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.
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. Journal of Shanghai Jiao Tong University (Medical Science)[J], 2025, 45(6): 727-734 doi:10.3969/j.issn.1674-8115.2025.06.007
阿尔茨海默病（Alzheimer's disease，AD）是一种认知记忆丧失的神经退行性疾病，主要发生在老年人群［1-2］。全世界有超过5 000万患者受到AD的影响，预计到2050年这一数字将增加1倍［3］。AD的表型特征是记忆力丧失、社会行为受损和人格改变［2，4］。AD的病因至今尚未清晰，治疗效果也不明显。因此，探索AD的新治疗策略具有极大的必要性和临床价值。大黄素（emodin，CAS号：518-82-1）是从中药大黄（蓼科多年生草本植物掌叶大黄的根及根茎）中提取的一种天然化合物，具有抗炎、抗氧化和抗肿瘤等特性［5-8］。研究［9］发现，大黄素可显著抑制AD小鼠海马区氧化应激和神经炎症。持续性内质网（endoplasmic reticulum，ER）应激被认为是许多慢性疾病的驱动因素。在神经退行性疾病中，由ER应激引起的反应可导致神经元功能障碍。细胞对ER应激的反应是通过诱导未折叠蛋白反应（unfolded protein response，UPR）来启动，且在大量的AD患者的大脑样本中观察到UPR的上调［10-11］。然而，大黄素是否影响AD的ER应激仍有待进一步阐明。鉴于此，本研究假设大黄素在AD中的保护作用是通过抑制星形胶质细胞ER应激介导的神经炎症而实现，拟通过动物模型对其进行验证。
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
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
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
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
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
The animal experiments involved in this study were approved by the Ethics Committee of Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital (S2023-030-05). The experimental operation process strictly follows the Guidelines for the Care and Use of Experimental Animals.
YANG Le and ZHOU Yi participated in the experimental design. YANG Le, ZHOU Yi and WANG Keyun participated in experimental operations, data collection, and data analysis. YANG Le, ZHOU Yi, WANG Keyun and LAI Yali participated in the writing and editing of the paper. All authors have read and agreed to submit the final manuscript.
利益冲突声明
所有作者声明不存在利益冲突。
COMPETING INTERESTS
All authors disclose no relevant conflict of interests.
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