Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an 710032, China.
Brain Res. 2013 Jun 23;1517:114-21. doi: 10.1016/j.brainres.2013.04.024. Epub 2013 Apr 19.
Hypoxia-inducible factor 1α (HIF-1α) is a master regulator of cellular adaptation to hypoxia and has been proposed as a potent therapeutic target for cerebral ischemia. However, research on the expression and effects of HIF-1α in subarachnoid hemorrhage (SAH) is limited. The aim of the present study was to investigate the expression of HIF-1α in the hippocampus and its possible protective effect against hippocampal apoptosis and cognitive dysfunction in a rat model of SAH. Seventy-two Sprague-Dawley (SD) rats were randomly divided into the sham group, the SAH+vehicle group, and the SAH+YC-1 group. Immunohistochemical staining and western blotting analyses revealed that the expression of HIF-1α and its downstream effectors, vascular endothelial growth factor (VEGF), erythropoietin (EPO), and glucose transporter 1 (GLUT1), increased in the hippocampus 48h after the induction of SAH. YC-1 blocked this upregulation. The number of active caspase-3-positive cells and the expression of active caspase-3 in the hippocampus significantly increased in the YC-1 group relative to the vehicle group. A cell death assay further revealed that DNA fragmentation was significantly increased at 48h in the YC-1 group compared with the vehicle group. In Morris water maze (MWM) tests, the YC-1 group showed increased escape latency times and distances as well as reduced time spent and distance traveled in the target quadrant. These results indicate that hippocampal apoptosis increased and cognitive function deteriorated when HIF-1α was inhibited, suggesting that HIF-1α has a neuroprotective effect in SAH and may represent an effective therapeutic target.
缺氧诱导因子 1α（HIF-1α）是细胞对缺氧适应的主要调节因子，已被提出作为脑缺血的有效治疗靶点。然而，蛛网膜下腔出血（SAH）中 HIF-1α 的表达和作用研究有限。本研究旨在探讨 HIF-1α 在大鼠 SAH 模型中海马中的表达及其对海马细胞凋亡和认知功能障碍的可能保护作用。72 只 Sprague-Dawley（SD）大鼠随机分为假手术组、SAH+vehicle 组和 SAH+YC-1 组。免疫组织化学染色和 Western blot 分析显示，SAH 诱导后 48 小时，海马中 HIF-1α 及其下游效应物血管内皮生长因子（VEGF）、促红细胞生成素（EPO）和葡萄糖转运蛋白 1（GLUT1）的表达增加。YC-1 阻断了这种上调。与 vehicle 组相比，YC-1 组海马中活性 caspase-3 阳性细胞数量和活性 caspase-3 的表达显著增加。细胞死亡测定进一步显示，与 vehicle 组相比，YC-1 组在 48 小时时 DNA 片段化明显增加。在 Morris 水迷宫（MWM）测试中，YC-1 组的逃避潜伏期时间和距离增加，在目标象限花费的时间和距离减少。这些结果表明，当 HIF-1α 被抑制时，海马细胞凋亡增加，认知功能恶化，提示 HIF-1α 在 SAH 中具有神经保护作用，可能是一种有效的治疗靶点。
