血糖升高通过PI3K/Akt/mTOR通路促进自噬加重大鼠脑缺血再灌注介导的海马组织损伤

Hyperglycemia aggravates hippocampal tissue damage caused by cerebral ischemia-reperfusion in rats by promoting autophagy through PI3K/Akt/mTOR

目的探究血糖升高促进自噬对大鼠脑组织缺血/再灌注损伤(CIRI)后海马组织损伤的影响和机制。方法将80只SD大鼠按照随机数字表法分为4组,每组各20只。除Sham组外,CIRI组、低剂量HG组和高剂量HG组通过结扎法建立CIRI模型。低剂量HG组、高剂量HG组大鼠分别于术前5 min、缺血后45 min和90 min腹腔内注射2.5 mL/kg和8 mL/kg的葡萄糖溶液,Sham组和CIRI组在相同时间注射等量的0.9%氯化钠溶液。比较各组大鼠脑梗死体积、脑水肿、认知功能、海马神经元增殖情况,炎症细胞因子[白细胞介素(IL)-1、IL-6、肿瘤坏死因子α(TNF-α)]水平,以及海马神经元中自噬相关蛋白和PI3k/Akt/mTOR通路表达水平。结果与Sham组相比,CIRI组脑梗死体积、脑含水量增加,认知功能受损,海马神经元增殖受抑制,IL-1、IL-6、TNF-α水平升高,Beclin-1和LC-3II蛋白水平升高,p62蛋白水平降低,PI3k、Akt和mTOR蛋白磷酸化水平降低,差异均有统计学意义(P<0.05);与CIRI组相比,低剂量HG组、高剂量HG组大鼠脑损伤和炎症反应加剧,海马神经元自噬增加,PI3K/Akt/mTOR通路表达被抑制,差异均有统计学意义(P<0.05)。结论血糖升高加重大鼠CIRI病情,抑制PI3K/Akt/mTOR通路促进海马神经元过度自噬,导致认知功能障碍。

Objective To explore the effect and mechanism of hyperglycemia to promote autophagy on hippocampal tissue injury after cerebral ischemia/reperfusion injury(CIRI)in rats.Methods Eighty SD rats were randomly divided into 4 groups with 20 rats in each group.Except for the Sham group,the CIRI group,low-dose HG group and high-dose HG group established CIRI models by ligation.The rats in the low-dose HG group and the high-dose HG group were intraperitoneally injected with 2.5 mL/kg and 8 mL/kg of glucose solution 5 minutes before operation,45 minutes and 90 minutes after ischemia,respectively.Sham group and CIRI group were injected with the same amount of 0.9%sodium chloride solution at the same time.The cerebral infarction volume,brain edema,cognitive function,hippocampal neuron proliferation,inflammatory cytokine[interleukin(IL)-1,IL-6,tumor necrosis factor alpha(TNF-α)]level,autophagy related protein and PI3K/Akt/mTOR pathway expression in hippocampal neurons were compared.Results Compared with Sham group,CIRI group increased cerebral infarction volume,brain water content,impaired cognitive function,inhibited hippocampal neuron proliferation,increased IL-1,IL-6,TNF-α,Beclin-1 and LC-3II protein levels,decreased p62 protein levels,and decreased PI3K,Akt and mTOR protein phosphorylation levels,the differences were statistically significant(P<0.05).Compared with CIRI group,low-dose HG group and the high-dose HG group had aggravated brain injury and inflammatory response,increased autophagy in hippocampal neurons,and inhibited the expression of PI3K/Akt/mTOR pathway,the differences were statistically significant(P<0.05).Conclusion Hyperglycemia aggravates the CIRI condition of rats,and inhibits PI3K/Akt/mTOR pathway to promote excessive autophagy of hippocampal neurons,leading to cognitive dysfunction.