银杏叶提取物调控PI3K/Akt信号通路介导的细胞焦亡对大鼠脑缺血/再灌注神经元损伤的保护作用  

The protective effect of ginkgo biloba extract on neuronal injury in rats with cerebral ischaemia reperfusion by regulating PI3K/Akt signaling pathway mediated pyroptosis

作　　者：张昊 刘丽 刘丹 ZHANG Hao;LIU Li;LIU Dan(Dept of Neurology,Zhumadian Central Hospital,Zhumadian,Henan 463000,China;Dept of Pharmacology,School of Pharmacy,Zhengzhou University,Zhengzhou Henan 450066,China)

机构地区：[1]驻马店市中心医院神经内科,河南驻马店463000 [2]郑州大学药学院药理学系,河南郑州450066

出　　处：《中国药理学通报》2025年第5期881-887,共7页Chinese Pharmacological Bulletin

基　　金：国家自然科学基金资助项目(No 82000775);河南省医学科技攻关项目(No LHGJ20221058)。

摘　　要：目的初步探究银杏叶提取物(ginkgo biloba extract,GBE)对大鼠脑缺血/再灌注(cerebral ischaemia reperfusion,CIR)神经元损伤及焦亡的作用及调控机制。方法雄性SD大鼠随机性分假手术组(Sham)、CIR组、GBE低剂量组(GBE-L,25 mg·kg^(-1)·d^(-1))、GBE高剂量组(GBE-H,100 mg·kg^(-1)·d^(-1))及PI3K抑制剂组(LY294002),每组各24只,采用线栓法构建大鼠CIR模型。给药7 d后,进行神经功能损伤评分,计算脑组织含水量;检测各组大鼠脑组织病理学变化,炎症因子水平、神经元焦亡指数、焦亡相关蛋白(NLRP3、ASC、caspase-1、GSDMD、IL-1β、IL-18)及PI3K/Akt通路蛋白表达。结果与Sham组相比,CIR组大鼠神经功能损伤评分,脑组织含水量均明显升高(P<0.01),神经结构出现明显病理损伤及梗死病灶,血清TNF-α、IL-6、IL-1β、IL-18水平,细胞焦亡指数、焦亡相关蛋白(NLRP3、ASC、cleaved-caspase-1/pro-caspase-1、GSDMD-N/GSDMD、IL-1β、IL-18)表达均明显升高(P<0.01),p-PI3K/PI3K、p-Akt/Akt降低(P<0.01)。GBE各剂量处理后能够降低大鼠神经功能损伤评分,脑组织含水量,血清TNF-α、IL-6、IL-1β、IL-18含量,细胞焦亡指数、焦亡相关蛋白表达(P<0.05或P<0.01),升高p-PI3K/PI3K、p-Akt/Akt(P<0.05或P<0.01),改善神经元损伤(P<0.05或P<0.01)。与GBE-H组相比,LY294002能够逆转GBE对CIR大鼠神经元损伤的保护作用,诱导神经元焦亡。结论GBE能够改善大鼠CIR神经元损伤,机制与促进PI3K/Akt信号通路活化,抑制神经元焦亡相关。Aim To investigate the effect of ginkgo biloba extract(GBE)interventional therapy on neuronal injury and pyroptosis in rats with cerebral ischaemia reperfusion(CIR)and its mechanism.Methods Male SD rats were randomly divided into sham operation group(sham),CIR group,GBE low-dose group(GBE-L,25 mg·kg^(-1)·d^(-1)),and GBE high-dose group(GBE-H,100 mg·kg^(-1)·d^(-1))and PI3K inhibitor group(LY294002),with 24 rats in each group.The CIR rat model was established by suture method.After seven days of administration,the neurological function damage was scored,and the water content of the brain tissue was calculated;the pathological changes in the brain tissue of the rats in each group,the levels of inflammatory factors,the neuron pyroptosis index,and the pyroptosis-related proteins(NLRP3,ASC,caspase-1,GSDMD,IL-1β,IL-18)and PI3K/Akt pathway protein expression were detected.Results The neurological function damage score,brain water content of the rats significantly increased(P<0.01).The neurological structures showed marked pathological damage and infarct lesions.Serum TNF-α,IL-6,IL-1β,IL-18 levels,the index of pyroptosis and the expressions of pyroptosis-related proteins(NLRP3,ASC,cleaved-caspase-1/pro-caspase-1,GSDMD-N/GSDMD,IL-1β,IL-18)all significantly increased(P<0.01),while p-PI3K/PI3K,p-Akt/Akt decreased in CIR group(P<0.01).Different doses of GBE could reduce the neurological function damage score and brain tissue water content,improve neurological structure damage(P<0.05 or P<0.01),reduce serum TNF-α,IL-6,IL-1β,the content of IL-18,the pyroptosis index,and the expression of pyroptosis-related proteins(P<0.05 or P<0.01),and increase p-PI3K/PI3K,p-Akt/Akt(P<0.05 or P<0.01).Compared with GBE-H group,LY294002 could reverse the protective effect of GBE on neuronal injury in CIR rats and induce neuronal pyroptosis.Conclusions GBE can improve neuronal injury in CIR rats,and its mechanism is related to promoting the activation of PI3K/Akt pathway and inhibiting neuronal pyroptosis.

关 键 词：银杏叶提取物 脑缺血/再灌注 焦亡 神经元 PI3K/AKT信号通路 

分 类 号：R-332[医药卫生] R284.1R322.81R392R743.31