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整合素αvβ3抑制剂西仑吉肽在大鼠急性脑缺血中的作用机制

Efficiency of integrinαvβ3 inhibitor Cilengitide in acute cerebral ischemia in rats

摘要:

目的:探讨整合素αvβ3抑制剂西仑吉肽在大鼠急性脑缺血中对血脑屏障通透性、脑水肿、细胞凋亡的影响及其与血管内皮生长因子VEGF变化的关系。方法采用右侧大脑中动脉线栓法制作局灶性脑缺血再灌注模型MCAO,造模成功大鼠根据随机数字表法分为(1)治疗组A,尾静脉注射西仑吉肽100μg/kg (n=30);(2)治疗组B,尾静脉注射西仑吉肽200μg/kg (n=28);(3)假手术组,不置入线栓,尾静脉注射生理盐水(n=31);(4)对照组,尾静脉注射生理盐水(n=27)。各组均在梗死后1 h后治疗,2 h再灌注及24 h后处死。检测脑含水量、血脑屏障通透性、梗死面积、细胞凋亡、VEGF、P-Flk及Cleaved-Caspase-3等指标。结果治疗组A、治疗组B的脑含水量较对照组降低[(80.8±1.1)%比(84.8±1.4)%、(81.0±1.4)%比(84.8±1.4)%, P<0.05];治疗组A、治疗组B的EB含量较对照组降低[(9.2±1.1)μg/g 比(12.2±0.8)μg/g、(8.6±0.6)μg/g 比(12.2±0.8)μg/g,P<0.05];治疗组A、治疗组B的TUNEL阳性细胞数较对照组减少[(36±4)个比(69±6)个、(35±3)个比(69±6)个, P<0.05];治疗组A、治疗组B的梗死面积较对照组降低[(31.9±4.9) mm3比(43.0±2.2) mm3、(29.2±3.5) mm3比(43.0±2.2) mm3,P<0.05];与对照组比较,治疗组A、治疗组B的VEGF、P-Flk、Cleaved-Caspase-3等蛋白表达降低(P<0.05);治疗组A、治疗组B与假手术组比较,脑含水量、血脑屏障通透性、梗死面积及VEGF、P-Flk、Cleaved-Caspase-3蛋白表达及凋亡细胞数降低( P<0.05);治疗组A与治疗组B比较,脑含水量、血脑屏障通透性、梗死面积及VEGF、P-Flk、Cleaved-Caspase-3蛋白表达及凋亡细胞数差异无统计学意义( P>0.05)。结论整合素αvβ3靶向抑制剂西仑吉肽可降低MCAO模型血脑屏障通透性,减轻脑水肿及抑制细胞凋亡,其作用机制可能与抑制 VEGF 介导的生物效应有关,梗死后1 h 后给予西仑吉肽100μg/kg 及200μg/kg两个浓度治疗23 h的效应未见剂量依赖关系。

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abstracts:

Objective To explore the effect of the integrin αvβ3 inhibitor Cilengitide on the blood brain barrier ( BBB) permeability, brain edema, neuronal cell apoptosis and the relation with the vascular endothelial growth factor ( VEGF) expression in acute cerebral ischemia rats.Methods A rat focal cerebral ischemia/reperfusion model was established by middle cerebral artery occlusion.Rats with middle cerebral artery occlusion, in accordance with the random number table, were divided into four groups:(1) the rats in Cilengitide group A ( n =30 ) were treated with Cilengitide at a dose of 100 μg/kg; ( 2 ) the rats in Cilengitide group B (n=28) were treated with Cilengitide at a dose of 200 μg/kg; (3) the rats in sham group (n=31), without inserting thread into middle cerebral artery,were treated with normal saline; (4) the rats in control group ( n=27 ) were treated with normal saline.All rats were treated with Cilengitide or saline 1 hour after infarction, given reperfusion 2 hours after infarction and were sacrificed 22 hours after reperfusion.The brain-water content was measured by dry/wet weight method.The permeability of BBB was measured by quantifying Evans Blue.The infarction volume was measured by 2,3,5-tripheyl tetrazolium Chloride ( TTC ) staining.Expression level of VEGF, P-Flk, Cleaved-Caspase-3 was measured by&nbsp;immunohistochemistry and Western blot, respectively.The neuronal cell apoptosis was evaluated by terminal deoxynucleotidyl transferased UTP nick end labeling ( TUNEL) .Results Compared with Control group, treatment groups with cilengitide at the dose of 100 μg/kg and 200 μg/kg reduced brain-water content [(80.8 ±1.1)%vs (84.8 ±1.4)%,(81.0 ±1.4)%vs (84.8 ±1.4)%, P<0.05],reduced exudation of Evans blue[(9.2 ±1.1) μg/g vs (12.2 ±0.8) μg/g,(8.6 ±0.6) μg/g vs (12.2 ±0.8) g/g,P<0.05],reduced infarction volume[(31.9 ±4.9) mm3 vs(43.0 ±2.2) mm3,(29.2 ±3.5) mm3 vs(43.0 ± 2.2) mm3,P<0.05] ,reduced neuronal cell apoptosis [(36 ±4)vs(69 ±6)、(35 ±3)vs (69 ±6), P<0.05].Compared with sham group, Cilengitide group A and Cilengitide group B had lower brain-water content, permeability of BBB, infarction volume, expression level of VEGF, P-Flk, Cleaved-Caspase-3 and neuronal cell apoptosis (P<0.05).When Cilengitide group A was compared with Cilengitide group B, there were no significant differences in brain-water content, permeability of BBB, infarction volume, expression level of VEGF, P-Flk, Cleaved-Caspase-3 and neuronal cell apoptosis ( P >0.05 ) .Conclusion The integrinαvβ3 inhibitor Cilengitide improves outcomes in the MCAO model by preserving the blood-brain barrier, attenuating brain edema and inhibiting neuronal cell apoptosis, which may occur in a VEGF-and VEGF-receptor-dependent manner, with the same efficacy between Cilengitide 100 μg/kg and 200 μg/kg after 23 hours treatment.

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作者: 陆林清 [1] 方婷 [1] 周达 [1] 童晓欣 [1] 吴军 [1] 易黎 [1]
期刊: 《中华医学杂志》2016年7期 559-564页 MEDLINEISTICPKUCSCD
栏目名称: 基础研究
DOI: 10.3760/cma.j.issn.0376-2491.2016.07.015
发布时间: 2016-04-14
基金项目:
深圳市科技创新计划资助项目( JCYJ20140415162543033)@@@@Fund program Grants from Scientific and Technological Innovation Committee of Shenzhen
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