二甲双胍在缺血性卒中中的作用研究

发布时间：2018-06-20 15:46

  本文选题：缺血性卒中 + 二甲双胍　； 参考：《上海交通大学》2014年硕士论文

【摘要】：背景与目的:试验表明二甲双胍-临床上常用的降糖药-能够减少糖尿病病人的卒中发病率以及缓解慢性炎症。但是,二甲双胍在缺血性卒中时的作用及其机制仍不甚清楚。本研究主要探讨二甲双胍在缺血性卒中时的作用及其可能机制。材料与方法:本研究应用线栓法对120只成年雄性CD1小鼠进行90分钟的左侧大脑中动脉栓塞。在脑缺血后每天给予200毫克/千克的二甲双胍,直至动物牺牲。缺血后评估小鼠的神经行为学、脑梗死和脑萎缩体积、炎症因子表达、血脑屏障通透性、神经血管再生以及单磷酸腺苷激酶(AMPK)信号通路。用b END.3在糖氧剥夺的条件下研究二甲双胍抑制炎症的信号通路。结果:与生理盐水组相比,二甲双胍组脑梗死以及脑萎缩体积明显减少(p0.05),神经功能恢复更好(p0.05)。二甲双胍治疗能减少炎症细胞浸润、减少血脑屏障破坏、以及减少炎症介质(IL-1b,IL-6,TNF-a)的释放(p0.05),同时二甲双胍能促进缺血后神经再生和血管新生(p0.05)。进一步研究证明二甲双胍可激活AMPK,促进e NOS磷酸化以及减少细胞间粘附因子(ICAM-1)的表达(p0.05)。应用b END.3细胞进行糖氧剥夺实验,证明二甲双胍可促进AMPK的磷酸化,减少b END.3细胞ICAM-1的表达。而Compound C,AMPK的抑制剂,能够抑制二甲双胍的这种作用。结论:二甲双胍在缺血性卒中发生时,有脑保护作用。在脑缺血急性期,二甲双胍通过AMPK信号通路依赖性机制,下调ICAM-1的表达,减少缺血区的中性粒细胞的浸润,减轻局部血脑屏障的破坏。在缺血恢复期,二甲双胍可以通过促进神经再生和血管新生,促进神经功能的恢复。提示二甲双胍可能成为治疗缺血性卒中的新药。
[Abstract]:Background & objective: metformin, a common antidiabetic drug, has been shown to reduce the incidence of stroke and alleviate chronic inflammation in diabetic patients. However, the role of metformin in ischemic stroke and its mechanism remain unclear. The purpose of this study was to investigate the role of metformin in ischemic stroke and its possible mechanism. Materials and methods: 120 adult male CD1 mice were embolized with left middle cerebral artery (MCAA) for 90 minutes. After cerebral ischemia, 200 mg / kg metformin was given daily until animals died. Brain infarction and atrophy volume, inflammatory factor expression, blood-brain barrier permeability, neurovascular regeneration and adenosine monophosphate kinase (AMPK) signaling pathway were evaluated after ischemia in mice. The signaling pathway of metformin in inhibiting inflammation was studied by using bEND.3 under the condition of glucose and oxygen deprivation. Results: compared with normal saline group, the volume of cerebral infarction and brain atrophy in metformin group was significantly reduced (P 0.05), and the recovery of nerve function was better than that in metformin group (P 0.05). Metformin treatment could reduce the infiltration of inflammatory cells, reduce the damage of blood-brain barrier, and reduce the release of IL-1bt6 / TNF-a. Metformin could promote nerve regeneration and neovascularization after ischemia. It is further demonstrated that metformin can activate AMPK, promote the phosphorylation of eNOS and decrease the expression of ICAM-1. It was proved that metformin could promote the phosphorylation of AMPK and decrease the expression of ICAM-1 in bEND.3 cells. The inhibitor of compound Con AMPK inhibits this effect of metformin. Conclusion: metformin has protective effect on ischemic stroke. In the acute phase of cerebral ischemia, metformin down-regulates ICAM-1 expression through AMPK signaling pathway, reduces neutrophil infiltration in ischemic area and attenuates the destruction of local blood-brain barrier. Metformin can promote the recovery of nerve function by promoting nerve regeneration and angiogenesis during ischemic recovery. It suggests that metformin may be a new drug in the treatment of ischemic stroke.
【学位授予单位】：上海交通大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R743.3
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本文编号：2044779