Enhancing expression of Nrf2-driven genes protects the blood-brain barrier after brain injury
Enhancing expression of Nrf2-driven genes protects the blood-brain barrier after brain injury
复制标题
DOI：
10.1523/jneurosci.1683-07.2007
复制
发表时间：
2007-09-19
影响因子：
5.3
通讯作者：
Dash, Pramod K.
中科院分区：
文献类型：
--
作者：
Zhao, Jing;Moore, Anthony N.;Dash, Pramod K.
血脑屏障（BBB）的完整性对于正常的脑功能至关重要，并且其损害有助于许多CNS疾病和损伤的病理生理学。使用啮齿动物模型的脑损伤，本研究探讨BBB中断的病理生理。免疫印迹和免疫组织化学分析表明，脑损伤导致毛细血管内皮细胞和紧密连接蛋白，血脑屏障的两个关键组成部分的损失。转录因子NF-E2相关因子-2（Nrf 2）的激活萝卜硫素，一种天然存在的化合物，在十字花科蔬菜中的高水平，显着增加了内源性细胞保护基因的表达，在脑组织和微血管中的实时PCR分析表明。损伤后给予莱菔硫烷减少了内皮细胞标志物和紧密连接蛋白的丢失，并保留了BBB功能。这些保护作用依赖于Nrf 2的活性。用含有Nrf 2结合位点的诱饵寡核苷酸预处理的受伤大鼠和缺乏Nrf 2基因的小鼠，没有从萝卜硫素给药中获益。这些发现表明Nrf 2激活分子在改善损伤后神经血管单位的功能方面具有潜在的治疗用途。
The integrity of the blood-brain barrier (BBB) is critical for normal brain function, and its compromise contributes to the pathophysiology of a number of CNS diseases and injuries. Using a rodent model of brain injury, the present study examines the pathophysiology of BBB disruption. Western blot and immunohistochemical analyses indicate that brain injury causes a loss of capillary endothelial cells and tight junction proteins, two critical components of the BBB. Activation of the transcription factor NF-E2-related factor-2 (Nrf2) by sulforaphane, a naturally occurring compound present in high levels in cruciferous vegetables, significantly increased the expression of endogenous cytoprotective genes in brain tissue and microvessels as indicated by real-time PCR analysis. Postinjury administration of sulforaphane reduced the loss of endothelial cell markers and tight junction proteins and preserved BBB function. These protective effects were dependent on the activity of Nrf2. Injured rats pretreated with decoy oligonucleotides containing the binding site of Nrf2, and mice lacking the nrf2 gene, did not benefit from sulforaphane administration. These findings indicate a potential therapeutic usefulness for Nrf2-activating molecules to improve the function of the neurovascular unit after injury.