Sinz E H, Kochanek P M, Dixon C E, Clark R S, Carcillo J A, Schiding J K, Chen M, Wisniewski S R, Carlos T M, Williams D, DeKosky S T, Watkins S C, Marion D W, Billiar T R
Department of Anesthesiology and Critical Care Medicine, Safar Center for Resuscitation Research, University of Pittsburgh, Pennsylvania 15260, USA.
J Clin Invest. 1999 Sep;104(5):647-56. doi: 10.1172/JCI6670.
Nitric oxide (NO) derived from the inducible isoform of NO synthase (iNOS) is an inflammatory product implicated both in secondary damage and in recovery from brain injury. To address the role of iNOS in experimental traumatic brain injury (TBI), we used 2 paradigms in 2 species. In a model of controlled cortical impact (CCI) with secondary hypoxemia, rats were treated with vehicle or with 1 of 2 iNOS inhibitors (aminoguanidine and L-N-iminoethyl-lysine), administered by Alzet pump for 5 days and 1. 5 days after injury, respectively. In a model of CCI, knockout mice lacking the iNOS gene (iNOS(-/-)) were compared with wild-type (iNOS(+/+)) mice. Functional outcome (motor and cognitive) during the first 20 days after injury, and histopathology at 21 days, were assessed in both studies. Treatment of rats with either of the iNOS inhibitors after TBI significantly exacerbated deficits in cognitive performance, as assessed by Morris water maze (MWM) and increased neuron loss in vulnerable regions (CA3 and CA1) of hippocampus. Uninjured iNOS(+/+) and iNOS(-/-) mice performed equally well in both motor and cognitive tasks. However, after TBI, iNOS(-/-) mice showed markedly worse performance in the MWM task than iNOS(+/+) mice. A beneficial role for iNOS in TBI is supported.
一氧化氮合酶（iNOS）诱导型异构体产生的一氧化氮（NO）是一种炎症产物，与脑损伤的继发性损伤和恢复均有关联。为了探讨iNOS在实验性创伤性脑损伤（TBI）中的作用，我们在两个物种中使用了两种范例。在伴有继发性低氧血症的控制性皮质撞击（CCI）模型中，大鼠分别在损伤后5天和1.5天通过Alzet泵接受载体或两种iNOS抑制剂（氨基胍和L-N-亚氨基乙基赖氨酸）中的一种治疗。在CCI模型中，将缺乏iNOS基因的敲除小鼠（iNOS(-/-)）与野生型（iNOS(+/+)）小鼠进行比较。在两项研究中均评估了损伤后前20天的功能结局（运动和认知）以及21天时的组织病理学。TBI后用任何一种iNOS抑制剂治疗大鼠，均显著加剧了认知功能障碍，这通过莫里斯水迷宫（MWM）评估得出，并且增加了海马易损区域（CA3和CA1）的神经元损失。未受伤的iNOS(+/+)和iNOS(-/-)小鼠在运动和认知任务中的表现同样良好。然而，TBI后，iNOS(-/-)小鼠在MWM任务中的表现明显比iNOS(+/+)小鼠差。这支持了iNOS在TBI中具有有益作用的观点。
