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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
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| 篇名： | 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 |
| TITLE： | Effect of Wenpi tongluo kaiqiao formula against neuronal necroptosis in mice with Alzheimer’s disease and its mechanism |
| 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、20.8g/kg，以生药量计）和盐酸多奈哌齐组（阳性对照，3mg/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30d。末次给药24h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ZBP1mRNA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（P＜0.05），穿越平台次数显著减少（P＜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ZBP1mRNA相对表达水平均显著升高（P＜0.05）；血清中IL-4水平显著降低（P＜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（P＜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 （P＜0.05）， the times of crossing platform reduced significantly （P＜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 （P＜0.05）， while the serum level of IL-4 was decreased significantly （P＜0.05）. Compared with model group， above indexes were reversed significantly in administration groups （P＜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. |
| 期刊： | 2025年第36卷第09期 |
| 作者： | 朱小敏；陈炜；符钰岚；卓桂锋；黄颖睿；张颖；吴林 |
| AUTHORS： | ZHU Xiaomin，CHEN Wei，FU Yulan，ZHUO Guifeng，HUANG Yingrui，ZHANG Ying，WU Lin |
| 关键字： | 温脾通络开窍方；阿尔茨海默病；ZBP1/MLKL信号通路；坏死性凋亡 |
| KEYWORDS： | Wenpi tongluo kaiqiao formula； Alzheimer’s disease； ZBP1/MLKL signaling pathway； necroptosis |
| 阅读数： | 4 次 |
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