HIF-1α对大鼠创伤后认知功能障碍的影响研究  

Effect of HIF-1alpha on post-traumatic cognitive disorder in rats

作　　者：张启财 张赛 孙中磊 ZHANG Qicai;ZHANG Sai;SUN Zhonglei(Department of Neurology,Tianjin Medical University,Tianjin 300070,China)

机构地区：[1]天津医科大学,天津300070 [2]武警特色医学中心,天津300162 [3]枣庄矿业集团中心医院,山东枣庄277800

出　　处：《中风与神经疾病杂志》2019年第5期395-400,共6页Journal of Apoplexy and Nervous Diseases

基　　金：国家重点研究发展计划(2016YFC1101500)

摘　　要：目的提高低氧诱导因子-1α(hypoxia inducible factor-1α,HIF-1α)的水平对大鼠颅脑创伤(Traumatic Brain Injury,TBI)后认知功能障碍的影响及其机制初步探索。方法将大鼠随机分为3组:sham组、TBI组、脯氨酸羟化酶(Prolyl Hydroxylase,PHD)抑制剂组,TBI组和PHD抑制剂组均采用皮质撞击致伤法构建模型;TBI完成3d后每组大鼠随机取10只,取海马组织,采用Westernblot法检测HIF-1α及其下游蛋白表达水平,荧光原位末端标记法(TdT-mediated dUTP nick end labeling,TUNEL)检测神经细胞凋亡;1m后采用Morris水迷宫试验检测大鼠记忆功能,取海马组织,检测认知功能障碍相关蛋白。结果大鼠TBI术后3dTBI组与sham组相比HIF-1α、促血管内皮生长因子(Vascular endothelial growth factor,VEGF)、促红细胞生成素(erythropoietin,EPO)表达水平升高(P<0.01),差异具有统计学意义,PHD抑制剂组与TBI组相比HIF-1α、VEGF、EPO表达水平升高(P<0.01),差异具有统计学意义;大鼠TBI术后1mTBI组与sham组相比平均逃避潜伏期延长(P<0.01),目标象限停留时间与穿越平台次数减少(P<0.01),海马组织中淀粉样蛋白β1-42(β-amyloid peptide1-42,Aβ1-42)、tau含量明显升高(P<0.01),差异具有统计学意义;PHD抑制剂组与TBI组相比平均逃避潜伏期缩短(P<0.01),目标象限停留时间与穿越平台次数增加(P<0.01),海马组织中Aβ1-42、tau含量明显减少(P<0.01),差异具有统计学意义。结论提高HIF-1α的表达水平可明显改善大鼠神经功能预后,提高大鼠记忆水平,减少TBI大鼠的海马组织中Aβ1-42和tau的含量,减少大鼠TBI后认知功能障碍的发生,为TBI后认知功能障碍的治疗及预防提供一个新的靶点。Objective To explore the effect of changing the level of HIF-1alpha on cognitive impairment after traumatic brain injury(TBI) in rats and its mechanism.Methods Rats were randomly divided into three groups:sham group,TBI group,PHD inhibitor group,TBI group and PHD inhibitor group.Cortical impact injury was used to construct the model.Three days after completion of TBI,10 rats in each group were randomly selected,hippocampus tissue was taken,HIF-1α and its downstream protein levels were detected by Western blot,and neuronal apoptosis was detected by fluorescent TdT-mediated dUTP nick end labeling(TUNEL).Morris water maze test was performed one month later.The memory function of rats was measured,and the hippocampus was taken to detect dementia-related proteins.Results The expression levels of HIF-1α,Vascular Endothelial Growth Factor(VEGF),Erythropoietin(EPO) in TBI group were significantly higher than those in sham group 3 days after TBI(P<0.01).The expression levels of HIF-1a,vascular endothelial growth factor and EPO in Prolyl Hydroxylase(PHD) inhibitor group were significantly higher than those in TBI group(P<0.01).The average escape latency of TBI group was longer than that of sham group one month after TBI operation(P<0.01),the target quadrant residence time was less than that of traversing the platform(P<0.01),and the contents of amyloid protein beta-42(Aβ1-42) and tau in hippocampus tissue were significantly increased(P<0.01),the difference was significant between PHD inhibitor group and TBI group.Compared with the control group,the average escape latency was shortened(P<0.01),the target quadrant residence time and platform crossing times were increased(P<0.01),and the contents of Aβ 1-42 and tau in hippocampus were significantly decreased(P<0.01).Conclusion Increasing the expression level of HIF-1α can significantly improve the prognosis of neurological function,improve the memory level of rats,reduce the content of Aβ1-42 and tau in hippocampus tissue of TBI rats,reduce the incidence of dementia aft

关 键 词：颅脑创伤 低氧诱导因子-1Α 认知功能障碍 淀粉样蛋白β1-42 TAU 促血管内皮生长因子 促红细胞生成素 

分 类 号：R749.12[医药卫生—神经病学与精神病学]