中国药理学与毒理学杂志2024，Vol.38Issue(7)：496-503,8.DOI:10.3867/j.issn.1000-3002.2024.07.002
辛伐他汀预防小鼠高脂血症合并脑缺血损伤及其对时钟基因的调控
Simvastatin prevents cerebral ischemia-reperfusion injury and regulates clock genes in hyperlipidemia mice
摘要
Abstract
OBJECTIVE To investigate the preventive effect and mechanism of simvastatin on cerebral ischemia-reperfusion injury(CIRI)in hyperlipidemic mice.METHODS Sixty C57BL/6J mice were randomly divided into Sham group,CIRI group(CIRI model was prepared by middle cerebral artery occlusion and reperfusion(MCAO/R)),hyperlipemia group(i.p poloxamer 407),hyperlipemia+CIRI group(i.p poloxamer 407,followed by MCAO/R operation after 24 h),and hyperlipemia+CIRI+simvastatin 5 and 10 mg·kg-1 groups(i.g simvastatin for 7 d,and then treated as the hyperlipemia+CIRI group).After reperfusion for 24 h,the neurological deficit score(NDS)was evaluated;the Rotarod experiment was used to determine the first drop latency;autonomous activity was used to test the hori-zontal and vertical movement frequency of mice;TTC staining was used to measure the volume of cerebral infarction;laser speckle flow imaging was used to detect cerebral blood flow in mice;the kits were used to detect total cholesterol(TC),triglycerides(TG),low-density lipoprotein cholesterol(LDL-C),malondialdehyde(MDA)levels,and glutathione peroxidase(GSH-PX)levels in serum;qPCR and Western blotting were used to detect the mRNA and protein expression levels of clock genes Rev-erbα and Bmal1 in the right cerebral cortex of mice,respectively.RESULTS Compared with the Sham group,the NDS of the CIRI group was significantly increased(P<0.01),the latency period was shortened(P<0.01),and the number of activities was reduced(P<0.01);Compared with the CIRI group,the hyperlipemia+CIRI group showed aggravated neurological damage(P<0.01);the volume of cerebral infarction was significantly increased(P<0.01);the cerebral blood flow was significantly decreased(P<0.01);the levels of TC,TG,LDL-C,and MDA in serum were significantly increased(P<0.01),while the level of GSH-PX was significantly decreased(P<0.01);the mRNA and protein expression levels of Rev-erbα in the cere-bral cortex were significantly downregulated(P<0.01);the mRNA and protein expression levels of Bmal1 were significantly upregulated(P<0.01).Compared with the hyperlipemia+CIRI group,the hyper-lipemia+CIRI+simvastatin 5 and 10 mg·kg-1 groups showed reduced neurological damage(P<0.01);the volume of cerebral infarction was significantly decreased(P<0.01);the cerebral blood flow was significantly increased(P<0.01);the levels of TC,TG,LDL-C,and MDA in serum were significantly reduced(P<0.01),while the level of GSH-PX was significantly increased(P<0.01);the mRNA and protein expression levels of Rev-erbα in the cerebral cortex were significantly upregulated(P<0.01);the mRNA and protein expression levels Bmal1 were significantly downregulated(P<0.01).CONCLU-SION Prophylactic administration of simvastatin can effectively alleviate hyperlipidemia combined with cerebral ischemic injury in mice,and the mechanism is related to the regulation of blood lipid and clock gene expression.关键词
辛伐他汀/高血脂/脑缺血再灌注损伤/时钟基因/Rev-erbα/Bmal1Key words
simvastatin/hyperlipidemia/cerebral ischemia reperfusion injury/clock genes/Rev-erbα/Bmal1分类
医药卫生引用本文复制引用
王敏,阙文轩,陈刚领..辛伐他汀预防小鼠高脂血症合并脑缺血损伤及其对时钟基因的调控[J].中国药理学与毒理学杂志,2024,38(7):496-503,8.基金项目
国家自然科学基金(82074058) （82074058）
中央高校基本科研业务费专项资金资助(2632023GR03) National Natural Science Foundation of China(82074058) （2632023GR03）
and Fundamental Research Funds for the Central Universities(2632023GR03) （2632023GR03）
