Role of c-Jun N-terminal kinase in early brain injury after subarachnoid Hemorrhage
Role of c-Jun N-terminal kinase in early brain injury after subarachnoid Hemorrhage
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DOI：
10.1002/jnr.21281
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发表时间：
2007-05-15
影响因子：
4.2
通讯作者：
Zhang, John H.
中科院分区：
文献类型：
--
作者：
Yatsushige, Hiroshi;Ostrowski, Robert P.;Zhang, John H.
c-Jun氨基末端激酶（JNK）是蛛网膜下腔出血（SAH）后急性脑缺血和损伤性血液成分诱导产生的。我们假设抑制JNK可以防止SAH后早期脑损伤对神经血管单位的损害。将99只雄性SD大鼠（300-350 g）随机分为假手术组、SAH组和JNK抑制剂治疗组。SAH由血管内穿孔引起。JNK抑制剂SP 600125在SAH前1小时和SAH后6小时腹腔内给药。SAH后24小时，JNK和c-Jun磷酸化水平升高，出血脑组织中出现神经血管损伤的迹象，包括水通道蛋白（AQP）-1表达和脑含水量增加，基质金属蛋白酶（MMP）-9活性增强，血管胶原IV丢失，VEGF组织水平升高和伊文思蓝外渗。脑组织中caspase-3表达、TUNEL阳性细胞和凋亡形态学的出现与SAH后神经功能缺损相关。JNK抑制可阻止c-Jun磷酸化并抑制AQP 1、MMP-9、VEGF和caspase-3的激活，同时减少神经元损伤、保护血脑屏障、减轻脑肿胀并改善SAH后大鼠的神经功能缺损。这项研究证实了JNK抑制的多种有益作用，包括在SAH后早期脑损伤中保护神经血管单位。(c)2007 Wiley-Liss，Inc.
The c-Jun N-terminal kinase (JNK) is induced by cerebral ischemia and injurious blood components acutely after subarachnoid hemorrhage (SAH). We hypothesized that inhibition of JNK will prevent damage to the neurovascular unit in the early brain injury period after SAH. Ninety-nine male SD rats (300-350 g) were randomly assigned to sham, SAH, and SAH treated with JNK inhibitor groups. SAH was induced by endovascular perforation. The JNK inhibitor SP600125 was administered intraperitoneally at 1 hr before and 6 hr after SAH. At 24 hr after SAH, we observed increased phosphorylation of JNK and c-Jun. Signs of neurovascular damage were observed in the hemorrhagic brains; these included the increases of aquaporin (AQP)-1 expression and brain water content as well as enhanced matrix metalloproteinase (MMP)-9 activity, vascular collagen IV loss, increased VEGF tissue level, and Evans blue extravasation. The appearances of cleaved caspase-3 expression, TUNEL-positive cells, and apoptotic morphology in cerebral tissues were associated with neurological deficit after SAH. JNK inhibition prevented c-Jun phosphorylation and suppressed AQP1, MMP-9, VEGF, and caspase-3 activation, with concomitant diminution of neuronal injury, blood-brain barrier preservation, reduced brain swelling, and improved neurological deficit in rats after SAH. This study demonstrates a multitude of beneficial effects of JNK inhibition, including protection of the neurovascular unit in early brain injury after SAH. (c) 2007 Wiley-Liss, Inc.