低氧脑水肿大鼠脑组织VEGF和AQPs基因及蛋白表达的变化

目的：探讨低氧脑水肿时血管内皮细胞生长因子（VEGF）、水通道蛋白（AQP1和AQP4）基因和蛋白表达变化,为阐明急性低氧对脑组织的损伤及低氧脑水肿的发病机制提供实验依据。方法：Wistar大鼠随机分为4个组：常氧对照组（Control）、低氧暴露4 000 m组（4 000 m）、低氧暴露6 000 m组（6 000 m）和低氧暴露8 000 m组（8 000 m）,低氧组于低压舱中模拟相应海拔高度持续暴露8 h建立低氧脑水肿模型。用干-湿重法测定脑组织水含量,常规光镜观察脑组织形态学的改变;用RT-PCR法和免疫组化法检测低氧脑水肿时大鼠脑组织VEGF、AQP1和AQP4mRNA和蛋白表达的变化。结果：①干-湿重法测定表明,低氧（≥6 000 m）暴露后,大鼠脑组织水含量明显增加（P〈0.01）。②常规光镜检测结果表明,低氧暴露4 000 m时大鼠脑神经细胞、血管内皮细胞和星形胶质细胞足突轻度肿胀,组织中出现漏出液;低氧暴露6 000 m时脑血管内皮细胞和星形胶质细胞足突肿胀加重,血管与组织间隙扩大,组织中漏出液增多;低氧暴露8 000m时脑血管内皮细胞和星形胶质细胞足突重度肿胀,血管与组织间隙进一步扩大,组织中漏出液明显增多。③低氧脑水肿时,VEGF、AQP1、AQP4mRNA表达水平增高,AQP1在内皮细胞异常表达,内皮细胞VEGF和AQP1、星形胶质细胞足突AQP4蛋白质表达水平增高。结论：低氧脑水肿时,VEGF、AQP1和AQP4表达和分布的变化可能是引起血脑屏障损伤、导致低氧脑水肿的发病机制之一。     

大鼠脑缺血再灌注时水通道蛋白4表达与血脑屏障通透性变化

目的:研究大鼠脑缺血/再灌注时脑组织中水通道蛋4(AQP4)表达与脑水肿、血脑屏障通透性间关系。方法:采用大鼠大脑中动脉线栓缺血模型,免疫组化法、蛋白印迹法测定AQP4表达,干湿重法测定脑水含量以评价脑水肿,伊文氏蓝(EB)法测定血脑屏障通透性。结果:脑缺血后再灌注4～6h,AQP4表达上调,至12h上调显著,48～72h达高峰。脑水含量、EB含量均与此趋势相一致,且AQP4表达与脑水含量、EB含量呈显著正相关(P0.05)。结论:AQP4表达参与了缺血性脑水肿的产生,且与BBB通透性改变呈正相关。     

脑水肿时紧密连接蛋白occludin及AQP4的表达变化

目的:采用枕大池内注入脂多糖(lipopolysaccharides,LPS)的方法建立大鼠脑水肿模型,观察脑组织病理形态学变化,脑组织含水量(brain water content,BWC),血脑屏障(blood brain barrier,BBB)的紧密连接蛋白Occludin和水通道蛋白-4(aquaporin 4,AQP4)表达水平的动态变化,研究AQP4及Occludin与脑水肿形成的关系,及其可能的作用机制,为临床脑水肿的治疗提供理论依据。方法:选用Wistar健康成年大鼠,随机分为正常对照组,生理盐水组和脂多糖组,后两组的观察时间点选定于造模后3 h、6h、12 h、24 h、72 h。采用经皮穿刺枕大池内注入脂多糖的方法制备脑水肿动物模型,正常对照组、生理盐水组及脂多糖组分别于各时间点进行开颅取脑,测定脑组织含水量,通过HE染色法观察脑组织的病理形态学变化,应用Western blot方法检测occludin的表达变化。应用RT-PCR技术测定脑组织内AQP4mRNA的表达变化。结果:生理盐水组各时间点中有少量AQP4mRNA及occludin蛋白的表达,与正常对照组之间无显著性差异;脂多糖组在造模后3 hAQP4的mRNA表达开始增加,6-12 h达高峰,此后明显下降,随后表达开始减弱,24-72 h表达显著低于生理盐水组;occludin蛋白表达下降出现于造模后3 h,12-24 h下降更明显,72 h表达开始升高。结论:枕大池内注入脂多糖(LPS)所建立脑水肿模型中,脑组织含水量及血脑屏障通透性增加,病理学特点是血管源性脑水肿出现早且持久,后期伴有细胞毒性脑水肿的改变。AQP4早期表达增强是胶质细胞的适应性反应,与血脑屏障的破坏有关,促进了血管源性脑水肿的发生。后期AQP4表达减弱是机体内在防御机制的表现,同时又促进细胞毒性脑水肿的形成。occludin在脑组织中表达量随脑水肿的加重而降低,即与脑水肿的程度呈负相关,目前认为这与脑水肿时内皮细胞通透性增加,血脑屏障的通透性改变,导致occludin的表达下调有关,促进了血管源性脑水肿的发生。针对以上特点,我们可以进一步研究调控AQP4及occludin表达的药物,从而减轻脑损伤后脑水肿的程度,为脑水肿的治疗提供新的临床策略。     

水通道蛋白4在脑缺血后脑水肿中的作用

脑缺血是由于动脉阻塞或灌注不足导致大脑局部血流减少无法满足代谢需求产生的功能障碍。脑水肿是脑组织间或细胞内液体过度积聚的病理现象,是脑缺血后较为严重的并发症,将会导致颅内压升高,脑组织受压而神经功能受损,甚至死亡。水通道蛋白(aquaporin)是一类分布在细胞膜上的蛋白质家族,目前已发现有13种亚型,主要调节细胞内外水平衡且参与细胞迁移和信号传导等多个生理病理过程。水通道蛋白4(aquaporin-4,AQP4)主要分布在中枢神经系统中星形胶质细胞的终足上,在细胞毒性水肿和血管源性水肿的形成和消除中起双重作用,与脑缺血后脑水肿有密切关系。机体通过转录过程及翻译后修饰等多个水平调节AQP4的表达协调其功能。本文回顾了目前AQP4在脑缺血后作用的最新进展,力图为治疗脑卒中后脑水肿提供新的研究方向。     

脑出血后脑组织中水通道蛋白4的定位分布变化

目的观察脑出血(intracerebral hemorrhage,ICH)后大鼠脑组织中水通道蛋白4(aquaporin 4,AQP4)的定位分布变化,以探讨AQP4在出血性脑水肿发生发展中的作用。方法 SD雄性大鼠随机分为假手术(sham)组和ICH组(ICH后1d、3d、7d),采用自体血注入法建立大鼠ICH动物模型,干湿重法检测脑水含量变化,透射电镜检测组织结构病理变化,免疫荧光双标记检测AQP4的定位分布变化。结果 ICH后1d、3d出血侧脑组织明显水肿,ICH后1d血肿周围组织结构破坏最为明显,可见毛细血管内皮细胞肿胀及血管周围间隙增宽等改变;免疫荧光结果显示,ICH后脑组织中,AQP4在血肿周围组织、外胶质界膜、内胶质界膜等与水转运密切相关的极性表达部位,其免疫反应发生变化;而在穹窿下器、齿状回等AQP4的非极性表达部位,AQP4的免疫反应无明显变化。结论结果表明,ICH后病理改变主要影响AQP4的极性表达非极性表达则不受影响。由此提示,AQP4极性表达变化可能促进出血性脑水肿的发展。     

AQP-4在几种常见类型脑水肿中的表达及其作用

脑水肿是指各种原因导致的脑组织水含量增多,可导致脑容积增大、颅内压增高,脑水肿发病机制复杂,是多种颅脑疾病如脑静脉血栓形成、脑缺血、脑出血、脑组织创伤等的主要病理生理改变之一,其形成严重影响疾病预后,是颅脑疾病中致残、致死的主要原因。水通道蛋白(Aquaporin,缩写为AQP)是一个具有高度选择性通透水的膜通道蛋白家族,包括200多个家族成员,其蛋白质分子结构中有一狭窄的亲水性孔道,通过该孔道水分子从水位势能高的一侧迅速扩散到势能低的一侧,而其它的物质则不能通过;AQP-4是脑内含量最多的水通道蛋白,最近研究表明AQP-4参与多种颅脑疾病的脑水肿的形成及消退。本文就AQP-4在几种常见类型脑水肿中的表达及作用进行综述。     

不同浓度中药怀牛膝加黄芪煎液对重型颅脑损伤大鼠脑组织含水量及AQP4表达的影响

目的观察低、中、高不同浓度中药怀牛膝加黄芪煎液对重型颅脑损伤大鼠脑组织含水量及水通道蛋白4(AQP4)表达的影响,探讨其治疗重型脑损伤性脑水肿最佳用药浓度及机制。方法将SD大鼠65只随机分为假手术组(5只),模型组(15只),低浓度怀牛膝加黄芪组(A组)15只,中浓度怀牛膝加黄芪组(B组)15只,高浓度怀牛膝加黄芪组(C组)15只,采用改良后Feency’s方法建立大鼠重型颅脑损伤模型。分别在1、3、7天3个时间点每组各取5只大鼠测定脑组织含水量,HE染色观察脑组织变化情况,并采用免疫组化方法检测脑组织AQP4的表达。结果模型组大鼠重型颅脑损伤后各时间点脑组织含水量、损伤灶周围AQP4的表达均高于假手术组(P0.05),HE染色观察发现模型组的脑组织肿胀水肿明显;A、B组各时间点脑组织含水量、AQP4表达水平与模型组相比较无明显降低(P0.05),HE染色观察发现与模型组基本一致;C组各时间点脑组织含水量、AQP4表达水平均较模型组降低(P0.05),HE染色观察发现与模型组比较,脑组织水肿情况有所改善。结论 C组改善重型颅脑损伤后引起的脑水肿效果最明显,其作用机制可能与减少AQP4在损伤脑组织中的表达、减轻脑细胞损害有关。     

水通道蛋白的生理功能 ——水通道基因敲除小鼠表型研究进展

水通道蛋白 (aquaporin, AQP) 是一族细胞膜上选择性高效转运水分子的特异孔道. 自从 Agre 等于 1992 年从红细胞膜发现第一个水通道蛋白 AQP1以来,有关水通道蛋白结构与功能的研究取得了迅速的、系列性的进展 . 已报道的哺乳动物 AQP 家族已有 11 个在蛋白质序列上有同源性成员 (AQP0~AQP10). AQP 在体内各系统组织中广泛表达,除了在与体液分泌和吸收密切相关的多种上皮和内皮细胞高表达外,在一些与体液转运无明显关系的组织细胞如红细胞、白细胞、脂肪细胞和骨骼肌细胞等处也有表达,提示 AQP 可能在多种器官生理和病理中发挥重要作用. 基因打靶技术是研究特定基因在体内生理功能的有力手段. 目前 AQP1、3、4、5 基因敲除和 AQP2 基因点突变的基因敲入小鼠模型 ( 模拟人类常染色体隐性遗传尿崩症 ) 已成功建立并广泛用于表型研究,在 AQP 水通道蛋白生理功能方面获得许多重要进展.     

脑外伤后ERK信号通路调节AQP4及其锚定蛋白DG的表达

脑外伤是青年人最主要的致死与致残疾病。脑水肿是脑外伤的严重并发症,其形成与脑内最主要的水通道蛋白4（aquaporin4, AQP4）关系密切。AQP4对水的转运与其在星形胶质细胞胞膜上的极性分布有关。肌营养不良-肌萎缩蛋白复合物（dystrophin-dystroglycan complex, DDC）可能与AQP4的锚定及极性分布有关。肌萎缩蛋白（dystroglycan, DG）是该复合物的核心成员,但其对AQP4锚定及极性表达的作用目前并不清楚。脑外伤后,AQP4的表达改变是否与DG有关,其二者表达变化的调控机制均不清楚。为了揭示以上科学问题,为临床治疗脑外伤后脑水肿提供理论依据,分别进行在体、离体及离体干扰实验。研究发现脑外伤后,AQP4、α-DG、β-DG的表达,于6 h增至峰值,后逐渐减弱,于24 h降至最低,48 h再次表达上调。在此过程中,其表达变化规律虽基本一致,但确实存在不一致的现象。排除其他因素干扰,在星形胶质细胞划伤后,DG与AQP4及p-ERK的表达改变完全一致;抑制及激活ERK信号通路后,分别导致DG与AQP4的表达下调及上调。以上结果证实,脑外伤后,DG参与AQP4在星形胶质细胞的锚定,但并非AQP4极性表达的专属锚定蛋白质;机械损伤后,早期ERK信号通路激活,并上调DG及AQP4的表达。     

小鼠隐球菌性脑膜炎模型AQP4与脑水肿关系的实验研究

目的 探讨隐球菌感染中枢神经系小鼠模型AQP4与脑水肿的关系.方法 尾静脉接种隐球菌构建小鼠中枢神经系感染模型,随机分为实验组和对照组,免疫抑制后实验组小鼠尾静脉注射隐球菌菌悬液,对照组注射等量生理盐水.两组均采用Western blotting技术于6h、12h、24 h、48 h、72 h动态检测小鼠脑组织中AQP4蛋白表达变化.结果 小鼠隐球菌中枢神经系统感染后,脑组织中AQP4蛋白表达24 h开始上升,48 h达峰值,在24h和48 h与对照组比较,实验组的标准化AQP4蛋白表达水平显著增加,与对照组差异有统计学意义(P＜0.05).结论 AQP4对隐球菌中枢神经系统感染所致脑水肿具有保护性作用.     

Expression of aquaporin-4 in human supratentorial meningiomas with peritumoral brain edema and correlation of VEGF with edema formation

Peritumoral brain edema is a common complication of meningiomas. It is believed that vascular endothelial growth factor (VEGF), as an angiogenic factor, plays a vital role in edema formation. Aquaporin-4 (AQP4) is a small integral membrane protein that regulates water in the normal brain. However, the expression of AQP4 and its relationship to VEGF in edematous meningiomas are not well known. We studied tumor specimens of 59 human supratentorial meningiomas. Western blot analysis was used to detect the expression of AQP4, and double-labeling immunofluorescence histochemical staining was performed to determine the relationship between AQP4 and VEGF. The AQP4 expression was significantly higher in the edema group, in which the protein level was correlated with the extent of edema. Greater VEGF expression was also observed in the edema group, and a relationship between AQP4 and VEGF was found. We conclude that AQP4 is involved in peritumoral brain edema formation in meningiomas and is also closely related to the expression of VEGF.     

Protection of Vascular Endothelial Growth Factor to Brain Edema Following Intracerebral Hemorrhage and Its Involved Mechanisms: Effect of Aquaporin-4

Vascular endothelial growth factor (VEGF) has protective effects on many neurological diseases. However, whether VEGF acts on brain edema following intracerebral hemorrhage (ICH) is largely unknown. Our previous study has shown aquaporin-4 (AQP4) plays an important role in brain edema elimination following ICH. Meanwhile, there is close relationship between VEGF and AQP4. In this study, we aimed to test effects of VEGF on brain edema following ICH and examine whether they were AQP4 dependent. Recombinant human VEGF165 (rhVEGF165) was injected intracerebroventricularly 1 d after ICH induced by microinjecting autologous whole blood into striatum. We detected perihemotomal AQP4 protein expression, then examined the effects of rhVEGF165 on perihemotomal brain edema at 1 d, 3 d, and 7 d after injection in wild type (AQP4^+/+) and AQP4 knock-out (AQP4^−/−) mice. Furthermore, we assessed the possible signal transduction pathways activated by VEGF to regulate AQP4 expression via astrocyte cultures. We found perihemotomal AQP4 protein expression was highly increased by rhVEGF165. RhVEGF165 alleviated perihemotomal brain edema in AQP4^+/+ mice at each time point, but had no effect on AQP4^−/− mice. Perihemotomal EB extravasation was increased by rhVEGF165 in AQP4^−/− mice, but not AQP4^+/+ mice. RhVEGF165 reduced neurological deficits and increased Nissl’s staining cells surrounding hemotoma in both types of mice and these effects were related to AQP4. RhVEGF165 up-regulated phospharylation of C-Jun amino-terminal kinase (p-JNK) and extracellular signal-regulated kinase (p-ERK) and AQP4 protein in cultured astrocytes. The latter was inhibited by JNK and ERK inhibitors. In conclusion, VEGF reduces neurological deficits, brain edema, and neuronal death surrounding hemotoma but has no influence on BBB permeability. These effects are closely related to AQP4 up-regulation, possibly through activating JNK and ERK pathways. The current study may present new insights to treatment of brain edema following ICH.     

Minocycline improves the functional recovery after traumatic brain injury via inhibition of aquaporin-4

Traumatic brain injury (TBI) is one of the main concerns worldwide as there is still no comprehensive therapeutic intervention. Astrocytic water channel aquaporin-4 (AQP-4) system is closely related to the brain edema, water transport at blood-brain barrier (BBB) and astrocyte function in the central nervous system (CNS). Minocycline, a broad-spectrum semisynthetic tetracycline antibiotic, has shown anti-inflammation, anti-apoptotic, vascular protection and neuroprotective effects on TBI models. Here, we tried to further explore the underlying mechanism of minocycline treatment for TBI, especially the relationship of minocycline and AQP4 during TBI treatment. In present study, we observed that minocycline efficaciously reduces the elevation of AQP4 in TBI mice. Furthermore, minocycline significantly reduced neuronal apoptosis, ameliorated brain edema and BBB disruption after TBI. In addition, the expressions of tight junction protein and astrocyte morphology alteration were optimized by minocycline administration. Similar results were found after treating with TGN-020 (an inhibitor of AQP4) in TBI mice. Moreover, these effects were reversed by cyanamide (CYA) treatment, which notably upregulated AQP4 expression level in vivo. In primary cultured astrocytes, small-interfering RNA (siRNA) AQP4 treatment prevented glutamate-induced astrocyte swelling. To sum up, our study suggests that minocycline improves the functional recovery of TBI through reducing AQP4 level to optimize BBB integrity and astrocyte function, and highlights that the AQP4 may be an important therapeutic target during minocycline treating for TBI.     

胆红素脑病SD乳鼠模型中脑水通道蛋白-4表达发生变化

神经细胞水肿是胆红素脑病（bilirubin encephalopathy,BE）发生发展过程中的重要病理变化。水通道蛋白-4（aquaporin-4,AQP4）的表达及分布异常与多种疾病所致细胞毒性脑水肿的发生发展具有密切联系。但胆红素脑病中AQP4的表达变化规律及其在病理进展中的作用尚不清楚。采用7日龄SD大鼠小脑延髓池注射胆红素溶液的方法,建立新生大鼠胆红素脑病模型。胆红素脑病模型根据胆红素作用时间的不同,分为12 h、24 h、48 h、72 h和7 d组。采用HE及尼氏染色,检测各新生大鼠脑组织的病理改变;应用透射电镜(TEM),检测胆红素作用24 h后,鼠脑组织超微结构的变化;应用免疫荧光及Western 印迹,检测 AQP4在脑组织中的表达变化。通过上述实验,以探讨AQP4的表达变化与胆红素所致脑损伤的关系。HE及尼氏染色结果显示,随着胆红素沉积时间的延长,神经细胞逐渐肿胀,细胞间隙增大,尼氏小体数量逐渐减少;电镜结果显示,胆红素脑病24 h后神经细胞线粒体出现肿胀;免疫荧光染色显示,24 h组AQP4的表达范围明显增加,其后表达范围逐渐减少,表达强度也随之减弱;Western 印迹结果显示,AQP4表达在不同时间点呈现先增高后降低的趋势,在24 h达到峰值（24 h组1.38 ± 0.11 vs 对照组0.87 ± 0.21, P＜0.05）,在之后的各时间点上,AQP4的表达呈现下降趋势,而72 h组与7 d组AQP4表达均低于48 h组（P＜0.05）,基本恢复到对照组的表达水平（P＞0.05）。上述结果提示,胆红素脑病中胆红素的毒性作用将引起AQP4表达量的改变,AQP4的表达变化与胆红素脑病中细胞毒性脑水肿的发生相关,并且可能在胆红素脑病脑损伤的进展中发挥作用。     

胆红素脑病SD乳鼠模型中脑水通道蛋白-4表达发生变化

神经细胞水肿是胆红素脑病（bilirubin encephalopathy,BE）发生发展过程中的重要病理变化。水通道蛋白-4（aquaporin-4,AQP4）的表达及分布异常与多种疾病所致细胞毒性脑水肿的发生发展具有密切联系。但胆红素脑病中AQP4的表达变化规律及其在病理进展中的作用尚不清楚。采用7日龄SD大鼠小脑延髓池注射胆红素溶液的方法,建立新生大鼠胆红素脑病模型。胆红素脑病模型根据胆红素作用时间的不同,分为12 h、24 h、48 h、72 h和7 d组。采用HE及尼氏染色,检测各新生大鼠脑组织的病理改变;应用透射电镜(TEM),检测胆红素作用24 h后,鼠脑组织超微结构的变化;应用免疫荧光及Western 印迹,检测 AQP4在脑组织中的表达变化。通过上述实验,以探讨AQP4的表达变化与胆红素所致脑损伤的关系。HE及尼氏染色结果显示,随着胆红素沉积时间的延长,神经细胞逐渐肿胀,细胞间隙增大,尼氏小体数量逐渐减少;电镜结果显示,胆红素脑病24 h后神经细胞线粒体出现肿胀;免疫荧光染色显示,24 h组AQP4的表达范围明显增加,其后表达范围逐渐减少,表达强度也随之减弱;Western 印迹结果显示,AQP4表达在不同时间点呈现先增高后降低的趋势,在24 h达到峰值（24 h组1.38 ± 0.11 vs 对照组0.87 ± 0.21, P＜0.05）,在之后的各时间点上,AQP4的表达呈现下降趋势,而72 h组与7 d组AQP4表达均低于48 h组（P＜0.05）,基本恢复到对照组的表达水平（P＞0.05）。上述结果提示,胆红素脑病中胆红素的毒性作用将引起AQP4表达量的改变,AQP4的表达变化与胆红素脑病中细胞毒性脑水肿的发生相关,并且可能在胆红素脑病脑损伤的进展中发挥作用。     

ALDH2 Protects Against Ischemic Stroke in Rats by Facilitating 4-HNE Clearance and AQP4 Down-Regulation

Aldehyde dehydrogenase 2 (ALDH2) is a new therapeutic target in the central nervous system. However, the association between ALDH2 and brain edema following ischemic stroke (IS) remains unclear. The present study was investigated to whether active ALDH2 can attenuate brain edema by using a rat model of IS, with the aim of clarifying the underlying mechanisms involved. Rats were administered the ALDH2 agonist Alda-1, vehicle or the ALDH2 inhibitor cyanamide (CYA) 15 min prior to a 1.5 h middle cerebral artery occlusion (MCAO) surgery. The effects of ALDH2 were subsequently investigated 24 h after reperfusion by evaluating neurological function, infarct sizes, brain edema volumes, 4-hydroxy-2-nonenal (4-HNE) levels, and aquaporin 4 (AQP4) protein expression. The results demonstrated that increasing ALDH2 activity significantly improved neurological deficits, reduced infarct sizes, and attenuated brain edema after MCAO. Alda-1 administration led to decreased 4-HNE levels and inhibited AQP4 protein expression in the peri-infarct section of the brain. Whereas, CYA administration increased 4-HNE levels, AQP4 expression, and simultaneously aggravated brain edema following MCAO. In conclusion, increasing ALDH2 activity can improve brain edema, infarct volumes, and reduce neurological impairment in a rat IS model. The therapeutic benefits of ALDH2 are related to 4-HNE clearance and AQP4 down-regulation.     

Expression of Aquaporin 4 and Breakdown of the Blood-Brain Barrier after Hypoglycemia-Induced Brain Edema in Rats

Background

Hypoglycemia-induced brain edema is a severe clinical event that often results in death. The mechanisms by which hypoglycemia induces brain edema are unclear.

Methods

In a hypoglycemic injury model established in adult rats, brain edema was verified by measuring brain water content and visualizing water accumulation using hematoxylin and eosin staining. Temporal expression of aquaporin 4 (AQP4) and the integrity of the blood-brain barrier (BBB) were evaluated. We assessed the distribution and expression of AQP4 following glucose deprivation in astrocyte cultures.

Results

Brain edema was induced immediately after severe hypoglycemia but continued to progress even after recovery from hypoglycemia. Upregulation of AQP4 expression and moderate breakdown of the BBB were observed 24 h after recovery. In vitro, significant redistribution of AQP4 to the plasma membrane was induced following 6 h glucose deprivation.

Conclusion

Hypoglycemia-induced brain edema is caused by cytotoxic and vasogenic factors. Changes in AQP4 location and expression may play a protective role in edema resolution.     

Conserved aquaporin 4 levels associated with reduction of brain edema are mediated by estrogen in the ischemic brain after experimental stroke

Aquaporin 4 (AQP4), the most abundant water channel protein in the brain, is involved in brain edema induced by ischemic insults. To evaluate whether the neuroprotective effects of estrogen are associated with AQP4 expression and edema formation, changes in AQP levels and ischemic edema were examined in the brains of male and female mice subjected to transient middle cerebral artery occlusion. Infarct volume and edema formation were markedly less in females than in males. AQP4 expression in the ischemic cortex of females was relatively well preserved, whereas it was significantly decreased in males. These effects disappeared in ovariectomized females but were reversed by estrogen replacement. Furthermore, AQP4 expression was decreased with increased brain edema in females treated with ICI182,780, an estrogen receptor antagonist. These findings suggest that the estrogen effect on the reduction of ischemic brain edema is associated with the preserved level of AQP4 that is partly mediated by estrogen receptors.