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.