Effect of <italic style="font-style: italic">Dihuang Yinzi Decoction</italic> （地黄饮子）on Retinal Insulin Content and Insulin Signaling Pathway Related Protein Expression in Alzheimer's Disease Model Mice

WU Dongyan; GUI Wanwei; WANG Xiaodan; LI Qinqing; CHAI Jinmiao; ZHANG Junlong

doi:10.13288/j.11-2166/r.2024.15.012

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Effect of Dihuang Yinzi Decoction （地黄饮子）on Retinal Insulin Content and Insulin Signaling Pathway Related Protein Expression in Alzheimer's Disease Model Mice

更新时间：2024-08-01

- Effect of Dihuang Yinzi Decoction （地黄饮子）on Retinal Insulin Content and Insulin Signaling Pathway Related Protein Expression in Alzheimer's Disease Model Mice
- Journal of Traditional Chinese Medicine Vol. 65, Issue 15, Pages: 1593-1601(2024)
- 作者机构：
  
  山西中医药大学，山西省晋中市榆次区大学街121号，030600
- 作者简介：
- 基金信息：
- DOI：10.13288/j.11-2166/r.2024.15.012
  CLC：
- Received：11 January 2024，
  
  Revised：2024-05-15，
  
  Published：02 August 2024
- 稿件说明：
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武东燕,桂婉威,王小丹等.地黄饮子对阿尔茨海默病模型小鼠视网膜胰岛素含量及胰岛素信号通路相关蛋白表达的影响[J].中医杂志,2024,65(15):1593-1601.

WU Dongyan,GUI Wanwei,WANG Xiaodan,et al.Effect of Dihuang Yinzi Decoction （地黄饮子）on Retinal Insulin Content and Insulin Signaling Pathway Related Protein Expression in Alzheimer's Disease Model Mice[J].Journal of Traditional Chinese Medicine,2024,65(15):1593-1601.
武东燕,桂婉威,王小丹等.地黄饮子对阿尔茨海默病模型小鼠视网膜胰岛素含量及胰岛素信号通路相关蛋白表达的影响[J].中医杂志,2024,65(15):1593-1601. DOI： 10.13288/j.11-2166/r.2024.15.012.

WU Dongyan,GUI Wanwei,WANG Xiaodan,et al.Effect of Dihuang Yinzi Decoction （地黄饮子）on Retinal Insulin Content and Insulin Signaling Pathway Related Protein Expression in Alzheimer's Disease Model Mice[J].Journal of Traditional Chinese Medicine,2024,65(15):1593-1601. DOI： 10.13288/j.11-2166/r.2024.15.012.

摘要

目的

以视网膜为窗口观察地黄饮子改善阿尔茨海默病（AD）认知功能障碍的可能作用机制。

方法

45只APP/PS1小鼠（AD模型小鼠）随机分为模型组、地黄饮子组、美金刚组，每组15只；15只同窝野生型C57BL/6J小鼠作为空白组。地黄饮子组小鼠予地黄饮子30.03 g/（kg·d）灌胃，美金刚组小鼠予盐酸美金刚6.1 mg/（kg·d）灌胃，空白组和模型组小鼠予生理盐水2 ml/（kg·d）灌胃，连续干预4周。每周检测小鼠空腹血糖。干预4周后进行口服糖耐量试验（OGTT）、胰岛素耐量试验（ITT）；采用莫里斯水迷宫检测小鼠空间记忆能力的变化；葡萄糖氧化酶法检测小鼠视网膜葡萄糖含量；酶联免疫吸附测定（ELISA）检测小鼠血清、视网膜胰岛素含量，计算胰岛素抵抗指数（HOMA-IR）。苏木素-伊红（HE）染色观察视网膜组织病理改变，并统计视网膜厚度和神经节细胞数；蛋白免疫印迹法检测视网膜通路相关蛋白［胰岛素受体底物1（IRS1）、磷酸化胰岛素受体底物1（pIRS1）、磷脂酰肌醇-3-羟激酶（PI3K）、蛋白激酶B（Akt1）、磷酸化蛋白激酶B（pAkt1）］表达量；免疫组化法检测视网膜葡萄糖转运蛋白4（GLUT4）表达。

结果

与空白组相比，模型组1、2、3、4周时小鼠空腹血糖，OGTT和ITT试验各时间点血糖及曲线下面积，空腹血清胰岛素和HOMA-IR均升高（

＜0.05或

＜0.01）；莫里斯水迷宫实验中第3~5天逃避潜伏期增加，穿越平台次数、目标象限运动距离占总距离的比例、目标象限运动时间占总时间的比例均减少（

＜0.05或

＜0.01）；视网膜外核层细胞排列稀疏，厚度变薄，神经节细胞数量减少（

＜0.01）；视网膜葡萄糖表达量升高，胰岛素含量、pIRS1/IRS1、PI3K/β-Actin、pAkt1/Akt1、GLUT4蛋白表达量降低（

＜0.01）。与模型组相比，地黄饮子组小鼠4周时空腹血糖、OGTT和ITT试验各时间点血糖及曲线下面积降低（

＜0.05或

＜0.01），空腹血清胰岛素和HOMA-IR降低（

＜0.05）；莫里斯水迷宫试验中第4、5天逃避潜伏期缩短、穿越平台次数、目标象限距离占总距离的比例、目标象限运动时间占总时间的比例减少（

＜0.05或

＜0.01）；视网膜病理改变减轻，视网膜厚度和神经节细胞数量增加（

＜0.01）；视网膜葡萄糖含量降低，视网膜pIRS1/IR

S1、PI3K/β-Actin、GLUT4蛋白表达量升高（

＜0.05或

＜0.01）。

结论

地黄饮子可以改善AD认知功能障碍，可能与调节视网膜胰岛素含量及胰岛素信号通路有关。

Abstract

Objective

To observe the possible mechanism of

Dihuang Yinzi Decoction

（地黄饮子） for improving cognitive dysfunction in Alzheimer's disease （AD） from the perspective of retina.

Methods

Forty-five APP/PS1 mice （AD model mice） were randomly divided into model group，

Dihuang Yinzi Decoction

group， and memantine group， with 15 mice in each group， while 15 wild-type C57BL/6J mice from the same litter were used as blank group. Mice in

Dihuang Yinzi Decoction

group were given

Dihuang Yinzi Decoction

30.03 g/（kg·d） by gavage， mice in the memantine group were given memantine hydrochloride 6.1 mg/（kg·d） by gavage， and mice in the blank group and the model group were given normal saline 2 ml/（kg·d） by gavage for 4 consecutive weeks. Fasting blood glucose was measured weekly. After 4 weeks of intervention， oral glucose tolerance test （OGTT） and insulin tolerance test （ITT） were performed； Morris water maze was used to detect the changes in spatial memory ability of mice； glucose oxidase method was used to detect retinal glucose content of mice； enzyme-linked immunosorbent assay （ELISA） was used to detect serum and retinal insulin content of mice， and Homeostatic Model Assessment of insulin resistance （HOMA-IR） was calculated. Hematoxylin-eosin （HE） staining was performed to observe the histopathological changes in the retina， and the retinal thickness and ganglion cell number were counted； protein immunoblotting was performed to detect the retinal pathway-associated proteins ［insulin receptor substrate 1 （IRS1）， phosphorylated insulin receptor substrate 1 （pIRS1）， phosphatidylinositol-3-hydroxykinase （PI3K）， protein kinase B （Akt1）， phosphorylated protein kinase B （pAkt1）］ expressi

on； retinal glucose transporter protein 4 （GLUT4） expression was detected by immunohistochemistry.

Results

Compared with the blank group， fasting blood glucose of mice in the model group at weeks 1， 2， 3， and 4， blood glucose and area under the curve （AUC） at different time point of OGTT and ITT test， fasting serum insulin， and HOMA-IR increased （

＜0.05，

＜0.01）； in the Morris water maze experiment， the escape latency increased from day 3 to day 5， and the number of crossing platforms， the percentage of target quadrant distance， and the percentage of target quadrant time decreased （

＜0.05，

＜0.01）； the outer nuclear layer of the retina became sparse， thinner， and the number of ganglion cells decreases （

＜0.01）； the expression level of retinal glucose increased， while the expression levels of insulin， pIRS1/IRS1， PI3K/β-Actin， pAkt1/Akt1， and GLUT4 proteins decreased （

＜0.01）. Compared with the model group， fasting blood glucose at week 4， blood glucose at each time point of the OGTT and ITT tests AUC decreased （

＜0.05，

＜0.01）， and fasting serum insulin and HOMA-IR decreased （

＜0.05） in

Dihuang Yinzi Decoction

group； In the Morris water maze test， the escape latency shortened on day 4 and day 5， number of platform crossings， target quadrant distance as a proportion of total distance， and target quadrant movement time as a proportion of total time decreased （

＜0.05，

＜0.01）； retinal pathological changes alleviated， and retinal thickness and ganglion cell number increased （

＜0.01）； retinal glucose content decreased， and retinal pIRS1/IRS1， PI3K/β-Actin， and GLUT4 protein expression elevated （

＜0.05 or

＜0.01）.

Conclusions

Dihuang Yinzi Decoction

can improve cognitive dysfunction of Alzhe

imer's disease， which may be related to regulating retinal insulin content and insulin signaling pathway.

关键词

Keywords

references

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Effect of Dihuang Yinzi Decoction （地黄饮子）on Retinal Insulin Content and Insulin Signaling Pathway Related Protein Expression in Alzheimer's Disease Model Mice

DOI：10.13288/j.11-2166/r.2024.15.012

摘要

Abstract

关键词

Keywords

references