New insights into water transport and edema in the central nervous system from phenotype analysis of aquaporin-4 null mice
New insights into water transport and edema in the central nervous system from phenotype analysis of aquaporin-4 null mice
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DOI：
10.1016/j.neuroscience.2004.06.088
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发表时间：
2004-01-01
期刊：
影响因子：
3.3
通讯作者：
Verkman, AS
中科院分区：
文献类型：
--
作者：
Manley, GT;Binder, DK;Verkman, AS
水通道蛋白4(Aquaporin-4，AQP4)是中枢神经系统的主要水通道。它在整个大脑和脊髓的液体-组织屏障(血-脑和脑-脑脊液屏障)上的表达表明，在正常和病理条件下，它在水的运输中发挥了作用。缺乏AQP4的转基因小鼠的表型研究已经为AQP4在脑水平衡和神经信号转导中的作用提供了证据。原代培养的AQP4缺失小鼠星形胶质细胞与野生型星形胶质细胞相比，渗透水通透性显著降低，表明AQP4是这些细胞的主要水通道。AQP4基因缺失的小鼠在水中毒和局灶性脑缺血后减少了脑肿胀并改善了神经预后，确立了AQP4在细胞毒性(细胞)脑水肿发展中的作用。相反，在冷冻损伤和脑肿瘤引起的血管源性(液体泄漏)水肿模型中，AQP4缺失的小鼠的脑肿胀和临床结果更差，可能是由于依赖AQP4的脑水清除受损。AQP4基因缺失的小鼠对化学惊厥的反应也显著降低了声学脑干反应电位，显著提高了惊厥阈值，提示AQP4参与了神经信号转导的调节。因此，AQP4功能的药理调节可能为治疗中风、肿瘤相关性水肿、癫痫、创伤性脑损伤以及其他与脑水平衡改变相关的中枢神经系统疾病提供新的治疗策略。(C)2004年IBRO。爱思唯尔有限公司出版。保留所有权利。
Aquaporin-4 (AQP4) is the major water channel in the CNS. Its expression at fluid-tissue barriers (blood-brain and brain-cerebrospinal fluid barriers) throughout the brain and spinal cord suggests a role in water transport under normal and pathological conditions. Phenotype studies of transgenic mice lacking AQP4 have provided evidence for a role of AQP4 in cerebral water balance and neural signal transduction. Primary cultures of astrocytes from AQP4-null mice have greatly reduced osmotic water permeability compared with wild-type astrocytes, indicating that AQP4 is the principal water channel in these cells. AQP4-null mice have reduced brain swelling and improved neurological outcome following water intoxication and focal cerebral ischemia, establishing a role of AQP4 in the development of cytotoxic (cellular) cerebral edema. In contrast, brain swelling and clinical outcome are worse in AQP4-null mice in models of vasogenic (fluid leak) edema caused by freeze-injury and brain tumor, probably due to impaired AQP4-dependent brain water clearance. AQP4-null mice also have markedly reduced acoustic brainstem response potentials and significantly increased seizure threshold in response to chemical convulsants, implicating AQP4 in modulation of neural signal transduction. Pharmacological modulation of AQP4 function may thus provide a novel therapeutic strategy for the treatment of stroke, tumor-associated edema, epilepsy, traumatic brain injury, and other disorders of the CNS associated with altered brain water balance. (C) 2004 IBRO. Published by Elsevier Ltd. All rights reserved.