地黄饮子抑制能量障碍诱导的APP/PS1小鼠内质网应激及神经元凋亡的作用机制

温彬宇; 张志辰; 高俊峰; 闫妍; 黄倩倩; 马涛

doi:10.13422/j.cnki.syfjx.20182139

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地黄饮子抑制能量障碍诱导的APP/PS1小鼠内质网应激及神经元凋亡的作用机制

地黄饮子治疗阿尔茨海默病的实验研究专题 | 更新时间：2024-09-23

- 地黄饮子抑制能量障碍诱导的APP/PS1小鼠内质网应激及神经元凋亡的作用机制
- Effect of Dihuang Yinzi on Endoplasmic Reticulum Stress and Neuronal Apoptosis Induced by Energy Disorders in APP/PS1 Mice
- 中国实验方剂学杂志 2018年24卷第21期页码：111-117
- 作者机构：
- 作者简介：
- 基金信息：
  
  国家自然科学基金项目（81673929）
- DOI：10.13422/j.cnki.syfjx.20182139
  中图分类号： R285.5
- 纸质出版日期：2018
- 稿件说明：
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温彬宇, 张志辰, 高俊峰, 等. 地黄饮子抑制能量障碍诱导的APP/PS1小鼠内质网应激及神经元凋亡的作用机制[J]. 中国实验方剂学杂志, 2018,24(21):111-117.

WEN Bin-yu, ZHANG Zhi-chen, GAO Jun-feng, et al. Effect of Dihuang Yinzi on Endoplasmic Reticulum Stress and Neuronal Apoptosis Induced by Energy Disorders in APP/PS1 Mice[J]. Chinese journal of experimental traditional medical formulae, 2018, 24(21): 111-117.
温彬宇, 张志辰, 高俊峰, 等. 地黄饮子抑制能量障碍诱导的APP/PS1小鼠内质网应激及神经元凋亡的作用机制[J]. 中国实验方剂学杂志, 2018,24(21):111-117. DOI： 10.13422/j.cnki.syfjx.20182139.

WEN Bin-yu, ZHANG Zhi-chen, GAO Jun-feng, et al. Effect of Dihuang Yinzi on Endoplasmic Reticulum Stress and Neuronal Apoptosis Induced by Energy Disorders in APP/PS1 Mice[J]. Chinese journal of experimental traditional medical formulae, 2018, 24(21): 111-117. DOI： 10.13422/j.cnki.syfjx.20182139.

摘要

目的：研究地黄饮子对能量代谢障碍诱导的APP/PS1转基因小鼠内质网应激（endoplasmic reticulum stress， ERS）活性转录因子4（activating transcription factor4，ATF4）/C/EBP同源蛋白（C/EBP homologous protein，CHOP）信号通路激活及其引发的神经元凋亡的作用机制。方法：4月龄APP/PS1转基因小鼠120只，随机分为正常组、模型组、阳性药（安理申，1 mg·kg-1）组、地黄饮子低、中、高剂量组（1.25，2.5，5 g·kg-1）。除正常组外，其余各组均腹腔注射100 mg·kg-1剂量的3-硝基丙酸（3-NP），正常组小鼠腹腔注射等体积的无菌生理盐水。经灌胃给予地黄饮子和安理申1周。实时荧光定量聚合酶链式方应（Real-time PCR）检测小鼠脑组织ATF4，CHOP mRNA水平。蛋白免疫印迹法（Western blot）检测小鼠脑组织内质网应激标志蛋白葡萄糖调节蛋白78（GRP78），ATF4，CHOP，B淋巴细胞瘤-2（B-cell lymphoma-2，Bcl-2），Bcl-2相关X蛋白（Bcl-2-associated X protein，Bax）蛋白表达水平。末端标记法（TUNEL）染色观察小鼠脑组织神经元凋亡，并计算凋亡率。结果：与正常组比较，3-NP诱导的能量代谢障碍可以显著增加ERS标记性蛋白GRP78表达量（P<0.01），提高ATF4，CHOP mRNA水平（P<0.01）和蛋白表达水平（P<0.01），下调抗凋亡蛋白Bcl-2（P<0.01）和上调促凋亡蛋白Bax（P<0.01），增加模型小鼠脑组织神经元凋亡率。与模型组比较，地黄饮子各剂量组能显著降低模型小鼠脑组织GRP78表达水平（P<0.05，P<0.01），ATF4，CHOP基因mRNA（P<0.05，P<0.01）及蛋白（P<0.05，P<0.01）水平；能够上调抗凋亡蛋白Bcl-2（P<0.05，P<0.01），下调促凋亡蛋白Bax（P<0.05，P<0.01），减少脑组织神经元凋亡。TUNEL结果显示地黄饮子可以显著减少小鼠脑组织神经元凋亡率。结论：地黄饮子可以抑制能量代谢障碍导致的ERS，抑制ATF4/CHOP信号通路激活，调节凋亡相关蛋白，显著减少神经元凋亡。

Abstract

Objective: To study the mechanism of Dihuang Yinzi on the activation of energy metabolism disorder-induced endoplasmic reticulum stress (ERS) activating transcription factor4 (ATF4)/C/EBP homologous protein (CHOP) signaling pathway in APP/PS1 transgenic mice

and investigate its mechanism on neuronal apoptosis. Method: The 120 APP/PS1 transgenic mice at 4-month-old were randomly divided into normal control group

model group

positive drug (Aricept

1 mg·kg-1) group

and low-dose

middle-dose

and high-dose groups of Dihuang Yinzi (1.25

2.5

5 g·kg-1). Except for the normal control group

the other groups were intraperitoneally injected with 3-nitropropionic acid (3-NP) at a dose of 100 mg·kg-1 to establish models. The mice in normal control group were injected intraperitoneally with an equal volume of normal saline. Dihuang Yinzi and Aricept were given by oral administration for 1 week. Then Real-time PCR was used to detect ATF4

CHOP mRNA levels in mouse brain. The protein expression levels of glucose-regulated protein 78(GRP78)

ATF4

CHOP

B-cell lymphoma-2 (Bcl-2)

and Bcl-2-associated X protein (Bax) in brain tissue of mice were detected by Western blot. Terminal-deoxynucleoitidyl transferase mediated nick end labeling(TUNEL) staining was used to evaluate the neuronal apoptosis in mouse brain and the apoptosis rate. Result: As compared with the normal group

3-NP-induced energy metabolism disorder significantly increased the expression of ERS marker protein GRP78 (P<0.01)

increased ATF4 and CHOP mRNA levels (P<0.01) and protein expression (P<0.01)

down-regulated anti-apoptosis protein Bcl-2 (P<0.01) and up-regulated of pro-apoptotic protein Bax (P<0.01)

and promoted the rate of neuronal apoptosis in the brain of model mice. As compared with the model group

Dihuang Yinzi could significantly reduce the mRNA and protein expression of GRP78 (P<0.05

P<0.01)

ATF4 and CHOP (P<0.05

P<0.01)

up-regulate anti-apoptotic protein Bcl-2 (P<0.05

P<0.01)

down-regulate pro-apoptotic protein Bax (P<0.05

P<0.01)

and reduce neuronal apoptosis in brain tissue. TUNEL results showed that Dihuang Yinzi can significantly reduce the neuronal apoptosis rate in mouse brain.

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