水通道蛋白4通过加重脑水肿的严重程度，成为创伤性脑损伤的一个潜在药物靶点。
Aquaporin-4 is a potential drug target for traumatic brain injury via aggravating the severity of brain edema.
作者信息
Xiong Ao, Xiong Renping, Yu Jing, Liu Yijia, Liu Ke, Jin Ge, Xu Jianzhong, Yan Jun
机构信息
Department of Orthopaedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450042, China.
State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing 400042, China.
出版信息
Burns Trauma. 2021 Mar 15;9:tkaa050. doi: 10.1093/burnst/tkaa050. eCollection 2021 Jan.
BACKGROUND
Traumatic brain edema (TBE) is caused by a specific water channel mediated by membrane aquaporins. Aquaporin-4 (AQP4) plays an especially important role in this process, but the relationship between AQP4 and TBE remains unclear. The purpose of this study was to explore expression of AQP4 in the hippocampus after traumatic brain injury (TBI), as well as the effect of brain edema on skeletal protein and its function in hippocampal neurons.
METHODS
The adult male Wistar rats we divided into a sham group and a TBI group, the latter of which was further divided into 1, 3, 6, 12, 24 and 72 hours (h) and 15 days (d) post injury subgroups. A proper TBI model was established, and brain edema was assessed in each group by water content. We measured the abundance of various proteins, including hypoxia inducible factor-1α (HIF-1α), AQP4, microtubule-associated protein 2 (MAP2), tau-5 protein, phosphorylated level of TAU, synaptophysin, cyclic adenosine monophosphate response element binding protein (CREB), phosphorylated CREB and general control nonrepressed 2, in each group. Hippocampal neurons and spatial memory test were analyzed in different time points.
RESULTS
Compared with that in the sham group, the level of AQP4 in hippocampal neurons began to significantly increase at 1 h post TBI and then decreased at 15 d post TBI. During this time frame, AQP4 level peaked at 12 and 72 h, and these peaks were closely correlated with high brain water content. HIF-1α displayed a similar trend. Conversely, levels of MAP2 began to decrease at 1 h post TBI and then increase at 15 d post TBI. In addition, the most severe brain edema in rats was found at 24 h post TBI, with neuronal loss and hippocampal dendritic spine injury. Compared to those in the sham group, rats in the TBI groups had significantly prolonged latency and significantly shortened exploration time.
CONCLUSIONS
AQP4 level was closely correlated with severity of brain edema, and abnormal levels thereof aggravated such severity after TBI.
背景
创伤性脑水肿（TBE）由膜水通道蛋白介导的特定水通道引起。水通道蛋白4（AQP4）在此过程中发挥着尤为重要的作用，但AQP4与TBE之间的关系仍不清楚。本研究旨在探讨创伤性脑损伤（TBI）后海马中AQP4的表达，以及脑水肿对海马神经元骨架蛋白及其功能的影响。
方法
将成年雄性Wistar大鼠分为假手术组和TBI组，后者再进一步分为伤后1、3、6、12、24和72小时（h）以及15天（d）的亚组。建立合适的TBI模型，并通过含水量评估每组的脑水肿情况。我们测量了每组中各种蛋白质的丰度，包括缺氧诱导因子-1α（HIF-1α）、AQP4、微管相关蛋白2（MAP2）、tau-5蛋白、TAU的磷酸化水平、突触素、环磷酸腺苷反应元件结合蛋白（CREB）、磷酸化CREB和一般控制非抑制2。在不同时间点分析海马神经元和空间记忆测试。
结果
与假手术组相比，海马神经元中AQP4水平在TBI后1小时开始显著升高，然后在TBI后15天下降。在此时间范围内，AQP4水平在12和72小时达到峰值，这些峰值与高脑含水量密切相关。HIF-1α呈现类似趋势。相反，MAP2水平在TBI后1小时开始下降，然后在TBI后15天升高。此外，大鼠在TBI后24小时出现最严重的脑水肿，伴有神经元丢失和海马树突棘损伤。与假手术组相比，TBI组大鼠的潜伏期显著延长，探索时间显著缩短。
结论
AQP4水平与脑水肿严重程度密切相关，其异常水平在TBI后加重了脑水肿严重程度。
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