阿托伐他汀预处理对高血糖诱导小鼠脑缺血后出血转化的影响  

Effect of atorvastatin preconditioning on hyperglycemia induced hemorrhagic transformation in mice after cerebral ischemia

作　　者：冷昌龙 周梅 李友维 林款 孙宾莲 舒细记[1] 柳威[2] Leng Changlong;Zhou Mei;Li Youwei;Lin Kuan;Sun Binlian;Shu Xiji;Liu Wei(School of Medicine,Jianghan University,Wuhan 430056,Hubei Province,China)

机构地区：[1]江汉大学医学部,武汉430056 [2]江汉大学脑血管病研究所

出　　处：《中华老年心脑血管病杂志》2024年第1期92-96,共5页Chinese Journal of Geriatric Heart,Brain and Vessel Diseases

基　　金：湖北省自然科学基金(2022CFC057)。

摘　　要：目的探究阿托伐他汀对高血糖诱导的小鼠脑缺血后出血转化(HT)的作用及机制。方法36只SPF级雄性C57BL/6小鼠随机分为假手术组、HT模型组和阿托伐他汀组,每组12只。比较各组小鼠神经功能评分、死亡率、HT发生率、HT分级评分,苏木精-伊红染色观察脑组织出血情况,免疫荧光染色评估血脑屏障通透性,Western blot检测缺血半暗带脑组织免疫球蛋白G(IgG)、闭锁连接蛋白1(ZO-1)、闭合蛋白(occludin)、紧密连接蛋白5(claudin5)、基质金属蛋白酶(MMP)2和MMP-9的蛋白表达。结果与假手术组比较,HT模型组神经功能评分、死亡率、HT发生率、HT评分、IgG荧光强度、IgG、MMP-2、MMP-9蛋白表达水平显著增高,ZO-1、occludin、claudin5蛋白表达水平明显降低(P<0.01)。与HT模型组比较,阿托伐他汀组神经功能评分、死亡率、HT发生率、HT评分、IgG荧光强度及IgG、MMP-2、MMP-9蛋白表达水平显著降低[(2.73±1.19)分vs(3.91±0.94)分,16.7%vs 41.6%,58.3%vs 91.6%,(1.00±1.04)分vs(2.58±1.13)分,(504.30±105.52)a.u vs(859.91±153.28)a.u,4.55±1.40 vs 12.06±3.73,1.87±0.41 vs 2.95±0.68,1.47±0.24 vs 2.12±0.23,P<0.05,P<0.01],ZO-1、occludin、claduin5蛋白表达显著升高(1.55±0.20 vs 0.53±0.10,0.92±0.11 vs 0.35±0.07、0.58±0.04 vs 0.30±0.05,P<0.01)。结论阿托伐他汀可通过抑制MMP-2、MMP-9激活,上调ZO-1、occludin、claudin5表达,降低血脑屏障通透性,从而抑制高血糖诱导的脑缺血后HT。Objective To investigate the role and underlying mechanism of atorvastatin on hyperglycemia induced hemorrhagic transformation(HT)in a mouse model of cerebral ischemia.Methods A total of 36 SPF-grade male C57BL/6 mice were randomly divided into sham operation group,HT model group and atorvastatin group,with 12 mice in each group.HE staining was used to observe cerebral hemorrhage,immunofluorescent staining was employed to detect the integrity of blood-brain barrier,and Western blotting was applied to measure the protein expression of IgG,ZO-1,occludin,claduin5,MMP-2 and-9 in ischemic penumbra brain tissues.Results Compared with sham operation group,the neurological deficit score,mortality rate,HT incidence,HT grading score,IgG fluorescence intensity,and protein levels of IgG,MMP-2 and-9 were significantly increased,while the protein levels of ZO-1,occludin and claudin5 were obviously decreased in the HT model group(P<0.01).Atorvastatin treatment resulted in significantly lower neurological deficit score(2.73±1.19 vs 3.91±0.94),mortality rate(16.7%vs 41.6%),HT incidence(58.3%vs 91.6%),HT grading score(1.00±1.04 vs 2.58±1.13),IgG fluorescence intensity(504.30±105.52 a.u vs 859.91±153.28 a.u),and protein levels of IgG(4.55±1.40 vs 12.06±3.73),MMP-2(1.87±0.41 vs 2.95±0.68)and-9(1.47±0.24 vs 2.12±0.23)(P<0.05,P<0.01),and increased protein levels of ZO-1(1.55±0.20 vs 0.53±0.10),occludin(0.92±0.11 vs 0.35±0.07)and claudin5(0.58±0.04 vs 0.30±0.05)(P<0.01)when compared with the HT model group.Conclusion Atorvastatin can reduce the permeability of blood-brain barrier by inhibiting the activation of MMP-2 and MMP-9 and up-regulating the protein levels of ZO-1,occludin and claudin5,and thus attenuate hyperglycemia-induced HT.

关 键 词：阿托伐他汀 小鼠 近交C57BL 模型 动物 脑缺血 脑出血 血脑屏障 

分 类 号：R743.3[医药卫生—神经病学与精神病学]