Neural Regeneration Research ›› 2018, Vol. 13 ›› Issue (4): 653-663.doi: 10.4103/1673-5374.230291

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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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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