表没食子儿茶素没食子酸酯靶向调控Nrf2⁃Keap1信号通路与脑梗死神经保护作用的关系

The relationship between EGCG targeted regulation of Nrf2⁃Keap1 signaling pathway and neuroprotective effect in cerebral infarction

目的分析表没食子儿茶素没食子酸酯(EGCG)对高血糖诱导的出血性转化(HT)的预防作用,并进一步探索了其潜在机制是否与涉及核因子E2相关因子2/Kelch样环氧氯丙烷相关蛋白1(Nrf2/Keap1)通路。方法将雄性SD大鼠随机分为假手术组(Sham,n=20)、模型组(n=27)、高血糖模型组(HG,n=43)、EGCG组(n=43)。模型组大鼠仅建立电凝脑缺血模型,HG组和EGCG组采用急性高血糖联合电凝脑缺血模型建立HT模型。此外,EGCG组在脑缺血前灌胃EGCG 5 d,剂量为50 mg/(kg·d)。通过网络药理学用于预测EGCG在HT发生中的潜在靶点和通路,进一步研究证实了相关靶点。结果与模型组相比,HG组大鼠死亡率显著升高[21.2%(6/27)vs.51.2%(22/43),P<0.05]。EGCG组大鼠死亡率较HG组显著降低[30.20%(13/43)vs.51.2%(22/43),P<0.05]。其次,EGCG组mNSS、Longa评分和梗死体积显著低于HG组(P<0.05)。HG组的HT发生率高于模型组(59.3%vs.90.7%)。EGCG显著降低高血糖诱导的HT发病率至69.8%。与HG组相比,EGCG使血红蛋白含量分别从(53.42±5.11)mg/dL降低到(37.04±2.39)mg/dL(P<0.05)。网络药理学显示Nrf2-Keap1介导的神经炎症可能与高血糖诱导的HT相关。HG组Nrf2和Keap1的表达显著降低和TLR4的表达、NF-κB的磷酸化显著增加,但EGCG逆转了这一过程。结论EGCG预处理防止了HT的发生,这可能与激活Nrf2-Keap1信号通路介导的神经保护作用有关。

Objective The preventive effect of epigallocatechin gallate(EGCG)on hyperglycemia⁃induced hemorrhagic transformation(HT)was analyzed,and the underlying mechanisms were further explored.Methods Male SD rats were randomly divided into sham operation group(Sham,n=20),model group(n=27),hyperglycemia model group(HG,n=43),and EGCG group(n=43).In the model group,only the electrocoagulation cerebral ischemia model was established,and the HG group and the EGCG group were used to establish the HT model with acute hyperglycemia combined with electrocoagulation cerebral ischemia model.In addition,EGCG was adminis⁃tered by gavage for 5 days before cerebral ischemia at a dose of 50 mg/kg/d.Further studies confirmed the relevant targets by using network pharmacology to predict the potential targets and pathways of EGCG in the occurrence of HT.Results Compared with the model group,the mortality rate of the rats in the HG group was significantly increased[21.2%(6/27)vs.51.2%(22/43),P<0.05].The mortality of rats in the EGCG group was significantly lower than that in the HG group[30.20%(13/43)vs.51.2%(22/43),P<0.05].Second,mNSS,Longa score and infarct volume in the EGCG group were significantly lower than those in the HG group(P<0.05).The incidence of HT in the HG group was higher than that in the model group(59.3%vs.90.7%).EGCG significantly reduced the incidence of hyperglycemia⁃induced HT to 69.8%.Compared with the HG group,EGCG decreased the hemoglobin content from(53.42±5.11)mg/dL to(37.04±2.39)mg/dL respectively(P<0.05).Network pharmacology revealed that Nrf2⁃Keap1⁃mediated neuroinflammation may be associated with hyperglycemia⁃induced HT.The expression of Nrf2 and Keap1 was significantly decreased and the expression of TLR4 and phosphorylation of NF⁃κB was significantly increased in the HG group,but EGCG reversed this process.Conclusion EGCG pretreatment prevents the occurrence of HT,which may be related to the neuroprotection mediated by activation of the Nrf2⁃Keap1 signaling pathway.