Department of Anesthesiology, The Affiliated Xiangya Hospital of Central South University, Changsha, 410078 Hunan Province, China.
Neurochem Res. 2013 Apr;38(4):686-93. doi: 10.1007/s11064-012-0953-4. Epub 2013 Jan 17.
Parecoxib, a novel COX-2 inhibitor, functions as a neuroprotective agent and rescues neurons from cerebral ischemic reperfusion injury-induced apoptosis. However, the molecular mechanisms underlying parecoxib neuroprotection remain to be elucidated. There is growing evidence that endoplasmic reticulum (ER) stress plays an important role in neuronal death caused by brain ischemia. However, very little is known about the role of parecoxib in mediating pathophysiological reactions to ER stress induced by ischemic reperfusion injury. Therefore, in the present study, we investigated whether delayed administration of parecoxib attenuates brain damage via suppressing ER stress-induced cell death. Adult male Sprague-Dawley rats were administered parecoxib (10 or 30 mg kg(-1), IP) or isotonic saline twice a day starting 24 h after middle cerebral artery occlusion (MCAO) for three consecutive days. The expressions of glucose-regulated protein 78 (GRP78) and oxygen-regulated protein 150 (ORP150) and C/EBP-homologous protein (CHOP) and forkhead box protein O 1 (Foxo1) in cytoplasmic and nuclear fraction were determined by Western blotting. The levels of caspase-12 expression were checked by immunohistochemistry analysis, served as a marker for ER stress-induced apoptosis. Parecoxib significantly suppressed cerebral ischemic injury-induced nuclear translocation of CHOP and Foxo1 and attenuated the immunoreactivity of caspase-12 in ischemic penumbra. Furthermore, the protective effect of delayed administration of parecoxib was accompanied by an increased GRP78 and ORP150 expression. Therefore, our study suggested that elevation of GRP78 and ORP150, and suppression of CHOP and Foxo1 nuclear translocation may contribute to parecoxib-mediated neuroprotection during ER stress responses.
帕瑞昔布，一种新型 COX-2 抑制剂，具有神经保护作用，可以挽救神经元免受脑缺血再灌注损伤诱导的凋亡。然而，帕瑞昔布神经保护的分子机制仍有待阐明。越来越多的证据表明，内质网（ER）应激在脑缺血引起的神经元死亡中起重要作用。然而，对于帕瑞昔布在介导缺血再灌注损伤引起的 ER 应激的病理生理反应中的作用知之甚少。因此，在本研究中，我们研究了延迟给予帕瑞昔布是否通过抑制 ER 应激诱导的细胞死亡来减轻脑损伤。成年雄性 Sprague-Dawley 大鼠在大脑中动脉闭塞（MCAO）后 24 小时开始每天两次给予帕瑞昔布（10 或 30mg/kg，IP）或等渗盐水，连续 3 天。通过 Western blot 测定细胞质和核部分中葡萄糖调节蛋白 78（GRP78）和氧调节蛋白 150（ORP150）以及 C/EBP 同源蛋白（CHOP）和叉头框蛋白 O1（Foxo1）的表达。通过免疫组织化学分析检查 caspase-12 表达水平，作为 ER 应激诱导凋亡的标志物。帕瑞昔布显著抑制了缺血半影区 CHOP 和 Foxo1 的核转位，并减弱了缺血半影区 caspase-12 的免疫反应性。此外，延迟给予帕瑞昔布的保护作用伴随着 GRP78 和 ORP150 表达的增加。因此，我们的研究表明，GRP78 和 ORP150 的升高以及 CHOP 和 Foxo1 核转位的抑制可能有助于帕瑞昔布在 ER 应激反应中介导的神经保护作用。
