通窍活血汤调控Caspase-3/GSDME通路介导的细胞焦亡改善阿尔茨海默病模型大鼠认知功能*

doi:10.3870/j.issn.1672-0741.25.04.028

摘要/Abstract

摘要： 目的探讨通窍活血汤(TQHXD)调控天冬氨酸特异性半胱氨酸蛋白酶-3(Caspase-3)/ Gasdermin E(GSDME)通路介导的细胞焦亡改善阿尔茨海默病(AD)模型大鼠认知功能的作用机制。方法大鼠随机分为正常组、AD组、TQHXD低剂量组、TQHXD高剂量组、多奈哌齐组、TQHXD高剂量+Caspase-3激活剂(Raptinal)组,每组12只。除正常组外,其他组大鼠均通过双侧海马注射β淀粉样蛋白25-35(Aβ_25-35)法构建AD模型,建模成功后分组给药处理,持续4周。Morris水迷宫实验检测各组大鼠认知功能;苏木精-伊红(HE)染色检测各组大鼠脑海马CA1区组织病理改变并进行神经病理评分;免疫荧光染色检测海马CA1区GSDME氨基端片段(GSDME-N)阳性细胞数;ELISA法检测海马CA1区中白细胞介素-1β(IL-1β)、IL-18水平;Western blot检测海马CA1区中裂解的半胱氨酸天冬氨酸蛋白酶3(cleaved Caspase-3)、GSDME-N蛋白表达水平。结果与正常组比较,AD组大鼠神经元排列紊乱,核固缩,炎性细胞浸润明显;逃避潜伏期增加,跨越平台数减少;神经病理评分,海马CA1区组织中GSDME-N阳性细胞数,IL-1β、IL-18水平及cleaved Caspase-3、GSDME-N蛋白表达水平升高(均P＜0.05)。与AD组比较,TQHXD低剂量组、TQHXD高剂量组、多奈哌齐组大鼠海马CA1区病理损伤减轻;逃避潜伏期减少,跨越平台数增加;神经病理评分,海马CA1区组织中GSDME-N阳性细胞数,IL-1β、IL-18水平及cleaved Caspase-3、GSDME-N蛋白表达水平降低(均P＜0.05)。与TQHXD高剂量组比较,TQHXD高剂量+Raptinal组海马CA1区病理损伤更为严重;逃避潜伏期增加,跨越平台数减少;神经病理评分,海马CA1区组织中GSDME-N阳性细胞数,IL-1β、IL-18水平及cleaved Caspase-3、GSDME-N蛋白表达升高(均P＜0.05)。结论 TQHXD可能通过抑制Caspase-3/GSDME通路抑制AD大鼠神经元焦亡及神经炎症,改善认知功能。

关键词: 通窍活血汤, 阿尔茨海默病, 神经元焦亡, 神经炎症, 认知功能

Abstract: Objective To investigate the mechanism by which Tongqiao Huoxue decoction(TQHXD) regulates the Caspase-3/Gasdermin E(GSDME)pathway-mediated pyroptosis to improve cognitive function in a rat model of Alzheimer's disease(AD). Methods Rats were randomly divided into the following groups(n=12):Normal group,AD group,TQHXD low-dose group,TQHXD high-dose group,donepezil group,and TQHXD high-dose+Caspase-3 activator(Raptinal)group.Except for the normal group,rats in the other groups received bilateral hippocampal injection of β-amyloid 25-35(Aβ_25-35)to establish the AD model.After successful modeling,treatments were administered once daily for 4 weeks.Cognitive function was assessed using the Morris water maze test;HE staining was used to examine histopathological changes in the hippocampal CA1 region and assess neuropathological scores;the number of Gasdermin E N-terminal fragment(GSDME-N)-positive cells in the hippocampal CA1 region was determined by immunofluorescence staining;levels of interleukin-1β(IL-1β)and IL-18 in the hippocampal CA1 region were measured by ELISA;and the protein levels of cleaved Caspase-3 and GSDME-N in the hippocampal CA1 region were determined by Western blotting. Results Compared with the normal group,the AD group showed disordered neuronal arrangement,nuclear pyknosis,significant inflammatory cell infiltration,increased escape latency,decreased number of platform crossings,and increased neuropathological scores,number of GSDME-N-positive cells,and levels of IL-1β,IL-18,cleaved Caspase-3,and GSDME-N protein in the hippocampal CA1 region(all P<0.05).Compared with the AD group,the TQHXD low-dose group,TQHXD high-dose group,and donepezil group exhibited alleviated pathological damage in the hippocampal CA1 region,decreased escape latency,increased number of platform crossings,and decreased neuropathological scores,number of GSDME-N-positive cells,and levels of IL-1β,IL-18,cleaved Caspase-3,and GSDME-N protein in the hippocampal CA1 region(all P<0.05).Compared with the TQHXD high-dose group,the TQHXD high-dose+Raptinal group showed more severe pathological damage in the hippocampal CA1 region,increased escape latency,decreased number of platform crossings,and increased neuropathological scores,number of GSDME-N-positive cells,and levels of IL-1β,IL-18,cleaved Caspase-3,and GSDME-N protein(all P<0.05). Conclusion TQHXD may inhibit neuronal pyroptosis and neuroinflammation in AD rats by suppressing the Caspase-3/GSDME pathway,thereby improving cognitive function.

Key words: Tongqiao Huoxue decoction, Alzheimer's disease, neuronal pyroptosis, neuroinflammation, cognitive function

中图分类号:

雷婷, 崔应麟, 程率芳, 王雪可. 通窍活血汤调控Caspase-3/GSDME通路介导的细胞焦亡改善阿尔茨海默病模型大鼠认知功能^*[J]. 华中科技大学学报（医学版）, 2026, 55(2): 214-219.

Lei Ting, Cui Yinglin, Cheng Shuaifang et al. Tongqiao Huoxue Decoction Improves Cognitive Function in Alzheimer's Disease Rats byRegulating Caspase-3/GSDME Pathway-Mediated Pyroptosis[J]. Acta Medicinae Universitatis Scientiae et Technologiae Huazhong, 2026, 55(2): 214-219.

参考文献

[1] Shagufta,Ali G,Khan A,et al.Evaluation of the ameliorative potential of 3,5-bis(2-hydroxyethyl)-1,3,5-thiadiazinane-2-thione against scopolamine-induced Alzheimer's disease[J].Int J Mol Sci,2024,25(16):9104.
[2] Mohammadbaghban E,Taravati A,Najafzadehvarzi H,et al.Oral administration of encapsulated catechin in chitosan-alginate nanoparticles improves cognitive function and neurodegeneration in an aluminum chloride-induced rat model of Alzheimer's disease[J].Physiol Rep,2024,12(13):e16095.
[3] 黄薇,叶树,丁志贤,等.破壁灵芝孢子粉调控NLRP3炎症体介导的焦亡对阿尔茨海默病大鼠学习记忆能力的影响[J].中华中医药杂志,2024,39(6):3073-3077.
Huang W,Ye S,Ding Z X,et al.Effects of sporoderm-broken spores of Ganoderma lucidum modulating NLRP3 inflammasome-mediated pyroptosis on learning memory ability in Alzheimer's disease rats[J].China Journal of Traditional Chinese Medicine and Pharmacy,2024,39(6):3073-3077.
[4] Cummings J,Zhou Y,Lee G,et al.Alzheimer's disease drug development pipeline:2023[J].Alzheimers Dement,2023,9(2):e12385.
[5] Wu J,Li X Y,Liang J,et al.Network pharmacological analysis of active components of Tongqiao Huoxue Decoction in the treatment of intracerebral hemorrhage[J].Ann Transl Med,2022,10(10):567.
[6] 江张胜,董婷,田丽伟,等.网络药理学结合分子对接研究通窍活血汤治疗阿尔茨海默病的潜在分子机制[J].现代中药研究与实践,2023,37(3):33-38.
Jiang Z S,Dong T,Tian L W,et al.Mechanism of Tongqiao Huoxue decoction in treatment of Alzheimer's disease based on network pharmacology and molecular docking technology[J].Research and Practice on Chinese Medicines,2023,37(3):33-38.
[7] 刘宏,吉王琦.通窍活血汤联合益智四项头针治疗阿尔茨海默病的效果及对患者认知功能的影响[J].大医生,2025,10(3):92-95.
Liu H,Ji W Q.Effect of Tongqiao Huoxue Decoction combined with Yizhi Sijitou Acupuncture on Alzheimer's disease and its influence on patients'cognitive function[J].Doctor,2025,10(3):92-95.
[8] Qin H,Lu N,Chen K,et al.Inhibiting caspase-3/GSDME-mediated pyroptosis ameliorates septic lung injury in mice model[J].Mol Immunol,2024,172:96-104.
[9] Wang Q,Guo S,Hu D,et al.Enhanced gasdermin-E-mediated pyroptosis in Alzheimer's disease[J].Neuroscience,2024,536:1-11.
[10] 张运辉,袁云川,杨梦琳,等.基于PINK1/Parkin信号通路探讨黄芪散改善阿尔茨海默病大鼠海马突触可塑性的机制[J].天然产物研究与开发,2025,37(4):612-623.
Zhang Y H,Yuan Y C,Yang M L,et al.Mechanism of Huangqisan improves hippocampal synaptic plasticity in Alzheimer's disease rats based on PINK1/Parkin signaling pathway[J].Natural Product Research and Development,2025,37(4):612-623.
[11] 王建民,孟蓓,王胜利,等.通窍活血汤对动脉粥样硬化大鼠SIRT1/PGC1α通路及斑块稳定性的影响[J].中国老年学杂志,2023,43(12):3009-3013.
Wang J M,Meng B,Wang S L,et al.Effects of Tongqiao Huoxue decoction on SIRT1/PGC1α pathway and plaque stability in atherosclerotic rats[J].Chinese Journal of Gerontology,2023,43(12):3009-3013.
[12] 张运辉,张训浩,杨梦琳,等.涤痰汤通过JNK/p53信号通路改善阿尔茨海默病大鼠铁死亡及认知功能障碍[J].中国现代应用药学,2025,42(2):190-198.
Zhang Y H,Zhang X H,Yang M L,et al.Improvement of ferroptosis and cognitive function impairment in Alzheimer's disease rats by Ditan decoction via the JNK/p53 signaling pathway[J].Chinese Journal of Modern Applied Pharmacy,2025,42(2):190-198.
[13] Palchaudhuri R,Lambrecht M J,Botham R C,et al.A small molecule that induces intrinsic pathway apoptosis with unparalleled speed[J].Cell Rep,2015,13(9):2027-2036.
[14] Alvarez F J,Alvarez A A,Rodríguez J J,et al.Effects of cannabidiol,hypothermia,and their combination in newborn rats with hypoxic-ischemic encephalopathy[J].eNeuro,2023,10(5):ENEURO.0417-22.2023.
[15] Hong W,Hu C,Wang C,et al.Effects of amyloid β(Aβ)₄₂ and Gasdermin D on the progression of Alzheimer's disease in vitro and in vivo through the regulation of astrocyte pyroptosis[J].Aging,2023,15(21):12209-12224.
[16] Gáll Z,Boros B,Kelemen K,et al.Melatonin improves cognitive dysfunction and decreases gliosis in the streptozotocin-induced rat model of sporadic Alzheimer's disease[J].Front Pharmacol,2024,15:1447757.
[17] Qi Y,Zhang J,Zhang Y,et al.Curcuma Wenyujin extract alleviates cognitive deficits and restrains pyroptosis through PINK1/Parkin mediated autophagy in Alzheimer's disease[J].Phytomedicine,2025,139:156482.
[18] Wang X,Qian J,Meng Y,et al.Salidroside ameliorates severe acute pancreatitis-induced cell injury and pyroptosis by inactivating Akt/NF-κB and caspase-3/GSDME pathways[J].Heliyon,2023,9(2):e13225.
[19] Ding M,Liu J,Lv H,et al.Knocking down GALNT6 promotes pyroptosis of pancreatic ductal adenocarcinoma cells through NF-κB/NLRP3/GSDMD and GSDME signaling pathway[J].Front Oncol,2023,13:1097772.
[20] Liu H,Liu L L,Chen J,et al.Muscone with attenuation of neuroinflammation and oxidative stress exerts antidepressant-like effect in mouse model of chronic restraint stress[J].Oxid Med Cell Longev,2022,2022:3322535.
[21] Qi Y,Wang Y,Ni M,et al.Safflower yellow alleviates cognitive impairment in mice by modulating cholinergic system function,oxidative stress,and CREB/BDNF/TrkB signaling pathway[J].J Ethnopharmacol,2025,340:118986.
[22] 梅佳.不同剂量多奈哌齐联合喹硫平对阿尔茨海默病患者认知功能及精神行为症状的影响分析[J].中外医疗,2024,43(29):17-20.
Mei J.Analysis of the impact of different doses of donepezil combined with quetiapine on cognitive function and psychobehavioral symptoms in patients with Alzheimer's disease[J].China Foreign Medical Treatment,2024,43(29):17-20.
[23] Zhao M,Xian W,Liu W,et al.Maresin1 alleviates neuroinflammation by inhibiting caspase-3/GSDME-mediated pyroptosis in mice cerebral ischemia-reperfusion model[J].J Stroke Cerebrovasc Dis,2024,33(8):107789.
[24] Bu X,Gong P,Zhang L,et al.Pharmacological inhibition of cGAS ameliorates postoperative cognitive dysfunction by suppressing caspase-3/GSDME-dependent pyroptosis[J].Neurochem Int,2024,178:105788.
[25] Wang F,Deng H,Zhou M,et al.Anti-PD-1 exacerbates bleomycin-induced lung injury in mice via Caspase-3/GSDME-mediated pyroptosis[J].Cell Death Dis,2025,16(1):3.

通窍活血汤调控Caspase-3/GSDME通路介导的细胞焦亡改善阿尔茨海默病模型大鼠认知功能^*

Tongqiao Huoxue Decoction Improves Cognitive Function in Alzheimer's Disease Rats byRegulating Caspase-3/GSDME Pathway-Mediated Pyroptosis

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