Activation of cyclo-oxygenase-2 contributes to motor and cognitive dysfunction following diffuse traumatic brain injury in rats
Activation of cyclo-oxygenase-2 contributes to motor and cognitive dysfunction following diffuse traumatic brain injury in rats
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DOI：
10.1046/j.1440-1681.2001.03549.x
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发表时间：
2001-11-01
影响因子：
2.9
通讯作者：
Vink, R
中科院分区：
文献类型：
--
作者：
Cernak, I;O'Connor, C;Vink, R
1. 创伤后炎症可能在创伤性脑损伤后迟发性继发性脑损伤的发生发展中起重要作用。在创伤后炎症期间，花生四烯酸的代谢产物，即前列腺素（前列腺素和血栓素）被释放，并加剧损伤过程。前列腺素的合成受环加氧酶（COX）的调控，COX至少存在于两种同工型中，COX-1（本构型）和COX-2（诱导型）。在本研究中，我们研究了COX-2表达的时空分布，以及COX-2抑制剂尼美舒利对弥漫性创伤性脑损伤后大鼠运动和认知结果的影响。采用弥漫性颅脑损伤2 m冲击加速度模型对成年雄性Sprague-Dawley大鼠进行损伤。在损伤后预先选择的时间点处死动物，采用western blotting技术检测COX-2在大鼠皮质和海马中的表达。COX-2的表达在损伤后3天在皮质中增加，早在损伤后3小时在海马中增加，并持续至少12天。在损伤后30分钟和10天的创伤后神经系统评估期间，每天给予尼美舒利（6 mg/kg, i.p），与对照组（2%二甲亚砜稀释在等压生理盐水中）相比，认知缺陷有显著改善，通过巴恩斯环形迷宫评估。在创伤后的第1天和第2天，通过旋转测试评估，运动功能障碍也明显改善。这些结果提示COX-2参与弥漫性创伤性脑损伤后的认知和运动功能障碍。
1. Post-traumatic inflammation may play a significant role in the development of delayed secondary brain damage following traumatic brain injury.2. During post-traumatic inflammation, metabolic products of arachidonic acid, known as prostanoids (prostaglandins and thromboxanes) are released and aggravate the injury process. Prostanoid synthesis is regulated by the enzyme cyclo-oxygenase (COX), which is present in at least two isoforms, COX-1 (the constitutive form) and COX-2 (the inducible form).3. In the present study, we examine the temporal and spatial profiles of COX-2 expression and the effects of the COX-2 inhibitor nimesulide on motor and cognitive outcome following diffuse traumatic brain injury in rats.4. Adult male Sprague-Dawley rats were injured using the 2 m impact acceleration model of diffuse traumatic brain injury. At preselected time points after injury, animals were killed and the expression of COX-2 was measured in the cortex and hippocampus by western blotting techniques.5. Increased expression of COX-2 was found in the cortex at 3 days and in the hippocampus as early as 3 h postinjury and this persisted for at least 12 days.6. Administration of nimesulide (6 mg/kg, i.p.) at 30 min after injury and daily over a 10 day post-traumatic neurological assessment period resulted in a significant improvement compared with vehicle (2% dimethylsulphoxide diluted in isotonic saline)-treated controls in cognitive deficits, as assessed by the Barnes circular maze. There was also a significant improvement in motor dysfunction as assessed by the rotarod test on days 1 and 2 post-trauma compared with vehicle-treated controls.7. These results implicate the involvement of COX-2 in cognitive and motor dysfunction following diffuse traumatic brain injury.