Cernak Ibolja, O'Connor Christine, Vink Robert
Department of Neuroscience, Georgetown University, Washington DC, USA.
Exp Brain Res. 2002 Nov;147(2):193-9. doi: 10.1007/s00221-002-1245-z. Epub 2002 Oct 2.
Prostanoid synthesis is regulated by the enzyme cyclo-oxygenase (COX) that is present in at least two isoforms: COX-1, the constitutive form, and COX-2, the inducible form. Expression of COX-2 has recently been shown to be an important determinant of the cytotoxicity connected with inflammation following ischemic injury to the brain. The present study examines the temporal and spatial profiles of COX-2 expression following diffuse traumatic brain injury (TBI) in rats, and the effects of the COX-2 inhibitor nimesulide on cognitive and motor outcomes. Adult, male Sprague-Dawley rats were injured using the 2-meter impact acceleration model of diffuse TBI. At preselected time points after injury, animals were killed and the expression of COX-2 was measured in the hippocampus and parietal cortex by immunohistochemistry and Western blotting techniques. Effects of nimesulide (6 mg/kg daily over ten days) on cognitive and motor outcome was assessed in a separate group of animals using the Barnes circular maze and rotarod test, respectively. A highly significant up-regulation of COX-2 expression was found in the hippocampus as early as 3 h post-trauma and persisting for at least 12 days after TBI. In contrast, a slight but significant upregulation of COX-2 expression occurred in the cortex only at 3 days after trauma. Administration of the COX-2 inhibitor nimesulide resulted in a significant and substantial improvement in cognitive function compared to vehicle-treated controls, while motor deficits after injury was only improved at 24 h after injury. We conclude that COX-2 is involved in the development of functional deficits following diffuse TBI, particularly cognitive deficits, and that these can be improved by administration of COX-2 inhibitors.
前列腺素合成受环氧化酶（COX）调节，该酶至少有两种同工型：COX-1，即组成型；COX-2，即可诱导型。最近研究表明，COX-2的表达是脑缺血损伤后与炎症相关细胞毒性的重要决定因素。本研究检测大鼠弥漫性创伤性脑损伤（TBI）后COX-2表达的时空特征，以及COX-2抑制剂尼美舒利对认知和运动结果的影响。成年雄性Sprague-Dawley大鼠采用2米撞击加速模型造成弥漫性TBI损伤。在损伤后的预选时间点，处死动物，通过免疫组织化学和蛋白质印迹技术检测海马体和顶叶皮质中COX-2的表达。在另一组动物中，分别使用巴恩斯圆形迷宫和转棒试验评估尼美舒利（连续十天每天6 mg/kg）对认知和运动结果的影响。发现创伤后3小时海马体中COX-2表达即出现高度显著上调，并在TBI后持续至少12天。相比之下，皮质中COX-2表达仅在创伤后3天出现轻微但显著的上调。与给予赋形剂处理的对照组相比，给予COX-2抑制剂尼美舒利可显著且实质性地改善认知功能，而损伤后的运动功能缺陷仅在损伤后24小时有所改善。我们得出结论，COX-2参与弥漫性TBI后功能缺陷的发生，尤其是认知缺陷，给予COX-2抑制剂可改善这些缺陷。
