银杏二萜内酯葡胺注射液对局灶性脑缺血大鼠SIRT1/HIF-1α/VEGF信号通路及突触可塑性的影响

The effects of Ginkgo biloba diterpene lactone glumine injection on SIRT1/HIF-1α/VEGF signal pathway and synaptic plasticity in rats with focal cerebral ischemia

目的研究银杏二萜内酯葡胺注射液对局灶性脑缺血大鼠沉默信息调节因子2相关酶1/缺氧诱导因子-1α/血管内皮生长因子(SIRT1/HIF-1α/VEGF)信号通路及突触可塑性的影响。方法SD大鼠随机分为假手术组(等量生理盐水)、模型组(等量生理盐水)、尼莫地平组(16.2 mg·kg^(-1))、银杏二萜内酯葡胺注射液低(1.3 mg·kg^(-1))、中(2.6 mg·kg^(-1))、高(5.2 mg·kg^(-1))组,模型组、尼莫地平组、银杏二萜内酯葡胺注射液低、中、高组采用大脑中动脉栓塞(MCAO)建立局灶性脑缺血大鼠模型,假手术组只分离颈总动脉及颈内、颈外动脉。术后24 h用药干预,每天1次,连续7 d。评估术后24 h、7 d各组大鼠神经功能缺损评分,检测脑含水量及脑梗死率,采用免疫印迹(WB)法检测缺血侧脑组织突触后密度蛋白-95(PSD-95)、突触素(SYN)及SIRT1、HIF-1α、VEGF蛋白表达量。结果术后7 d,与假手术组比较,模型组大鼠神经功能缺损评分、脑含水量、脑梗死率显著增加(P<0.05),脑组织SIRT1、HIF-1α、VEGF、PSD-95、SYN蛋白表达量显著降低(P<0.05);与模型组比较,尼莫地平组、银杏二萜内酯葡胺注射液低、中、高组大鼠神经功能缺损评分、脑含水量、脑梗死率显著降低(P<0.05),脑组织SIRT1、HIF-1α、VEGF、PSD-95、SYN蛋白表达量显著升高(P<0.05),其中银杏二萜内酯葡胺注射液中、高组依次优于尼莫地平组(P<0.05)。结论银杏二萜内酯葡胺注射液可对抗局灶性脑缺血,改善大鼠神经功能,可能与促进SIRT1/HIF-1α/VEGF信号通路激活及脑缺血后突触可塑性形成有关。

Objective To investigate the effects of Ginkgo biloba diterpene lactone glumine injection on the silent information regulator 2 related enzyme 1/hypoxia-inducible factor 1α/vascular endothelial growth factor(SIRT1/HIF-1α/VEGF)signal pathway and synaptic plasticity in rats with focal cerebral ischemia.Methods The SD rats were randomly divided into three groups:sham operation group(equal amount of saline),model group(equal amount of saline),nimodipine group(16.2 mg·kg^(-1)),low(1.3 mg·kg^(-1)),medium(2.6 mg·kg^(-1)),high(5.2 mg·kg^(-1))Ginkgo biloba diterpene lactone glumine injection groups,the middle cerebral artery occlusion(MCAO)was used in the model group,nimodipine group and low,medium and high Ginkgo biloba diterpene lactone glumine injection groups,while in sham operation group,only common carotid artery,internal carotid artery and external carotid artery were separated.The intervention was started 24 hours after operation,once a day for 7 days.The neurological deficit scores were evaluated 24 hours and 7 days after operation,brain water content and cerebral infarction rate were measured,and the expressions of postsynaptic density protein-95(PSD-95),synaptophysin(SYN),SIRT1,HIF-1αand VEGF proteins in the ischemic brain were measured by Western blot(WB).Results On the 7th day after operation,compared with the sham operation group,the neurological deficit score,brain water content and cerebral infarction rate in the model group increased significantly(P<0.05).The expressions of SIRT1,HIF-1α,VEGF,PSD-95 and SYN proteins in brain decreased significantly(P<0.05).Compared with the model group,the neurological deficit score,brain water content and cerebral infarction rate of nimodipine group and low,medium and high Ginkgo biloba diterpene lactone glumine injection groups were significantly reduced(P<0.05),the expressions of SIRT1,HIF-1α,VEGF,PSD-95 and SYN proteins in brain tissue increased significantly(P<0.05),and the medium and high Ginkgo biloba diterpene lactone glumine injection groups were better than nimodipine group(P<0.05).Conclusion Ginkgo biloba diterpene lactone glumine injection can antagonize focal cerebral ischemia and improve nerve function in rats,which may be related to the activation of SIRT1/HIF-1α/VEGF signal pathway and the formation of synaptic plasticity after cerebral ischemia.