瘦素通过线粒体STAT3信号通路对大鼠局灶性脑缺血影响研究
发布时间：2018-07-15 18:49
【摘要】：研究背景:缺血性脑卒中是脑血管疾病中最常见类型,是指各种原因所致脑部血液供应障碍,导致脑组织缺血、缺氧性坏死,并出现相应神经功能缺损。急性缺血性脑卒中病灶由核心梗死区及周围的缺血半暗带构成。位于梗死区中心的细胞在缺血缺氧条件下会迅速不可逆的坏死。而在梗死中心周围的缺血半暗带由于有侧支循环存在,仍有大量神经细胞存活。缺血半暗带内存在着大量处于休眠状态或半休眠状态的脑细胞,这些细胞仅能维持自身形态的完整,由于缺少能量的供应,无法行使原有的正常功能。缺血半暗带脑细胞损伤的可逆性是缺血性脑卒中急诊治疗的病理性基础之一。如果能及时挽救处于缺血半暗带中的细胞,恢复其功能和活性,会对患者的预后有极大的改善。在低灌注环境下,线粒体功能能否保持完整性对脑细胞的生存至关重要。近年来的研究结果表明在脑缺血时瘦素可能对脑神经细胞起积极的保护作用,可有显著减少缺血缺氧引起的神经细胞死亡,为治疗脑血管疾病提供了新的研究方向。信号传导和转录激活因子3(Signal transducers and activators of transcription 3,STAT3)是瘦素与受体结合后的细胞内信号传导的主要通路之一,STAT3转位于细胞核内可作为转录因子影响细胞核内特定基因的表达;此外,转位于线粒体内的STAT3还可提高线粒体缺氧耐受能力。基于大鼠大脑中动脉阻塞(Middle cerebral artery occlusion,MCAO)模型的研究表明,瘦素可促进细胞核内STAT3蛋白的磷酸化,然而,迄今未见有文献报道瘦素激活线粒体STAT3信号通路对缺血脑组织线粒体的影响。研究目的:探讨瘦素通过线粒体STAT3信号通路对缺血性脑卒中核心梗死区和缺血半暗带的影响,本研究成果将首次在分子信号转导水平阐述瘦素诱导线粒体STAT3蛋白磷酸化对线粒体氧化应激的影响机制。本研究的完成还将有利于为瘦素对急性缺血性脑卒中神经保护作用提供有力证据,为寻找治疗急性缺血性脑卒中提供新的思路。研究方法:通过线栓法制作大鼠MCAO模型观察瘦素通过线粒体STAT3信号通路对SD大鼠局灶性脑缺血核心梗死区和缺血半暗带的影响;健康雄性SD大鼠随机分为三实验组:一、假手术组,二、脑缺血组,三、瘦素组。对各组大鼠体重、脑水肿程度、脑梗死面积和神经功能缺陷进行测量和评分,并对各组的核心梗死区及缺血半暗带进行活性氧(Reactive oxygen species,ROS)含量、线粒体STAT3蛋白磷酸化水平、线粒体呼吸链酶活性测定。研究结果:1、瘦素减少大鼠神经功能缺损,但并不影响体重变化。2、瘦素减少大鼠脑梗死面积和水肿程度。3、瘦素促进大鼠脑核心梗死区和缺血半暗带线粒体STAT3磷酸化。4、瘦素减少大鼠脑核心梗死区和缺血半暗带ROS的生成。5、瘦素增加大鼠脑核心梗死区和缺血半暗带线粒体呼吸链I和II酶活性。结论1、瘦素预处理可以促进大鼠脑核心梗死区和缺血半暗带中线粒体STAT3磷酸化,保护线粒体呼吸链I和II免受缺血性损伤造成的酶活性降低,减少因线粒体功能障碍导致的ROS生成。2、瘦素预处理减少脑缺血损伤,具有神经保护作用。
[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.
【学位授予单位】：广西医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R743.3
本文编号：2125047
[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.
【学位授予单位】：广西医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R743.3
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相关期刊论文 前2条
1 宋新建;卢红建;马丹;王兴山;沈晓明;;缺血性脑卒中患者血清瘦素水平与颈动脉粥样硬化的研究[J];中华临床医师杂志(电子版);2014年18期
2 陈伟伟;高润霖;刘力生;朱曼璐;王文;王拥军;吴兆苏;胡盛寿;;中国心血管病报告2013概要[J];中国循环杂志;2014年07期
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