本文選題：缺血性卒中 + 二甲雙胍��； 參考：《上海交通大學(xué)》2014年碩士論文

【摘要】：背景與目的:試驗(yàn)表明二甲雙胍-臨床上常用的降糖藥-能夠減少糖尿病病人的卒中發(fā)病率以及緩解慢性炎癥。但是,二甲雙胍在缺血性卒中時(shí)的作用及其機(jī)制仍不甚清楚。本研究主要探討二甲雙胍在缺血性卒中時(shí)的作用及其可能機(jī)制。材料與方法:本研究應(yīng)用線栓法對(duì)120只成年雄性CD1小鼠進(jìn)行90分鐘的左側(cè)大腦中動(dòng)脈栓塞。在腦缺血后每天給予200毫克/千克的二甲雙胍,直至動(dòng)物犧牲。缺血后評(píng)估小鼠的神經(jīng)行為學(xué)、腦梗死和腦萎縮體積、炎癥因子表達(dá)、血腦屏障通透性、神經(jīng)血管再生以及單磷酸腺苷激酶(AMPK)信號(hào)通路。用b END.3在糖氧剝奪的條件下研究二甲雙胍抑制炎癥的信號(hào)通路。結(jié)果:與生理鹽水組相比,二甲雙胍組腦梗死以及腦萎縮體積明顯減少(p0.05),神經(jīng)功能恢復(fù)更好(p0.05)。二甲雙胍治療能減少炎癥細(xì)胞浸潤(rùn)、減少血腦屏障破壞、以及減少炎癥介質(zhì)(IL-1b,IL-6,TNF-a)的釋放(p0.05),同時(shí)二甲雙胍能促進(jìn)缺血后神經(jīng)再生和血管新生(p0.05)。進(jìn)一步研究證明二甲雙胍可激活A(yù)MPK,促進(jìn)e NOS磷酸化以及減少細(xì)胞間粘附因子(ICAM-1)的表達(dá)(p0.05)。應(yīng)用b END.3細(xì)胞進(jìn)行糖氧剝奪實(shí)驗(yàn),證明二甲雙胍可促進(jìn)AMPK的磷酸化,減少b END.3細(xì)胞ICAM-1的表達(dá)。而Compound C,AMPK的抑制劑,能夠抑制二甲雙胍的這種作用。結(jié)論:二甲雙胍在缺血性卒中發(fā)生時(shí),有腦保護(hù)作用。在腦缺血急性期,二甲雙胍通過AMPK信號(hào)通路依賴性機(jī)制,下調(diào)ICAM-1的表達(dá),減少缺血區(qū)的中性粒細(xì)胞的浸潤(rùn),減輕局部血腦屏障的破壞。在缺血恢復(fù)期,二甲雙胍可以通過促進(jìn)神經(jīng)再生和血管新生,促進(jìn)神經(jīng)功能的恢復(fù)。提示二甲雙胍可能成為治療缺血性卒中的新藥。
[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.
【學(xué)位授予單位】：上海交通大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R743.3
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本文編號(hào)：2044779