本文選題：缺血再灌注損傷　切入點：布洛芬　出處：《中國人民解放軍醫(yī)學(xué)院》2017年碩士論文

【摘要】：研究背景和目的:腦卒中是一種急性的腦血管疾病。因其具有高發(fā)病率、高復(fù)發(fā)率、高致殘率和死亡率,嚴重影響著患者的生活質(zhì)量。其中,缺血性腦卒中較出血性腦卒中具有更高的發(fā)病率,占腦卒中總數(shù)的60%-70%。缺血性腦卒中的發(fā)病機制和病理生理過程極其復(fù)雜,因此給臨床治療帶來了極大的困難。酸中毒是組織缺血缺氧后的一個重要病理生理變化。近年來研究發(fā)現(xiàn),胞外pH值下降能激活一種特殊的配體門控通道,酸敏感離子通道(Ac id-sensing ion channels—AS I Cs),這極大地改變了人們對缺血性腦損傷機制的認識[1]。目前,已經(jīng)克隆出六種ASIC亞基(1a、1 b、2a、2b、3和4) [2],其中,H+敏感性高且對Ca2+通透ASIC1 a同聚體通道和ASIC1 a/2b通道在參與腦缺血和再灌注損傷過程中發(fā)揮著重要作用[3-8]。布洛芬是臨床上常用的抗炎鎮(zhèn)痛藥,早在上世紀九十年代就有文章報道了其腦保護作用[9,10]。但是,對于其神經(jīng)保護作用的機制目前還沒有統(tǒng)一的定論。自從ASICs被發(fā)現(xiàn)以來,已有多篇文獻[11-13]報道了布洛芬對ASICs的作用。本研究旨在①觀察大腦中動脈阻塞(MCAO)后大鼠皮層缺血半暗帶ASIC1a和ASIC2a表達變化情況并探討其意義;②觀察布洛芬的神經(jīng)保護作用及其對ASIC1a和ASIC2a表達和上膜的影響,探索其以ASIC2a為靶點的神經(jīng)保護作用的機制。方法:①20只SD大鼠隨機分為假手術(shù)組(sham) 10只和MCAO模型組(MCAO) 10只,于術(shù)后24h取腦,提取腦組織蛋白和分離膜蛋白,用Western blot檢測ASIC1a和ASIC2a的總蛋白和膜蛋白情況;②48只SD大鼠隨機分為假手術(shù)+溶媒組(S+R n=12)、假手術(shù)+布洛芬組(S+B n=12)、MCAO模型+溶媒組(C+R n=12)、MCAO模型+布洛芬組(C+B n=12),于術(shù)后24h通過神經(jīng)行為學(xué)評分、TTC染色等方法觀察布洛芬的腦保護作用和用Western blot觀察布洛芬對皮層缺血半暗帶ASIC1a和ASIC2a蛋白含量的影響。結(jié)果:①腦缺血再灌注24h后,與假手術(shù)組相比,MCAO模型組皮層缺血半暗帶的ASIC1a的表達沒有明顯變化(P=0.7004),其膜蛋白含量增加(P 0.001),ASIC2a的表達明顯上調(diào)(P 0.001);②布洛芬能提高MCAO模型大鼠的神經(jīng)行為學(xué)評分(P0.05),減少腦梗死容積(P0.01),并且能降低皮層缺血半暗帶ASIC1a膜蛋白的含量(P 0.05)和下調(diào)ASIC2a的表達(P0.01)。結(jié)論:布洛芬能夠明顯改善大鼠腦缺血再灌注損傷后的神經(jīng)行為學(xué)障礙,縮小腦梗死的范圍,具有神經(jīng)保護作用;布洛芬可能通過下調(diào)皮層缺血半暗帶ASIC2a的表達,減少ASIC1a的膜上分布,發(fā)揮神經(jīng)保護作用。
[Abstract]:Background and objective: stroke is an acute cerebrovascular disease. Because of its high incidence, high recurrence rate, high disability rate and mortality, it seriously affects the quality of life of patients. The incidence of ischemic stroke is higher than that of hemorrhagic stroke, accounting for 60-70% of the total stroke. The pathogenesis and pathophysiological process of ischemic stroke are extremely complex. Acidosis is an important pathophysiological change after ischemia and hypoxia. In recent years, it has been found that the decrease of extracellular pH can activate a special ligand gated channel. The acid-sensitive ion channel, ac id-sensing ion channels-AS I CSN, has greatly changed the understanding of the mechanism of ischemic brain injury [1]. Six subunits of ASIC have been cloned, I. e., 1 ASIC subunit, 1 BX, 2a, 2bt3 and 4) [2], of which H sensitive and transparent to ASIC1 a homopolymer channel and ASIC1 a / 2b channel play an important role in the process of cerebral ischemia and reperfusion injury [3-8]. Ibuprofen is a common clinical practice. Used as an anti-inflammatory analgesics, As early as the nineties of the last century, it was reported that its brain protective effect [9]. However, there is no uniform conclusion on the mechanism of its neuroprotective effect. Since the discovery of ASICs, The effect of ibuprofen on ASICs has been reported in several papers [11-13]. The purpose of this study was to observe the changes of ASIC1a and ASIC2a expression in ischemic penumbra of rat cortex after middle cerebral artery occlusion (MCAO) and to explore its significance. Protective effects and their effects on the expression of ASIC1a and ASIC2a, and on the membrane, Methods one hundred and twenty Sprague-Dawley rats were randomly divided into sham group (n = 10) and MCAO model group (n = 10). Brain tissue proteins and membrane proteins were extracted 24 hours after operation. The total protein and membrane protein of ASIC1a and ASIC2a were detected by Western blot. 248 SD rats were randomly divided into sham-operated medium group and sham-operated ibuprofen group, and the sham-operated ibuprofen group and the sham-operated ibuprofen group were divided into two groups: the sham-operated ibuprofen group and the sham-operated ibuprofen group. The protective effect of ibuprofen on brain and the effect of ibuprofen on the contents of ASIC1a and ASIC2a protein in ischemic penumbra of cortex were observed by neurobehavioral score and TTC staining in 24 hours. Results after 24 hours of cerebral ischemia and reperfusion, the effects of ibuprofen on the contents of ASIC1a and ASIC2a in cerebral ischemia penumbra were observed. Compared with the sham-operated group, the expression of ASIC1a in the ischemic penumbra of the MCAO model group did not change significantly. The increase of membrane protein content in the MCAO model group increased the expression of ASIC2a and increased the neurobehavioral score (P0.05) of the MCAO model rats. Conclusion: ibuprofen can significantly improve neurobehavioral disorders after cerebral ischemia reperfusion injury in rats, and can decrease the content of ASIC1a membrane protein in ischemic penumbra of cortex and down-regulate the expression of ASIC2a. Ibuprofen may play a neuroprotective role by down-regulating the expression of ASIC2a in the ischemic penumbra of cortex and reducing the distribution of ASIC1a on the membrane.
【學(xué)位授予單位】：中國人民解放軍醫(yī)學(xué)院
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R743.3

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本文編號：1660097