中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2018, Vol. 13 ›› Issue (12): 2111-2118.doi: 10.4103/1673-5374.241461

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

脑缺血再灌注后5 h内给予2-(2-苯并呋喃基)-2-咪唑啉可保护大脑

  

  • 收稿日期:2018-08-10 出版日期:2018-12-15 发布日期:2018-12-15
  • 基金资助:

    中国国家自然科学基金项目（81571114，81771267），中国国家自然科学基金青年科学基金项目（81325007）；长江学者奖励计划项目（T2014251）；温州市科技项目（Y20120154，Y2014068），中国国家自然科学国际交流合作项目（81620108011）

2-(2-Benzofuranyl)-2-imidazoline treatment within 5 hours after cerebral ischemia/reperfusion protects the brain

Zheng Zhang1, 2, 3, Jin-Long Yang4, Lin-Lei Zhang1, Zhen-Zhen Chen5, Jia-Ou Chen1, Yun-Gang Cao1, Man Qu1, Xin-Da Lin1, Xun-Ming Ji3, 6, Zhao Han1   

  1. 1 Department of Neurology, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
    2 Department of Neurology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
    3 Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China
    4 Department of Neurology, Shan Xian Central Hospital, Heze, Shandong Province, China
    5 Department of Children Rehabilitation, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
    6 China-America Institute of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China
  • Received:2018-08-10 Online:2018-12-15 Published:2018-12-15
  • Contact: Xun-Ming Ji, MD, PhD, jixm@ccmu.edu.cn; Zhao Han, MD, wzhanzhao@aliyun.com.
  • Supported by:

    This study was supported by the National Natural Science Foundation of China, No. 81571114 and 81771267 (to ZH); the National Science Funds for Distinguished Youth Scholars of China, No. 81325007 (to XMJ); the Distinguished Professor of Cheung Kong Scholars Program in China, No. T2014251 (to XMJ); the Wenzhou Municipal Sci-Tec Bureau Programs in China, No. Y20120154 (to ZZ) and Y20140686 (to ZH); the Projects of International Cooperation and Exchanges National Natural Science Foundation of China, No. 81620108011 (to XMJ).

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摘要：

作者既往研究显示，在脑缺血后立即给予咪唑啉I2受体激动剂——2-(2-苯并呋喃基)-2-咪唑啉，可保护大脑免受缺血损伤。但是在临床上很难实现发病后立即给药，所以需探索2-(2-苯并呋喃基)-2-咪唑啉的治疗时间窗。实验对由温州医科大学提供的SD大鼠右侧大脑中动脉闭塞120min，分别于再灌注后0，1，3，5，7，9h尾静脉注射3mg/kg2-(2-苯并呋喃基)-2-咪唑啉。然后，以Longa法评价神经功能缺陷，以TTC染色检测脑梗死体积，以苏木精-伊红染色及透射电镜观察脑组织病理变化，以TUNEL染色检测损伤侧皮质中神经元的凋亡情况，以免疫组化染色检测脑组织中Bcl-2和Bax的表达。结果发现：（1）再灌注后5h内使用2-(2-苯并呋喃基)-2-咪唑啉干预可显著改善大鼠的神经功能；（2）再灌注后9h内给予2-(2-苯并呋喃基)-2-咪唑啉可减少大鼠脑梗死体积，并减少细胞凋亡；（3）不同再灌注时间进行2-(2-苯并呋喃基)-2-咪唑啉干预均能减轻大鼠缺血半暗带的病理损伤，减少凋亡神经元数量，但其中5h内给药时保护作用更为明显；（4）再灌注后5h内给予2-(2-苯并呋喃基)-2-咪唑啉可明显增加脑组织中Bcl-2的表达，同时降低BAX的表达；（5）结果表明在再灌注后5h内给予2-(2-苯并呋喃基)-2-咪唑啉具有明显有效的神经保护作用，且其作用可能是通过上调Bcl-2和下调BAX表达实现的。

orcid:0000-0003-0293-2744(Xun-Ming Ji)

 

关键词: 脑缺血/再灌注, 2-(2-苯并呋喃基)-2-咪唑啉, 神经保护, 时间窗, 细胞凋亡, Bcl-2, BAX, 神经再生

Abstract:

We previously demonstrated that administering 2-(2-benzofuranyl)-2-imidazolin (2-BFI), an imidazoline I2 receptor agonist, immediately after ischemia onset can protect the brain from ischemic insult. However, immediate administration after stroke is difficult to realize in the clinic. Thus, the therapeutic time window of 2-BFI should be determined. Sprague-Dawley rats provided by Wenzhou Medical University in China received right middle cerebral artery occlusion for 120 minutes, and were treated with 2-BFI (3 mg/kg) through the caudal vein at 0, 1, 3, 5, 7, and 9 hours after reperfusion. Neurological function was assessed using the Longa’s method. Infarct volume was measured by 2,3,5-triphenyltetrazolium chloride assay. Morphological changes in the cortical penumbra were observed by hematoxylin-eosin staining under transmission electron microscopy . The apoptosis levels in the ipsilateral cortex were examined with terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay. The protein expression of Bcl-2 and BAX was detected using immunohistochemistry. We found the following: Treatment with 2-BFI within 5 hours after reperfusion obviously improved neurological function. Administering 2-BFI within 9 hours after ischemia/reperfusion decreased infarct volume and alleviated apoptosis. 2-BFI administration at different time points after reperfusion alleviated the pathological damage of the ischemic penumbra and reduced the number of apoptotic neurons, but the protective effect was more obvious when administered within 5 hours. Administration of 2-BFI within 5 hours after reperfusion remarkably increased Bcl-2 expression and decreased BAX expression. To conclude, 2-BFI shows potent neuroprotective effects when administered within 5 hours after reperfusion, seemingly by up-regulating Bcl-2 and down-regulating BAX expression. The time window provided clinical potential for ischemic stroke by 2-BFI.

Key words: nerve regeneration, ischemia/reperfusion, 2-(2-benzofuranyl)-2-imidazoline, neuroprotection, time window, apoptosis, Bcl-2, BAX, neural regeneration