Wada K, Chatzipanteli K, Kraydieh S, Busto R, Dietrich W D
Department of Neurology, University of Miami School of Medicine, Florida 33101, USA.
Neurosurgery. 1998 Dec;43(6):1427-36. doi: 10.1097/00006123-199812000-00096.
We investigated the time course of inducible nitric oxide synthase (iNOS) enzymatic activity and immunocytochemical localization of iNOS expression after traumatic brain injury (TBI), as well as the possible role of iNOS in the pathogenesis of TBI.
Male Sprague-Dawley rats were anesthetized and underwent moderate parasagittal fluid-percussion brain injury. Rats were decapitated 5 minutes, 6 hours, 1 day, 3 days, 7 days, or 14 days later, and iNOS enzymatic activities were measured (n = 6-8). To determine whether nitric oxide produced by iNOS contributed to the histopathological consequences of TBI, inhibition of iNOS activity using aminoguanidine (intraperitoneal injections of 100 mg/kg aminoguanidine [n = 9] or vehicle [n = 8], twice each day) was conducted for 3 days.
Significantly elevated iNOS activity was detected at 3 days (276.8+/-72.3% of contralateral value, means +/- standard errors; P < 0.05), and the most robust increase occurred 7 days after TBI (608.0+/-127.0%, P < 0.01) in the injured parietal cerebral cortex. Immunostaining for iNOS and glial fibrillary acidic protein, at 3 and 7 days after TBI, revealed that the major cellular sources of iNOS expression were cortical Layer 1 astrocytes and macrophages within the subarachnoid space. Administration of aminoguanidine did not reduce contusion volume significantly; however, treatment reduced total cortical necrotic neuron counts (1367.6+/-210.3; P < 0.01, compared with vehicle, 2808.5+/-325.1).
These data indicate that iNOS is expressed after moderate parasagittal fluid-percussion brain injury, in a time-dependent manner, and that inhibition of iNOS synthesis improves histopathological outcomes. Thus, inhibition of iNOS activation may represent a potential therapeutic strategy for the treatment of TBI.
我们研究了创伤性脑损伤（TBI）后诱导型一氧化氮合酶（iNOS）酶活性的时间进程以及iNOS表达的免疫细胞化学定位，以及iNOS在TBI发病机制中的可能作用。
雄性Sprague-Dawley大鼠麻醉后接受中度矢状旁流体冲击性脑损伤。在损伤后5分钟、6小时、1天、3天、7天或14天断头，测量iNOS酶活性（n = 6 - 8）。为了确定iNOS产生的一氧化氮是否导致TBI的组织病理学后果，使用氨基胍（腹腔注射100 mg/kg氨基胍[n = 9]或赋形剂[n = 8]，每天两次）抑制iNOS活性，持续3天。
在损伤后3天检测到iNOS活性显著升高（对侧值的276.8±72.3%，均值±标准误；P < 0.05），最显著的升高发生在TBI后7天（608.0±127.0%，P < 0.01），在受伤的顶叶大脑皮层。TBI后3天和7天对iNOS和胶质纤维酸性蛋白进行免疫染色，结果显示iNOS表达的主要细胞来源是蛛网膜下腔内的皮质第1层星形胶质细胞和巨噬细胞。给予氨基胍并没有显著减少挫伤体积；然而，治疗减少了皮质坏死神经元总数（1367.6±210.3；与赋形剂组相比，P < 0.01，赋形剂组为2808.5±325.1）。
这些数据表明，在中度矢状旁流体冲击性脑损伤后，iNOS以时间依赖性方式表达，并且抑制iNOS合成可改善组织病理学结果。因此，抑制iNOS激活可能是治疗TBI的一种潜在治疗策略。
