Effect of Wenpi tongluo kaiqiao formula against neuronal necroptosis in mice with Alzheimer’s disease and its mechanism

ZHU Xiaomin; CHEN Wei; FU Yulan; ZHUO Guifeng; HUANG Yingrui; ZHANG Ying; WU Lin

doi:10.6039/j.issn.1001-0408.2025.09.05

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Effect of Wenpi tongluo kaiqiao formula against neuronal necroptosis in mice with Alzheimer’s disease and its mechanism

更新时间：2025-05-09

- Effect of Wenpi tongluo kaiqiao formula against neuronal necroptosis in mice with Alzheimer’s disease and its mechanism
- ZHONGGUO YAOFANG Vol. 36, Issue 9, Pages: 1046-1051(2025)
- 作者机构：
  
  1.广西中医药大学第一临床医学院，南宁　530022
  2.广西中医药大学第一附属医院脑病科一区，南宁　530022
  3.广西中医药大学研究生院，南宁　530200
- 作者简介：
- 基金信息：
- DOI：10.6039/j.issn.1001-0408.2025.09.05
  CLC： R285.5
- Received：13 January 2025，
  
  Revised：19 March 2025，
  
  Accepted：2025-03-20，
  
  Published：15 May 2025
- 稿件说明：
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朱小敏,陈炜,符钰岚等.温脾通络开窍方抑制AD小鼠神经元坏死性凋亡的作用及机制 ^Δ[J].中国药房,2025,36(09):1046-1051.

ZHU Xiaomin,CHEN Wei,FU Yulan,et al.Effect of Wenpi tongluo kaiqiao formula against neuronal necroptosis in mice with Alzheimer’s disease and its mechanism[J].ZHONGGUO YAOFANG,2025,36(09):1046-1051.
朱小敏,陈炜,符钰岚等.温脾通络开窍方抑制AD小鼠神经元坏死性凋亡的作用及机制 ^Δ[J].中国药房,2025,36(09):1046-1051. DOI： 10.6039/j.issn.1001-0408.2025.09.05.

ZHU Xiaomin,CHEN Wei,FU Yulan,et al.Effect of Wenpi tongluo kaiqiao formula against neuronal necroptosis in mice with Alzheimer’s disease and its mechanism[J].ZHONGGUO YAOFANG,2025,36(09):1046-1051. DOI： 10.6039/j.issn.1001-0408.2025.09.05.

摘要

目的

基于Z-DNA结合蛋白1（ZBP1）/混合谱系激酶结构域样蛋白（MLKL）信号通路探讨温脾通络开窍方对阿尔茨海默病（AD）小鼠神经元坏死性凋亡的影响及机制。

方法

将40只

APP

PS1

转基因AD小鼠随机分为模型组，温脾通络开窍方低、高剂量组（10.4、20.8 g/kg，以生药量计）和盐酸多奈哌齐组（阳性对照，3 mg/kg），每组10只；并以10只C57BL/6J小鼠作为正常对照组。灌胃给药，每天1次，连续30 d。末次给药24 h后通过Morris水迷宫实验评估小鼠学习记忆能力，观察海马组织病理形态，检测血清中肿瘤坏死因子α（TNF-α）、白细胞介素4（IL-4）水平，检测海马组织中Tau蛋白、淀粉样前体蛋白（APP）和ZBP1/MLKL信号通路相关蛋白表达水平，检测海马组织神经元内磷酸化受体相互作用蛋白激酶3（p-RIPK3）阳性表达及海马组织中ZBP1 mRNA相对表达水平。

结果

与正常对照组比较，模型组小鼠第3～5天的逃避潜伏期均显著延长（

＜0.05），穿越平台次数显著减少（

＜0.05），海马组织出现明显病理性改变；TNF-α水平，APP、p-Tau、ZBP1蛋白表达水平和RIPK1、RIPK3、MLKL蛋白磷酸化水平，p-RIPK3荧光强度和ZBP1 mRNA相对表达水平均显著升高（

＜0.05）；血清中IL-4水平显著降低（

＜0.05）。与模型组比较，各给药组小鼠上述指标水平均显著逆转（

＜0.05），海马组织病理损伤减轻。

结论

温脾通络开窍方可通过抑制ZBP1/MLKL信号通路，减少AD小鼠神经元坏死性凋亡，抑制炎症反应，进而改善AD小鼠学习和空间记忆能力。

Abstract

OBJECTIVE

To investigate the effects and mechanism of Wenpi tongluo kaiqiao formula （WPTL） against neuronal necroptosis in Alzheimer’s disease （AD） mice based on the Z-DNA binding protein 1 （ZBP1）/mixed lineage kinase domain-like protein （MLKL） signaling pathway.

METHODS

Forty

APP/PS1

transgenic AD mice were randomly divided into model group， WPTL low-dose （WPTL-L） group （10.4 g/kg， calculated by the raw medicine）， WPTL high-dose （WPTL-H） group （20.8 g/kg， calculated by the raw medicine） and donepezil hydrochloride group （3 mg/kg）， with 10 mice in each

group； another 10 C57BL/6J mice were selected as normal control group. Intragastric administration， once a day， for 30 consecutive days. Twenty-four hours after the last administration， Morris water maze test was performed to evaluate learning and memory abilities； the pathological morphology of hippocampal tissues was observed； the serum levels of tumor necrosis factor-α （TNF-α） and interleukin-4 （IL-4） were determined； the expressions of amyloid precursor protein （APP）， Tau protein， and ZBP1/MLKL signaling pathway-related proteins in hippocampal tissues were detected； the positive expression of phosphorylated receptor-interacting protein kinase 3 （p-RIPK3） in the neurons of hippocampal tissues and mRNA expression of ZBP1 were measured in hippocampal tissues.

RESULTS

Compared with normal control group， the escape latency of mice in model group was prolonged significantly on day 3 to 5 （

＜0.05）， the times of crossing platform reduced significantly （

＜0.05）， and obvious pathological changes were observed in the hippocampal tissue. The level of TNF-α， the expressions of APP， p-Tau and ZBP1， the phosphorylation levels of RIPK1， RIPK3 and MLKL， the fluorescence intensity of p-RIPK3 as well as the mRNA expression of ZBP1 were significantly increased （

＜0.05）， while the serum level of IL-4 was decreased significantly （

＜0.05）. Compared with model group， above indexes were reversed significantly in administration groups （

＜0.05）， and pathological damage of hippocampal tissue was alleviated.

CONCLUSIONS

WPTL can inhibit the ZBP1/MLKL signaling pathway， reduce neuronal necroptosis in AD mice， and inhibit inflammatory responses， thereby improving learning and spatial memory abilities in AD mice.

关键词

Keywords

references

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