大黄素改善阿尔茨海默病认知障碍、内质网应激和神经炎症的研究

doi:10.3969/j.issn.1674-8115.2025.06.007

上海交通大学学报（医学版） ›› 2025, Vol. 45 ›› Issue (6): 727-734.doi: 10.3969/j.issn.1674-8115.2025.06.007

大黄素改善阿尔茨海默病认知障碍、内质网应激和神经炎症的研究

杨乐¹, 周怡¹, 王钶韵², 赖娅莉¹()

^1.成都医学院第二附属医院，核工业四一六医院神经内科，成都 610041
^2.四川省医学科学院·四川省人民医院神经内科，成都 610072

收稿日期:2024-11-18 接受日期:2025-02-18 出版日期:2025-06-28 发布日期:2025-06-28
通讯作者: 赖娅莉，副主任医师，硕士；电子信箱：838856089@qq.com。
作者简介:杨乐（1988—），男，副主任医师，硕士；电子信箱：yulele594@163.com。
基金资助:
2020年四川省卫生健康科研课题立项项目(20ZD009)

Research on the improvement of cognitive impairment, endoplasmic reticulum stress and neuroinflammation in Alzheimer's disease by emodin

YANG Le¹, ZHOU Yi¹, WANG Keyun², LAI Yali¹()

^1.Department of Neurology, The Second Affiliated Hospital of Chengdu Medical College, 416 Nuclear Industry Hospital, Chengdu 610041, China
^2.Department of Neurology, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu 610072, China

Received:2024-11-18 Accepted:2025-02-18 Online:2025-06-28 Published:2025-06-28
Contact: LAI Yali, E-mail: 838856089@qq.com.
Supported by:
2020 Sichuan Province Health Research Project(20ZD009)

摘要/Abstract

摘要：

目的·探讨大黄素在阿尔茨海默病（Alzheimer's disease，AD）中的作用及其潜在机制。方法·将野生型C57BL/6J小鼠和3×Tg-AD小鼠分为6组：对照组（C57BL/6J小鼠）、AD组（3×Tg-AD小鼠）、大黄素25 mg/kg组（3×Tg-AD小鼠+大黄素25 mg/kg）、大黄素50 mg/kg组（3×Tg-AD小鼠+大黄素50 mg/kg）、大黄素100 mg/kg组（3×Tg-AD小鼠+大黄素100 mg/kg）和多奈哌齐组（3×Tg-AD小鼠+多奈哌齐3 mg/kg）。采用Morris水迷宫实验分析小鼠学习记忆能力，采用免疫组织化学法检测胶质纤维酸性蛋白（glial fibrillary acidic protein，GFAP）、葡萄糖调节蛋白78（glucose-regulated protein 78kDa，GRP78）和肌醇需求酶1α（inositol-requiring enzyme 1α，IRE1α）的表达，采用酶联免疫吸附试验（enzyme-linked immunosorbent assay，ELISA）分析脑组织中肿瘤坏死因子-α（tumor necrosis factor-α，TNF-α）、白介素-1β（interleukin-1β，IL-1β）和IL-6的含量，采用Western blotting检测NF-κB p65、p-NF-κB p65、p38、p-p38的蛋白表达。结果·与对照组相比，AD组小鼠认知能力下降，GFAP表达升高，TNF-α、IL-1β、IL-6含量增多，GRP78和IRE1α表达升高，NF-κB p65、p38磷酸化表达升高。与AD组相比，大黄素改善AD小鼠的认知能力障碍，抑制星形胶质细胞过度激活和神经炎症，并降低脑组织GRP78、IRE1α、磷酸化NF-κB p65和磷酸化p38的表达。结论·大黄素能有效改善AD小鼠认知能力障碍，其机制可能与抑制星形胶质细胞内质网应激介导的神经炎症有关。

关键词: 阿尔茨海默病, 大黄素, 神经炎症, 内质网应激

Abstract:

Objective ·To explore the effects and potential mechanisms of emodin on Alzheimer's disease (AD). Methods ·Wild-type C57BL/6J mice and 3×Tg-AD mice were divided into 6 groups: Control group (C57BL/6J mice), AD group (3×Tg-AD mice), Emodin 25 mg/kg group (3×Tg-AD mice + Emodin 25 mg/kg), Emodin 50 mg/kg group (3×Tg-AD mice + Emodin 50 mg/kg), Emodin 100 mg/kg group (3×Tg-AD mice + Emodin 100 mg/kg) and Donepezil group (3×Tg-AD mice + Donepezil 3 mg/kg). The Morris water maze test was used to evaluate the learning and memory abilities of mice. The expression of glial fibrillary acidic protein (GFAP), glucose-regulated protein 78kDa (GRP78), and inositol-requiring enzyme 1α (IRE1α) was detected by immunohistochemistry. The levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 in brain tissue were measured by enzyme-linked immunosorbent assay (ELISA). Western blotting was used to detect the expression of NF-κB p65, p-NF-κB p65, p38, and p-p38 proteins. Results ·Compared with the control group, mice in the AD group showed impaired cognition, increased GFAP expression, elevated levels of TNF-α, IL-1β and IL-6, and increased expression of GRP78 and IRE1α, along with enhanced phosphorylation of NF-κB p65 and p38. Compared with the AD group, emodin improved cognitive impairment of AD mice, inhibited astrocyte overactivation and neuroinflammation, and decreased the expression of GRP78, IRE1α, phosphorylated NF-κB p65, and phosphorylated p38 in brain tissue. Conclusion ·Emodin can effectively improve cognitive impairment in AD mice, which may be related to the inhibition of endoplasmic reticulum stress-mediated neuroinflammation in astrocytes.

Key words: Alzheimer's disease (AD), emodin, neuroinflammation, endoplasmic reticulum stress

中图分类号:

R741.02

杨乐, 周怡, 王钶韵, 赖娅莉. 大黄素改善阿尔茨海默病认知障碍、内质网应激和神经炎症的研究[J]. 上海交通大学学报（医学版）, 2025, 45(6): 727-734.

YANG Le, ZHOU Yi, WANG Keyun, LAI Yali. Research on the improvement of cognitive impairment, endoplasmic reticulum stress and neuroinflammation in Alzheimer's disease by emodin[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(6): 727-734.

图/表 5

图1 大黄素对AD小鼠认知能力障碍的影响Note： A. Tracks of the mice in the probe trial. B. Escape latency in the Morris water maze test. C. Number of platform crossings. D. Time spent in the target quadrant. E. Total swimming distance in the target quadrant. 1—Control group, 2—AD group, 3—Emodin 25 mg/kg group, 4—Emodin 50 mg/kg group, 5—Emodin 100 mg/kg group, 6—Donepezil group. ①P<0.001, compared with the control group; ②P=0.015, ③P=0.003, ④P=0.022, ⑤P=0.001, ⑥P=0.038, ⑦P=0.004, ⑧P=0.033, ⑨P=0.007, ⑩P<0.001, compared with the AD group.

Fig 1 Effect of emodin on cognitive impairment in AD mice

图2 大黄素对星形胶质细胞激活的影响Note： A. Immunohistochemical detection of GFAP expression in the mouse cerebral cortex (×400). B. Percentage of GFAP-positive expression. 1—Control group, 2—AD group, 3—Emodin 25 mg/kg group, 4—Emodin 50 mg/kg group, 5—Emodin 100 mg/kg group, 6—Donepezil group. ①P<0.001, compared with the control group. ②P=0.016, ③P=0.002, ④P<0.001, compared with the AD group.

Fig 2 Effect of emodin on the activation of astrocytes

图3 大黄素对ER应激相关蛋白表达的影响Note： A. Immunohistochemical staining of GRP78 and IRE1α in mouse cerebral cortex (×400). B. Double immunofluorescence staining of GFAP and GRP78 in mouse brain tissue (×400). C. Percentage of GRP78-positive expression. D. Percentage of IRE1α-positive expression. E. Percentage of GFAP-labeled GRP78+ cells.1—Control group, 2—AD group, 3—Emodin 25 mg/kg group, 4—Emodin 50 mg/kg group, 5—Emodin 100 mg/kg group, 6—Donepezil group. ①P<0.001, compared with the control group. ②P=0.027, ③P=0.005, ④P=0.018, ⑤P=0.002, ⑥P=0.013, ⑦P=0.009, ⑧P<0.001, compared with the AD group.

Fig 3 Effect of emodin on the expression of ER stress-related proteins

图4 大黄素对AD小鼠炎症反应的影响Note： A. TNF-α expression levels in brain tissue. B. IL-6 expression levels in brain tissue. C. IL-1β expression levels in brain tissue. 1—Control group, 2—AD group, 3—Emodin 25 mg/kg group, 4—Emodin 50 mg/kg group, 5—Emodin 100 mg/kg group, 6—Donepezil group. ①P<0.001, compared with the control group. ②P=0.031, ③P=0.004, ④P=0.037, ⑤P=0.008, ⑥P=0.043, ⑦P=0.003, ⑧P<0.001, compared with the AD group.

Fig 4 Effect of emodin on inflammatory response in AD mice

图5 大黄素对炎症信号的影响Note： A. Western blotting images of NF-κB p65, p-NF-κB p65, p38, and p-p38. B. Relative expression of p-NF-κB p65/NF-κB p65. C. Relative expression of p-p38/p38. 1—Control group, 2—AD group, 3—Emodin 25 mg/kg group, 4—Emodin 50 mg/kg group, 5—Emodin 100 mg/kg group, 6—Donepezil group. ①P<0.001, compared with the control group. ②P=0.035, ③P=0.042, ④P=0.028, ⑤P=0.007, ⑥P<0.001, compared with the AD group.

Fig 5 Effect of emodin on the inflammation signaling pathways

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大黄素改善阿尔茨海默病认知障碍、内质网应激和神经炎症的研究

Research on the improvement of cognitive impairment, endoplasmic reticulum stress and neuroinflammation in Alzheimer's disease by emodin

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