Role of the Nrf2-ARE Pathway in Early Brain Injury After Experimental Subarachnoid Hemorrhage
Role of the Nrf2-ARE Pathway in Early Brain Injury After Experimental Subarachnoid Hemorrhage
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Nrf2-ARE通路在实验性蛛网膜下腔出血后早期脑损伤中的作用
DOI：
10.1002/jnr.22577
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发表时间：
2011-04-01
影响因子：
4.2
通讯作者：
Wang, Zhong
中科院分区：
文献类型：
--
作者：
Chen, Gang;Fang, Qi;Wang, Zhong
核因子红细胞2相关因子2和抗氧化反应元件（Nrf 2-ARE）通路是调节炎症和氧化损伤的关键调节因子，参与蛛网膜下腔出血（SAH）后早期脑损伤（EBI）的发病机制。已有研究表明Nrf 2-ARE通路在创伤性脑损伤、脑缺血和脑出血模型中发挥神经保护作用，但Nrf 2-ARE通路是否以及在何种程度上被SAH诱导尚不清楚，Nrf 2-ARE通路在SAH后EBI发展中的作用也不清楚。实验1旨在研究SAH早期皮层Nrf 2-ARE激活的时间过程。在实验2中，我们评估了莱菔硫烷（SUL;一种特异性Nrf 2激活剂）对SAH模型中Nrf 2-ARE通路的调节作用，并评估了SUL对SAH后EBI的影响。采用大鼠蛛网膜下腔出血模型，视交叉前池注入新鲜动脉血0.3ml，持续20秒。结果，Nrf 2及其靶基因产物血红素加氧酶-1（HO-1）在SAH后皮质中上调，并在SAH后24小时达到峰值。腹腔注射SUL后，在血液注射后48小时，在皮质中检测到Nrf 2-ARE相关因子如Nrf 2、HO-1、NAD（P）H：醌氧化还原酶1（NQO 1）和谷胱甘肽S-转移酶-α 1（GST-α 1）的表达升高。在SUL治疗组，早期脑损伤，如脑水肿，血脑屏障（BBB）的损害，皮质细胞凋亡，和运动障碍显着改善与车辆治疗的SAH大鼠相比。我们的研究结果表明，Nrf 2-ARE通路在SAH后的大脑中被激活，在EBI的发展中发挥了有益的作用，可能通过诱导抗氧化和解毒酶抑制脑氧化应激。(C)2011 Wiley-Liss，Inc.
The nuclear factor erythroid 2-related factor 2 and antioxidant-response element (Nrf2-ARE) pathway is a key regulator for modulating inflammation and oxidative damage, which are involved in the pathogenesis of early brain injury (EBI) after subarachnoid hemorrhage (SAH). Previous studies have demonstrated that Nrf2-ARE pathway play neural protective roles in traumatic brain injury, cerebral ischemia, and intracerebral hemorrhage models; however, it has not been investigated whether, and to what degree, the Nrf2-ARE pathway is induced by SAH, and the role of the Nrf2-ARE pathway in development of EBI following SAH remains unknown. Experiment 1 sought to investigate the time course of Nrf2-ARE activation in the cortex in the early stage of SAH. In experiment 2, we assessed the effect of sulforaphane (SUL; a specific Nrf2 activator) on regulation of the Nrf2-ARE pathway in the SAH model and evaluated the impact of SUL on EBI after SAH. The rat SAH model was used injection of 0.3 ml fresh arterial, nonheparinized blood into the prechiasmatic cistern over 20 sec. As a result, Nrf2 and its target gene product, heme oxygenase-1 (HO-1), were up-regulated in the cortex after SAH and peaked at 24 hr post-SAH. After intraperitoneal SUL administration, the elevated expression of Nrf2-ARE-related factors such as Nrf2, HO-1, NAD(P)H:quinone oxidoreductase 1 (NQO1), and glutathione S-transferase-alpha 1 (GST-alpha 1) was detected in the cortex at 48 hr following blood injection. In the SUL-treated group, early brain damage such as brain edema, blood brain barrier (BBB) impairment, cortical apoptosis, and motor deficits was significantly ameliorated compared with vehicle-treated SAH rats. Our results suggest that the Nrf2-ARE pathway is activated in the brain after SAH, playing a beneficial role in EBI development, possibly through inhibiting cerebral oxidative stress by inducing antioxidant and detoxifying enzymes. (C) 2011 Wiley-Liss, Inc.