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Journal of Peking University (Health Sciences) ›› 2025, Vol. 57 ›› Issue (4): 764-771. doi: 10.19723/j.issn.1671-167X.2025.04.022

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

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

  1. 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)

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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

CLC Number: 

  • R749.16

Table 1

Information of AD model Caenorhabditis elegans strains"

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

Figure 1

Survival count of CL2006 and N2 in different doses of escin (ESC) and dextromethor phan (DEX) Survival count of Alzheimer disease (AD) model CL2006 and N2 C. elegans after different drug treatments. Survival count of CL2006 after different doses of DEX (A) or ESC (B) treatment; survival count of N2 after different doses of DEX (C) or ESC (D) treatment. MEM, memantine. *P < 0.05 compared with control (Crtl). n=3."

Table 2

Survival time of CL2006 under different concentrations of escin and dextromethorphan"

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

Figure 2

Effects of escin and dextromethorphan on nematode activity Effects on nematode activity post 3-to 9-day treatment of ESC or DEX. A and B, body bending frequency of AD model CL4176 (A) and N2 (B) C. elegans; C and D, head swing frequency of CL4176 (C) and N2 (D) C. elegans. Crtl, control; MEM, memantine; DEX, dextromethorphan; ESC, escin. *P < 0.05 compared with control. n=3."

Figure 3

Effects of escin and dextromethorphan on the chemotaxis index of Caenorhabditis elegans Effects of ESC and DEX on the chemotaxis index of AD model (A) and normal N2 (B) C. elegans strains. A and B represent chemotaxis index of AD model CL2355 and normal N2 C. elegans. Crtl, control; MEM, memantine; DEX, dextromethorphan; ESC, escin. *P < 0.05, compared with control ESC. n=3."

Figure 4

Changes of Aβ protein content in AD model Caenorhabditis elegans in each groups Changes of Aβ protein content in AD model CL2006 C. elegans. CL2006 worms were treated with ESC, DEX, or MEM followed by measurement of Aβ levels. Normal N2 worms were included for comparison. Crtl, control; MEM, memantine; DEX, dextromethorphan; ESC, escin. *P < 0.05, compared with control. n=3."

Figure 5

Changes of ROS content in AD model (CL2006) Changes of ROS levels in AD model CL2006 C. elegans. Crtl, control; H2O2, hydrogen peroxide as positive control; MEM, memantine; DEX, dextromethorphan; ESC, escin. *P < 0.05 compared with control, n=3."

Table 3

mRNA expression in each intervention group"

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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