右美托咪定通过抑制铁死亡发挥对小鼠脑缺血再灌注损伤的保护作用  

Dexmedetomidine exerts its protective effect on cerebral ischemia reperfusion injury in mice by inhibiting ferroptosis

作　　者：胡淼 门运政 陈蕾 黄杰 段方方 张雨鑫 董淑英 HU Miao;MEN Yunzheng;CHEN Lei;HUANG Jie;DUAN Fangfang;ZHANG Yuxin;DONG Shuying(Department of Pharmacology,School of Pharmacy,Bengbu Medical College,Bengbu Anhui 233030;Basic and Clinical Key Laboratory of Cardiovascular and Cerebrovascular Diseases,Bengbu Medical College,Bengbu Anhui 233030,China)

机构地区：[1]蚌埠医学院药学院药理学教研室,安徽蚌埠233030 [2]蚌埠医学院心脑血管疾病基础与临床重点实验室,安徽蚌埠233030

出　　处：《中南大学学报（医学版）》2022年第5期600-609,共10页Journal of Central South University ：Medical Science

基　　金：国家自然科学基金(81402930);蚌埠医学院“512人才培养计划”(BY51201104);蚌埠医学院心血管损伤与保护基础与临床应用创新团队(BYKC20190)。

摘　　要：目的:脑卒中是危害人类生命健康的重大疾病之一,其中缺血性脑卒中的发病率占脑卒中的70%以上。缺血性脑卒中引起的脑缺血再灌注(ischemia reperfusion,IR)损伤的发生机制极为复杂。右美托咪定作为临床上常用的麻醉辅助用药,其在对抗脑IR损伤中的作用近年来被广泛研究,但具体作用机制尚未阐明。因此,本研究基于铁死亡探讨右美托咪定对抗小鼠脑IR损伤的作用及机制。方法:采用改良线栓法制备小鼠大脑中动脉栓塞(middle cerebral artery occlusion,MCAO)模型。将雄性ICR小鼠随机分成:假手术(sham)组、IR组、IR+D1组(给予IR和25μg/kg的右美托咪定)、IR+D2组(给予IR和50μg/kg的右美托咪定)、IR+D3组(给予IR和100μg/kg的右美托咪定)、IR+D2+ML385组(给予IR、50μg/kg的右美托咪定和30 mg/kg的ML385)。采用Longa五分法进行小鼠神经行为学评分;2,3,5-三苯基四唑氮(triphenyltetrazolium chloride,TTC)染色法检测小鼠脑梗死体积;蛋白质印迹法检测小鼠脑组织中核因子E2相关因子2(nuclear factor erythroid 2-related factor 2,Nrf2)、转铁蛋白受体1(transferrin receptor 1,TFR1)、谷胱甘肽过氧化物酶4(glutathione peroxidase 4,GPX4)及胱氨酸/谷氨酸逆向转运蛋白溶质载体家族7成员11(solute carrier family 7 member 11,SLC7A11)蛋白质的表达水平。使用透射电镜观察线粒体形态。检测小鼠脑组织中MDA、GSH和Fe^(2+)的含量。结果:与sham组相比,IR组小鼠神经行为学评分、脑梗死体积、MDA和Fe^(2+)含量明显增加,TFR1蛋白质表达水平明显升高,GSH含量、SLC7A11和GPX4蛋白质表达水平显著降低(均P<0.05),脑组织神经细胞中的线粒体皱缩,嵴减少,膜密度增加;使用右美托咪定预处理后,相较于IR组,小鼠神经学行为评分、MDA和Fe^(2+)含量、TFR1蛋白质表达水平显著降低,脑梗死体积明显缩小,GSH含量、SLC7A11和GPX4蛋白质表达水平显著升高(均P<0.05),线粒体受损情况显著改�Objective:Stroke is one of the major diseases that can threaten human life and health.The incidence of ischemic stroke accounts for more than 70%of stroke.The mechanism of ischemia reperfusion(IR)injury caused by ischemic stroke is extremely complex.In recent years,dexmedetomidine has been increasingly studied in anti-cerebral IR injury as a common clinical anesthetic adjunct,but its specific mechanism is not fully understood.Therefore,this study aims to explore the effects and mechanisms of dexmedetomidine on cerebral IR injury in mice.Methods:The mouse middle cerebral artery occlusion(MCAO)model was prepared by modified suture method.Male ICR mice were randomly divided into a sham group,an IR group,an IR+D1 group(IR+administered 25μg/kg dexmedetomidine),an IR+D2 group(IR+administered 50μg/kg dexmedetomidine),an IR+D3 group(IR+administered 100μg/kg dexmedetomidine),and an IR+D2+ML385 group(IR+administered 50μg/kg dexmedetomidine and 30 mg/kg ML385).The neurologic behavior of mice was evaluated by Longa’s five-point method.2,3,5-triphenyltetrazolium chloride(TTC)staining was used to detect the percentage of cerebral infarct volume in mice.The protein expressions of nuclear factor erythroid 2-related factor 2(Nrf2),transferrin receptor 1(TFR1),glutathione peroxidase 4(GPX4),and solute carrier family 7 member 11(SLC7A11)in the cerebral tissues of mice were detected by Western blotting.Mitochondrial morphology was observed under the transmission electron microscope.The contents of MDA,Fe^(2+),and GSH in the cerebral tissues of mice were detected.Results:Compared with the sham group,neurobehavioral scores,cerebral infarct volume,the contents of MDA and Fe^(2+),as well as the protein expression of TFR1 were significantly increased;the contents of GSH and the protein expression of SLC7A11 and GPX4 were significantly reduced(all P<0.05);mitochondria in cerebral tissue were wrinkled,cristae were reduced,and membrane density was increased in the IR group.Compared with the IR group,neurobehavioral scores,cerebral inf

关 键 词：右美托咪定 脑缺血再灌注 铁死亡 核因子E2相关因子2 谷胱甘肽过氧化物酶4 胱氨酸/谷氨酸逆向转运蛋白溶质载体家族7成员11 

分 类 号：R614[医药卫生—麻醉学]