Alzheimer's Disease and Its Mechanism Based on Kidney-brain Correlation
- Chinese Journal of Experimental Traditional Medical Formulae Vol. 28, Issue 9, Pages: 158-167(2022)
- 作者机构：
  
  山西省中医药大学中药与食品工程学院，中药炮制山西省重点实验室，山西晋中 030619
- 作者简介：
- 基金信息：
- DOI：10.13422/j.cnki.syfjx.20220612
  CLC： R285;R289;R22;R2-031;R33
- Received：27 October 2021，
  
  Published Online：07 March 2022，
  
  Published：05 May 2022
- 稿件说明：
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祁晓鸣,刘晓琴,苏晓娟等.基于肾脑相关的龟鹿二仙膏抗阿尔茨海默病作用及其机制[J].中国实验方剂学杂志,2022,28(09):158-167.

QI Xiao-ming,LIU Xiao-qin,SU Xiao-juan,et al.Effect of Guilu Erxiangao on Alzheimer's Disease and Its Mechanism Based on Kidney-brain Correlation[J].Chinese Journal of Experimental Traditional Medical Formulae,2022,28(09):158-167.
祁晓鸣,刘晓琴,苏晓娟等.基于肾脑相关的龟鹿二仙膏抗阿尔茨海默病作用及其机制[J].中国实验方剂学杂志,2022,28(09):158-167. DOI： 10.13422/j.cnki.syfjx.20220612.

QI Xiao-ming,LIU Xiao-qin,SU Xiao-juan,et al.Effect of Guilu Erxiangao on Alzheimer's Disease and Its Mechanism Based on Kidney-brain Correlation[J].Chinese Journal of Experimental Traditional Medical Formulae,2022,28(09):158-167. DOI： 10.13422/j.cnki.syfjx.20220612.

摘要

目的

基于“肾脑相关”理论，探讨龟鹿二仙膏对氢化可的松联合

淀粉样蛋白（A

）诱导的阿尔茨海默病（AD）大鼠模型的作用及其机制。

方法

采用腹腔注射氢化可的松并脑室注射A

诱导大鼠AD模型，龟鹿二仙膏不同浓度进行干预。测定大鼠的海马、肾脏和肾上腺指数；采用Morris水迷宫实验观察大鼠空间学习记忆能力；酶联免疫吸附测定法（ELISA）检测血清样品中皮质酮（CORT）及睾酮（T）水平；液相色谱-质谱联用（LC-MS）代谢组学技术采集和分析模型大鼠血清代谢数据；利用中药系统药理学数据库及分析平台（TCMSP）、中药分子机制的生物信息学分析工具（BATMAN-TCM）和中医药综合数据库（TCMID）收集龟鹿二仙膏活性成分及相应靶点；利用人类基因数据库（GeneCards）和在线人类孟德尔遗传数据库（OMIM）检索得到的AD相关靶标信息；构建蛋白质-蛋白质相互作用（PPI）网络，进行京都基因与基因组百科全书（KEGG）代谢通路富集分析、基因本体论（GO）富集分析；蛋白免疫印迹法（Western blot）检测大鼠海马组织中白细胞介素-6（IL-6）的表达水平。

结果

与模型组比较，龟鹿二仙膏高、中、低剂量组海马指数、肾脏指数和肾上腺指数均显著升高，其中龟鹿二仙膏高剂量组升高最为显著（

0.01）；龟鹿二仙膏高、低剂量组大鼠穿越平台次数均显著增加（

0.05，

0.01），Ⅲ象限路程（%）和Ⅲ象限时间（%）均显著延长（

0.05，

0.01）；龟鹿二仙膏高、中、低剂量组大鼠血清CORT含量均显著降低（

0.01）；龟鹿二仙膏高、中、低剂量组大鼠海马组织中IL-6表达水平均显著降低（

0.01）。代谢组学技术共鉴定了24个与AD相关的血清差异代谢物；网络药理学方法共筛选出50个治疗AD的高频共性化合物，高频共性靶点187个，得出磷脂酰肌醇3-激酶（PI3K）/蛋白激酶B（Akt）信号通路在AD复杂的病理机制网络中起到重要作用。

结论

龟鹿二仙膏可显著改善氢化可的松并A

诱导的AD模型大鼠认知功能障碍，降低血清CORT，抑制海马组织炎症因子IL-6表达，并调节AD模型大鼠的代谢水平，为其临床应用提供依据。

Abstract

Objective

To investigate the effect and mechanism of Guilu Erxiangao on Alzheimer's disease （AD） model rats induced by hydrocortisone and amyloid

-protein（A

） based on the theory of kidney-brain correlation.

Method

Intraperitoneal injection of hydrocortisone and intracerebroventricular injection of A

were performed to induce AD in rats， and different concentrations of Guilu Erxiangao were used for intervention. The indexes of hippocampus， kidney and adrenal gland were measured， and the spatial learning and memory ability of AD rats was observed by Morris water maze experiment. The levels of testosterone （T） and corticosterone （CORT） in serum samples were determined by enzyme-linked immunosorbent assay （ELISA）. Liquid chromatography-mass spectrometry （LC-MS） was used to collect and analyze the serum metabolic data of model rats. The active components and corresponding targets of Guilu Erxiangao were collected using Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform（TCMSP）， a Bioinformatics Analysis Tool for Molecular mechANism of Traditional Chinese Medicine （BATMAN-TCM） and Traditional Chinese Medicine Integrated Database（TCMID）. GeneCards and Online Mendelian Inheritance in Man （OMIM） were retrieved to obtain AD-related targets， and protein-protein interaction （PPI） network was constructed to perform gene ontology （GO）and Kyoto Encyclopedia of Genes and Genomes （KEGG） enrichment analysis. The expression level of interleukin-6 （IL-6） in the hippocampus of rats was detected by Western blot.

Result

Compared with the model group， the low-， medium- and high-dose groups of Guilu Erxiangao exhibited significantly increased hippocampus index， kidney index and adrenal gland index， reduced CORT levels in serum and down-regulated IL-6 levels in hippocampal tissues. According to the results of water maze experiment， as compared with the model group， the platform crossing times of rats was significantly increased in the low- and high-dose groups of Guilu Erxiangao， with evidently prolonged distance traveled in quadrant Ⅲ （%） and time in quadrant Ⅲ （%）. A total of 24 serum differential metabolites associated with AD were identified by LC-MS， and 50 high-frequency common compounds and 187 high-frequency common targets for AD treatment were screened by network pharmacology method. Results demonstrated phosphatidylinositol 3-kinases（PI3K）/protein kinase B（Akt） signaling pathway plays an important role in the complex AD pathological mechanism.

Conclusion

Guilu Erxiangao can significantly improve the cognitive dysfunction of AD model rats induced by hydrocortisone and A

， reduce serum CORT levels and IL-6 levels in hippocampal tissues， and regulate the metabolic level， which provides a reference for its clinical application.

关键词

Keywords

references

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