發(fā)布時間：2018-07-15 18:49

【摘要】：研究背景:缺血性腦卒中是腦血管疾病中最常見類型,是指各種原因所致腦部血液供應障礙,導致腦組織缺血、缺氧性壞死,并出現相應神經功能缺損。急性缺血性腦卒中病灶由核心梗死區(qū)及周圍的缺血半暗帶構成。位于梗死區(qū)中心的細胞在缺血缺氧條件下會迅速不可逆的壞死。而在梗死中心周圍的缺血半暗帶由于有側支循環(huán)存在,仍有大量神經細胞存活。缺血半暗帶內存在著大量處于休眠狀態(tài)或半休眠狀態(tài)的腦細胞,這些細胞僅能維持自身形態(tài)的完整,由于缺少能量的供應,無法行使原有的正常功能。缺血半暗帶腦細胞損傷的可逆性是缺血性腦卒中急診治療的病理性基礎之一。如果能及時挽救處于缺血半暗帶中的細胞,恢復其功能和活性,會對患者的預后有極大的改善。在低灌注環(huán)境下,線粒體功能能否保持完整性對腦細胞的生存至關重要。近年來的研究結果表明在腦缺血時瘦素可能對腦神經細胞起積極的保護作用,可有顯著減少缺血缺氧引起的神經細胞死亡,為治療腦血管疾病提供了新的研究方向。信號傳導和轉錄激活因子3(Signal transducers and activators of transcription 3,STAT3)是瘦素與受體結合后的細胞內信號傳導的主要通路之一,STAT3轉位于細胞核內可作為轉錄因子影響細胞核內特定基因的表達;此外,轉位于線粒體內的STAT3還可提高線粒體缺氧耐受能力�；诖笫蟠竽X中動脈阻塞(Middle cerebral artery occlusion,MCAO)模型的研究表明,瘦素可促進細胞核內STAT3蛋白的磷酸化,然而,迄今未見有文獻報道瘦素激活線粒體STAT3信號通路對缺血腦組織線粒體的影響。研究目的:探討瘦素通過線粒體STAT3信號通路對缺血性腦卒中核心梗死區(qū)和缺血半暗帶的影響,本研究成果將首次在分子信號轉導水平闡述瘦素誘導線粒體STAT3蛋白磷酸化對線粒體氧化應激的影響機制。本研究的完成還將有利于為瘦素對急性缺血性腦卒中神經保護作用提供有力證據,為尋找治療急性缺血性腦卒中提供新的思路。研究方法:通過線栓法制作大鼠MCAO模型觀察瘦素通過線粒體STAT3信號通路對SD大鼠局灶性腦缺血核心梗死區(qū)和缺血半暗帶的影響;健康雄性SD大鼠隨機分為三實驗組:一、假手術組,二、腦缺血組,三、瘦素組。對各組大鼠體重、腦水腫程度、腦梗死面積和神經功能缺陷進行測量和評分,并對各組的核心梗死區(qū)及缺血半暗帶進行活性氧(Reactive oxygen species,ROS)含量、線粒體STAT3蛋白磷酸化水平、線粒體呼吸鏈酶活性測定。研究結果:1、瘦素減少大鼠神經功能缺損,但并不影響體重變化。2、瘦素減少大鼠腦梗死面積和水腫程度。3、瘦素促進大鼠腦核心梗死區(qū)和缺血半暗帶線粒體STAT3磷酸化。4、瘦素減少大鼠腦核心梗死區(qū)和缺血半暗帶ROS的生成。5、瘦素增加大鼠腦核心梗死區(qū)和缺血半暗帶線粒體呼吸鏈I和II酶活性。結論1、瘦素預處理可以促進大鼠腦核心梗死區(qū)和缺血半暗帶中線粒體STAT3磷酸化,保護線粒體呼吸鏈I和II免受缺血性損傷造成的酶活性降低,減少因線粒體功能障礙導致的ROS生成。2、瘦素預處理減少腦缺血損傷,具有神經保護作用。
[Abstract]:Background: ischemic stroke is the most common type of cerebral vascular disease. It refers to the cerebral blood supply disorder caused by various causes, leading to cerebral ischemia, hypoxic necrosis and corresponding neural function defect. The acute ischemic stroke focus is composed of the ischemic and semi dark zone of the core infarction area and circumference. There is a rapid and irreversible necrosis of the cells under ischemic and anoxic conditions. And the ischemic penumbra around the center of the infarct still has a large number of neurons surviving due to the existence of collateral circulation. The ischemic penumbra is in a large number of dormant or semi dormant brain cells, which can only maintain the integrity of its own morphology because of the lack of energy. The reversibility of the cerebral cell damage in the ischemic penumbra is one of the pathological bases for the emergency treatment of ischemic stroke. If the cells in the ischemic penumbra can be saved in time to restore their function and activity, the prognosis of the patients will be greatly improved. In a low perfusion environment, mitochondria It is very important for the survival of brain cells to maintain integrity. In recent years, the results show that leptin may have a positive protective effect on cerebral nerve cells during cerebral ischemia, which can significantly reduce the death of nerve cells caused by ischemia and hypoxia, and provide a new direction for the treatment of cerebrovascular diseases. Signal conduction and transcription activation. Factor 3 (Signal transducers and activators of transcription 3, STAT3) is one of the main pathways of intracellular signaling transduction after the combination of leptin and receptor. The transfer of STAT3 to the nucleus can affect the expression of specific genes in the nucleus as a transcription factor. In addition, the transformation of STAT3 in mitochondria can also improve the mitochondrial hypoxia tolerance energy. Force. Based on the study of Middle cerebral artery occlusion (MCAO) model in rat, leptin can promote the phosphorylation of STAT3 protein in the nucleus. However, there has been no report on the effect of leptin activating mitochondrial STAT3 signaling pathway on the mitochondria of ischemic brain tissue. The effect of TAT3 signaling pathway on the infarct area and the ischemic penumbra in ischemic stroke. The results of this study will explain the effect of leptin induced mitochondrial STAT3 phosphorylation on mitochondrial oxidative stress for the first time at the level of molecular signal transduction. The completion of this study will also be beneficial to the protection of leptin for acute ischemic stroke. The effect provides powerful evidence to find new ideas for the treatment of acute ischemic stroke. Methods: the effect of leptin on the infarct area and the ischemic penumbra in the focal cerebral ischemia of SD rats through the mitochondrial STAT3 signal pathway was observed by the thread emboli method. The healthy male SD rats were randomly divided into three experimental groups: 1, The sham operation group, two, cerebral ischemia group, three, leptin group. The body weight, the degree of cerebral edema, the area of cerebral infarction and the defect of nerve function were measured and graded. The content of Reactive oxygen species, ROS, the level of mitochondrial STAT3 protein phosphorylation and the mitochondrial respiratory chain enzyme activity were carried out in the core infarct area and the ischemic penumbra of each group. Results: 1, leptin reduces the nerve function defect in rats, but does not affect the body weight change.2, leptin reduces the area of cerebral infarction and the degree of edema.3 in rats. Leptin promotes the core infarct area and the mitochondrial STAT3 phosphorylation.4 in the brain of the rat brain, and leptin reduces the formation of.5 and leptin in the cerebral core infarct area and the ischemic penumbra ROS in rats. Conclusion 1, leptin preconditioning can promote the phosphorylation of mitochondrial STAT3 in the infarct and ischemic penumbra of rats, protect mitochondrial respiratory chain I and II from ischemic injury and reduce the activity of enzymes caused by ischemic injury, and reduce mitochondrial dysfunction caused by the dysfunction of mitochondria. 1 ROS produced.2, leptin preconditioning reduced cerebral ischemia injury, and had neuroprotective effect.
【學位授予單位】：廣西醫(yī)科大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R743.3

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本文編號：2125047