基于秀丽线虫模型探究七叶皂苷和右美沙芬对阿尔茨海默病的保护作用

doi:10.19723/j.issn.1671-167X.2025.04.022

北京大学学报（医学版） ›› 2025, Vol. 57 ›› Issue (4): 764-771. doi: 10.19723/j.issn.1671-167X.2025.04.022

基于秀丽线虫模型探究七叶皂苷和右美沙芬对阿尔茨海默病的保护作用

张一平¹, 李璐迪¹, 朱安², 肖武生¹, 王旗¹^,*()

1. 北京大学公共卫生学院毒理学系，国家中医药管理局中药配伍减毒重点研究室，食品安全毒理学研究与评价北京市重点实验室，北京 100191
2. 福建医科大学基础医学院消化道恶性肿瘤教育部重点实验室，福州 350108

收稿日期:2025-02-08 出版日期:2025-08-18 发布日期:2025-08-02
通讯作者: 王旗
基金资助:
国家自然科学基金(82174068)

Protective effects of escin and dextromethorphan on Alzheimer disease in Caenorhabditis elegans models

Yiping ZHANG¹, Ludi LI¹, An ZHU², Wusheng XIAO¹, Qi WANG¹^,*()

1. Department of Toxicology, Peking University School of Public Health, Key Laboratory of State Administration of Traditional Chinese Medicine for Compatibility Toxicology, Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Beijing 100191, China
2. Key Laboratory of Gastrointestinal Malignant Tumors, Basic Medical College, Fujian Medical University, Ministry of Education, Fuzhou 350108, China

Received:2025-02-08 Online:2025-08-18 Published:2025-08-02
Contact: Qi WANG
Supported by:
the National Nature Science Foundation of China(82174068)

摘要/Abstract

摘要：

目的: 探究七叶皂苷(escin，ESC)和右美沙芬(dextromethorphan，DEX)是否具有延缓阿尔茨海默病(Alzheimer disease，AD)的作用。方法: 使用秀丽隐杆线虫β-淀粉样蛋白(amyloid β-protein，Aβ)转基因构建的AD模型，采用固体暴露方式，给予不同浓度的ESC和DEX处理，以美金刚(memantine，MEM)50 μmol/L作为阳性对照组，检测线虫的寿命变化、运动能力和认知功能变化、Aβ蛋白表达量，以及活性氧含量。通过实时荧光定量PCR检测氧化应激通路相关基因的表达。结果: 高剂量处理(1 000 μmol/L ESC或DEX)对野生型N2线虫活动无明显影响。与空白对照组相比，20 μmol/L ESC组和60 μmo/L DEX组显著延长AD模型线虫的生存时间。在AD发病中期，ESC和DEX可减少AD模型线虫的身体弯曲频率的降低，且DEX能明显改善AD模型线虫的头部摆动频率降低。早期的认知功能测试的趋化指数ESC组和DEX组及阳性对照组显著高于空白对照组，这与其体内Aβ蛋白的含量降低相关。ESC组和DEX组的活性氧含量相较于空白对照组有所减少；且基因表达结果显示，ESC可通过上调抗氧化应激基因skn1的表达来减轻AD模型线虫体内的氧化损伤。结论: ESC和DEX能改善AD模型线虫运动能力和认知功能的降低，延缓AD相关症状的加重。ESC可能通过激活SKN-1/Nrf2通路，降低AD模型线虫的氧化应激进而延缓AD进展。

关键词: 阿尔茨海默病, 七叶皂苷, 右美沙芬, 秀丽隐杆线虫

Abstract:

Objective: To investigate whether escin (ESC) and dextromethorphan (DEX) have the protective effects on the progression and symptoms of Alzheimer disease (AD). Methods: The AD model of Caenorhabditis elegans (C. elegans) was established by transgenic amyloid β-protein (Aβ protein). Different concentrations of ESC or DEX or 50 μmol/L memantine (MEM) were used to treat the AD model worms, and their lifespan was detected. The movement ability of AD model C. elegans was evaluated by body bending frequency and head swinging frequency. The changes in cognitive functions of AD model C. elegans before and after treatment were detected by chemotaxis experiments. The changes in Aβ protein and reactive oxygen species (ROS) content in C. elegans were detected. The changes in gene pathways related to oxidative stress were detected by Real-time quantitative polymerase chain reaction (RT-qPCR). Results: At high dose 1 000 μmol/L, ESC or DEX treatment showed no significant effects on the activity of C. elegans. Compared with untreated worms, the survival time of AD model C. elegans in the 20 μmol/L ESC and 60 μmol/L DEX intervention groups was significantly extended. In the middle stage of AD progression, the body bending frequency and head swinging frequency of AD model worms after ESC or DEX treatment was significantly increased compared with the untreated control group with DEX being more effective in the recovery of head swinging frequency. For the early cognitive function tests, the chemotaxis index of ESC or DEX treated worms was significantly higher than that of the untreated worms, which correlated with marked reductions in the Aβ protein levels. The reactive oxygen species content in the drug intervention group was also lower than that in the control group. RT-qPCR results showed that ESC could inhibit oxidative stress in the AD model C. elegans by a 2-fold upregulation of skn1 expression. Conclusion: ESC and DEX could improve the reductions of movement ability and cognitive function in the AD model worms and delay the aggravation of AD-related symptoms. ESC delays the progression of AD possibly by activating the SKN-1/Nrf2 pathway to protect against oxidative injury in the AD model.

Key words: Alzheimer disease, Escin, Dextromethorphan, Caenorhabditis elegans

中图分类号:

R749.16

张一平, 李璐迪, 朱安, 肖武生, 王旗. 基于秀丽线虫模型探究七叶皂苷和右美沙芬对阿尔茨海默病的保护作用[J]. 北京大学学报（医学版）, 2025, 57(4): 764-771.

Yiping ZHANG, Ludi LI, An ZHU, Wusheng XIAO, Qi WANG. Protective effects of escin and dextromethorphan on Alzheimer disease in Caenorhabditis elegans models[J]. Journal of Peking University (Health Sciences), 2025, 57(4): 764-771.

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Strain	Genotype	Description
CL2006	dvIs2 [pCL12(unc-54/human Aβ peptide 1-42 minigene)+rol-6(su1006)]	Adult onset paralysis and egg-laying deficiency
CL2355	dvIs50 [pCL45 (snb-1:: Abeta 1-42:: 3′ UTR(long)+mtl-2:: GFP] Ⅰ	Pan-neuronal expression of human Aβ peptide. Strain shows deficits in chemotaxis, associative learning, and thrashing in liquid
CL4176	dvIs27 [myo-3p: : Abeta (1-42): : let-851 3′UTR)+rol-6(su1006)] Ⅹ	Adult onset paralysis quickly

Items	Concentration/(μmo/L)	Sample size，n	Medium lifespan/d	Mean lifespan/d, ${\bar x}$±s
Crtl		40	8.00	14.71±0.23
MEM		40	11.00	20.41±0.25
ESC	20	40	15.00	25.13±0.71
	40	40	13.00	20.93±0.63
	60	40	13.00	20.73±0.54
	80	40	13.00	21.49±0.42
	100	40	8.00	17.54±0.46
DEX	20	40	11.00	20.60±0.14
	40	40	11.00	21.16±0.23
	60	40	13.00	25.20±0.47
	80	40	11.00	20.59±0.25
	100	40	12.00	20.38±0.58

Items	skn-1	daf-16	daf-2	sod-2	jjk-1	aak-2
Crtl	1.0±0.1	1.0±0.2	1.0±0.0	1.0±0.0	1.0±0.1	1.0±0.1
MEM	1.1±0.0	0.9±0.2	1.1±0.2	1.3±0.2	1.2±0.0	1.1±0.0
ESC	1.9±0.2^*	1.1±0.1	1.2±0.1	1.1±0.1	1.2±0.2	1.1±0.1
DEX	1.1±0.1	0.9±0.1	0.8±0.1	0.9±0.1	0.8±0.1	0.9±0.2

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基于秀丽线虫模型探究七叶皂苷和右美沙芬对阿尔茨海默病的保护作用

Protective effects of escin and dextromethorphan on Alzheimer disease in Caenorhabditis elegans models

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