摘要
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.
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.
基金
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
