[1]邓华江,张双,明扬,等.环孢菌素A通过PI3K-Akt通路保护小鼠脑缺血再灌注后血脑屏障损伤[J].陆军军医大学学报(原第三军医大学学报),2016,38(01):32-37.
 Deng Huajiang,Zhang Shuang,Ming Yang,et al.Cyclosporine A repairs blood-brain barrier damage in mice after cerebral ischemia-reperfusion injury via PI3K-Akt pathway[J].J Amry Med Univ (J Third Mil Med Univ),2016,38(01):32-37.
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陆军军医大学学报(原第三军医大学学报)[ISSN:1000-5404/CN:51-1095/R]

卷:
38卷
期数:
2016年第01期
页码:
32-37
栏目:
基础医学
出版日期:
2016-01-15

文章信息/Info

Title:
Cyclosporine A repairs blood-brain barrier damage in mice after cerebral ischemia-reperfusion injury via PI3K-Akt pathway
作者:
邓华江张双明扬刘洛同万伟峰葛红飞谭亮陈礼刚冯华
泸州医学院附属医院神经外科;第三军医大学西南医院神经外科
Author(s):
Deng Huajiang Zhang Shuang Ming Yang Liu Luotong Wan Weifeng Ge Hongfei Tan Liang Chen Ligang Feng Hua

Department of Neurosurgery, Affiliated Hospital of Luzhou Medical College, Luzhou, Sichuan Province, 646000; Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China

关键词:
脑缺血再灌注损伤环孢菌素A血脑屏障
Keywords:
cerebral ischemia-reperfusion cyclosporin A blood-brain barrier
分类号:
R743.31; R969; R979.5
文献标志码:
A
摘要:

目的      探讨环孢菌素A(cyclosporine A, CsA)对小鼠脑缺血再灌注后血脑屏障的影响及其可能机制。      方法        通过线栓法对C57BL/6J及载脂蛋白E基因敲除(ApoE-/-)小鼠建立大脑中动脉栓塞(middle cerebral artery occlusion, MCAO)模型,用不同剂量(10、20 mg/kg)CsA进行干预,并将两种小鼠各自分为5组:假手术组(Sham)、手术组(I/R)、溶剂组(Vehicle)、小剂量组(10 mg/kg CsA)及大剂量组(20 mg/kg CsA)。观察小鼠脑缺血再灌注后神经功能评分、梗死灶体积、脑组织水含量及伊文思蓝漏出量的变化情况,并用Western blot检测各组p-Akt及Claudin-5蛋白表达量的变化。      结果      ①神经功能评分结果显示:MCAO后小鼠出现严重的神经功能障碍,经CsA干预后其损伤情况明显缓解,且大剂量组优于小剂量组(P<0.05);②小鼠在脑缺血再灌注后表现出现严重的脑水肿、脑梗死及伊文思蓝渗漏,且各组ApoE-/-小鼠表现得比C57小鼠更为明显(P<0.05),而CsA能缓解这些症状,且大剂量组效果明显优于小剂量组(P<0.05);③Western blot检测结果显示:ApoE-/-小鼠脑组织中p-Akt蛋白表达量高于C57小鼠,而Claudin-5相对较低(P<0.05)。经MCAO处理后各组小鼠均出现p-Akt蛋白表达明显增高从而引起Claudin-5减少(P<0.05),CsA干预后,该效应出现逆转,且大剂量组的效果明显优于小剂量组(P<0.05)。      结论      CsA可保护脑缺血再灌注后血脑屏障的损伤,从而起到改善预后的作用,其机制与PI3K/Akt信号通路有关,而ApoE-/-可通过该途径加重脑梗死。

Abstract:

Objective      To determine the effect of cyclosporine A (CsA) on blood-brain barrier after cerebral ischemia-reperfusion (I/R) injury in mice and investigate its possible mechanism.       Methods      Middle cerebral artery occlusion (MCAO) model were established by Longa’s method in C57 BL/6J mice and apolipoprotein E knockout (ApoE-/-) mice. Then the C57BL/6J mice and  ApoE-/- mice were assigned into 5 groups, that is, sham operation group (n=5), I/R group (n=14), vehicle group (n=14) , low- and high- dose CsA intervention groups (10 and 20 mg/kg, given intraperitoneally in 15 min, and 24 and 48 h after model establishment, n=14). After neurological function was evaluated, the mice were sacrificed in 1, 3, 5 and 7 d after surgery, and the brain tissues were harvested for infarct volume, brain water content, and the permeability of blood-brain barrier (Evans blue leakage). Western blotting was used to detect the expression levels of p-Akt and Claudin-5.       Results       (1) Neurological function evaluation showed that MCAO resulted in severe neurological dysfunction in the mice, but CsA intervention obviously attenuated the injury, with the high-dose group superior to the low-dose group (P<0.05). (2) Cerebral I/R injury induced severe cerebral edema, cerebral infarction and reduced leakage of blood-brain barrier, and the ApoE-/- mice were injured more heavily than the C57 mice (P<0.05). However, CsA alleviated the symptoms, and the effects were more significant in the high- than low-dose intervention group (P<0.05). (3) Western blot results showed that the protein level of p-Akt was higher, while that of Claudin-5 was lower in the brain tissue of normal ApoE-/- mice than normal C57BL/6J mice (P<0.05). After MCAO, the expression of p-Akt was significantly increased and then Claudin-5 was decreased (P<0.05). CsA inhibited the process, and the high-dose group had greater effect than the low-dose group (P<0.05).       Conclusion      CsA repairs the blood-brain barrier damage induced by I/R injury, and then improves the prognosis, which is related with PI3K/Akt signal pathway. Besides, ApoE-/- mice have more severe cerebral infarction through this signal pathway.

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更新日期/Last Update: 2016-01-06