The Cyclooxygenase-2 Inhibitor NS-398 Ameliorates Ischemic Brain Injury in Wild-Type Mice but not in Mice with Deletion of the Inducible Nitric Oxide Synthase Gene
The Cyclooxygenase-2 Inhibitor NS-398 Ameliorates Ischemic Brain Injury in Wild-Type Mice but not in Mice with Deletion of the Inducible Nitric Oxide Synthase Gene
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DOI：
10.1097/00004647-199911000-00005
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发表时间：
1999-11
影响因子：
6.3
通讯作者：
M. Nagayama;K. Niwa;T. Nagayama;M. E. Ross;C. Iadecola
中科院分区：
文献类型：
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作者：
M. Nagayama;K. Niwa;T. Nagayama;M. E. Ross;C. Iadecola
作者研究了木兰素合成酶环氧合酶-2（考克斯-2）在局灶性脑缺血机制中的作用及其与诱导型一氧化氮合酶（iNOS）的相互作用。通过永久性阻塞小鼠大脑中动脉（MCA）造成局灶性脑缺血。96小时后，通过计算机辅助面积测量法在硫堇染色的脑切片中测量脑体积。从MCA闭塞后6小时开始，每天两次给予高选择性考克斯-2抑制剂NS 398（20 mg/kg;腹腔内），可减少C57 BL/6（-23%）和129/SVeV小鼠（-21%）的总梗死体积，并改善MCA闭塞产生的运动缺陷（P 0.05）。相反，在MCA闭塞后5分钟给予神经元NOS抑制剂7-NI（50 mg/kg;腹腔内），可使iNOS −/−小鼠的新皮质梗死体积减少20%（P 0.05）。这些数据表明，考克斯-2反应产物，在小鼠和大鼠，有助于缺血性脑损伤。然而，NS 398未能减少iNOS缺失小鼠的梗死体积，这表明iNOS衍生的NO是考克斯-2的有害作用发生所必需的。因此，考克斯-2反应产物可能是iNOS衍生的NO促进缺血性脑损伤的另一种机制。
The authors investigated the role of the prostaglandin-synthesizing enzyme cyclooxygenase-2 (COX-2) in the mechanisms of focal cerebral ischemia and its interaction with inducible nitric oxide synthase (iNOS). Focal cerebral ischemia was produced by permanent occlusion of the middle cerebral artery (MCA) in mice. Infarct volume was measured 96 hours later by computer-assisted planimetry in thionin-stained brain sections. The highly selective COX-2 inhibitor NS398 (20 mg/kg; intraperitoneally), administered twice a day starting 6 hours after MCA occlusion, reduced total infarct volume in C57BL/6 (–23%) and 129/SVeV mice (–21%), and ameliorated the motor deficits produced by MCA occlusion (P .05). In contrast, the neuronal NOS inhibitor 7-NI (50 mg/kg; intraperitoneally), administered once 5 minutes after MCA occlusion, reduced neocortical infarct volume by 20% in iNOS −/− mice (P .05). The data suggest that COX-2 reaction products, in mouse as in rat, contribute to ischemic brain injury. However, the failure of NS398 to reduce infarct volume in iNOS null mice suggests that iNOS-derived NO is required for the deleterious effects of COX-2 to occur. Thus, COX-2 reaction products may be another mechanism by which iNOS-derived NO contributes to ischemic brain injury.