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 (4): 653-663.doi: 10.4103/1673-5374.230291

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

Exendin-4抑制高原脑水肿：保护血脑屏障的完整性

  

  • 收稿日期:2018-02-28 出版日期:2018-04-15 发布日期:2018-04-15
  • 基金资助:

    中国国家重大科技研发项目（2016YFC1101500），中国国家自然科学基金项目（11672332, 11102235, 31200809, 81772018），天津市重点科技支持基金项目（17YFZCSY00620），天津市自然科学基金项目（15JCYBJC28600, 17JCZDJC35400）

Exendin-4 inhibits high-altitude cerebral edema by protecting against neurobiological dysfunction

Zhong-Lei Sun1, 2,, Xian-Feng Jiang1, 3, Yuan-Chi Cheng4, Ying-Fu Liu5, Kai Yang6, Shuang-Long Zhu3, Xian-Bin Kong7, Yue Tu1 ,
Ke-Feng Bian5, Zhen-Lin Liu1, Xu-Yi Chen1   

  1. 1 Affiliated Hospital of Logistics University of Chinese People’s Armed Police Forces, Institute of Traumatic Brain Trauma and Neurological of CAPF, Neurotrauma Repair Key Laboratory of Tianjin, Tianjin, China
    2 Jinzhou Medical University, Jinzhou, Liaoning Province, China
    3 Tianjin Medical University, Tianjin, China
    4 Central Hospital of Fengxian District of Shanghai, Shanghai, China
    5 Logistics University of People’s Armed Police Force, Tianjin, China
    6 The No. 2 Hospital of Nanjing, Nanjing, Jiangsu Province, China
    7 Tianjin University of Traditional Chinese Medicine, Tianjin, China
  • Received:2018-02-28 Online:2018-04-15 Published:2018-04-15
  • Contact: Xu-Yi Chen, M.D., Ph.D. or Zhen-Lin Liu, M.D., Ph.D.,chenxuyi1979@126.com or wjzhenlin817@163.com.
  • Supported by:

    This work was supported by the National Key Research and Development Plan of China, No. 2016YFC1101500; the National Natural Science Foundation of China, No. 11672332, 11102235, 31200809, 81772018; the Key Science and Technology Support Foundation of Tianjin City of China, No. 17YFZCSY00620; the Natural Science Foundation of Tianjin City of China, No. 15JCYBJC28600, 17JCZDJC35400.

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摘要：

研究显示Exendin-4具有抗炎和抗氧化的作用，其是否也对高原脑水肿具有抗炎和抗氧化的作用，目前尚未见报道，故设计该实验。首先以模拟6000和7000m海拔高度的氧气环境以不同干预时间建立高原脑水肿模型，比较大鼠脑组织含水量、伊文思蓝渗漏水平以及大脑组织中超氧化物歧化酶、谷胱甘肽和丙二醛水平，发现模拟7000m海拔高度的氧气环境缺氧72h最适合建立高原脑水肿模型。然后对模拟7000m海拔高度的氧气环境缺氧72h的小鼠进行2，10，100μg Exendin-4腹腔注射的预处理，以旷场测试和悬尾试验测试检测行为能力，以常规方法血液成分变化，以苏木精-伊红染色检测脑组织病理变化，以大脑干湿重比例检测大脑含水量，以伊文思蓝检测血脑屏障完整性，以ELISA测量脑组织中的超氧化物歧化酶、谷胱甘肽和丙二醛、白细胞介素6，肿瘤坏死因子α和cAMP表达水平，以Western blot分析检测脑组织中occludin，ZO-1，SOCS-3，血管内皮生长因子，EPAC1，NF-κB，以及水通道蛋白4的表达水平。结果显示Ex-4预处理能降低高原脑水肿大鼠大脑含水量，抑制炎症和氧化应激状态，减轻脑组织损伤，维持血脑屏障完整性，有效改善高原脑水肿大鼠运动能力。从而表明Ex-4具有治疗高原脑水肿的潜力。

orcid:0000-0002-6293-1340(Xu-Yi Chen)

 

关键词: 高原脑水肿, exendin-4, 环磷酸腺苷, EPAC1, SOCS-3, 血管内皮生长因子, 缺氧, 炎症, 氧化应激

Abstract:

The anti-inflammatory and antioxidant effects of exendin-4 (Ex-4) have been reported previously. However, whether (Ex-4) has anti-inflammatory and antioxidant effects on high-altitude cerebral edema (HACE) remains poorly understood. In this study, two rat models of HACE were established by placing rats in a hypoxic environment with a simulated altitude of either 6000- or 7000-m above sea level (MASL)for 72 hours. An altitude of 7000 MASL with 72-hours of hypoxia was found to be the optimized experimental paradigm for establishing HACE models. Then, in rats where a model of HACE was established by introducing them to a 7000 MASL environment with 72-hours of hypoxia treatment, 2, 10 and, 100 μg of Ex-4 was intraperitoneally administrated. The open field test and tail suspension test were used to test animal behavior. Routine methods were used to detect change in inflammatory cells. Hematoxylin-eosin staining was performed to determine pathological changes to brain tissue. Wet/dry weight ratios were used to measure brain water content. Evans blue leakage was used to determine blood-brain barrier integrity. Enzyme-linked immunosorbent assay (ELISA) was performed to measure markers of inflammation and oxidative stress including superoxide dismutase, glutathione, and malonaldehyde values, as well as interleukin-6,tumor necrosis factor-alpha, cyclic adenosine monophosphate levels in the brain tissue. Western blot analysis was performed to determine the levels of occludin, ZO-1, SOCS-3, vascular endothelial growth factor, EPAC1, nuclear factor-kappa B, and aquaporin-4. Our results demonstrate that Ex-4 preconditioning decreased brain water content, inhibited inflammation and oxidative stress, alleviated brain tissue injury, maintain blood-brain barrier integrity, and effectively improved motor function in rat models of HACE. These findings suggest that Ex-4 exhibits therapeutic potential in the treatment of HACE.

Key words: high-altitude cerebral edema, exendin-4, cyclic adenosine monophosphate, EPAC1, suppressor of cytokine signaling 3, vascular endothelial growth factor, hypoxia, inflammation, oxidative stress