Wada K, Chatzipanteli K, Busto R, Dietrich W D
Neurotrauma Research Center, Department of Neurological Surgery, University of Miami School of Medicine, Florida 33101, USA.
J Neurosurg. 1998 Nov;89(5):807-18. doi: 10.3171/jns.1998.89.5.0807.
Although nitric oxide (NO) has been shown to play an important role in the pathophysiological process of cerebral ischemia, its contribution to the pathogenesis of traumatic brain injury (TBI) remains to be clarified. The authors investigated alterations in constitutive nitric oxide synthase (NOS) activity after TBI and the histopathological response to pharmacological manipulations of NO.
Male Sprague-Dawley rats underwent moderate (1.7-2.2 atm) parasagittal fluid-percussion brain injury. Constitutive NOS activity significantly increased within the ipsilateral parietal cerebral cortex, which is the site of histopathological vulnerability, 5 minutes after TBI occurred (234.5+/-60.2% of contralateral value [mean+/-standard error of the mean ¿SEM¿], p < 0.05), returned to control values by 30 minutes (114.1+/-17.4%), and was reduced at 1 day after TBI (50.5+/-13.1%, p < 0.01). The reduction in constitutive NOS activity remained for up to 7 days after TBI (31.8+/-6.0% at 3 days, p < 0.05; 20.1+/-12.7% at 7 days, p < 0.01). Pretreatment with 3-bromo-7-nitroindazole (7-NI) (25 mg/kg), a relatively specific inhibitor of neuronal NOS, significantly decreased contusion volume (1.27+/-0.17 mm3 [mean+/-SEM], p < 0.05) compared with that of control (2.52+/-0.35 mm3). However, posttreatment with 7-NI or pre- or posttreatment with nitro-L-arginine-methyl ester (L-NAME) (15 mg/kg), a nonspecific inhibitor of NOS, did not affect the contusion volume compared with that of control animals (1.87+/-0.46 mm3, 2.13+/-0.43 mm3, and 2.18+/-0.53 mm3, respectively). Posttreatment with L-arginine (1.1+/-0.3 mm3, p < 0.05), but not 3-morpholino-sydnonimine (SIN-1) (2.48+/-0.37 mm3), significantly reduced the contusion volume compared with that of control animals.
These data indicate that constitutive NOS activity is affected after moderate parasagittal fluid percussion brain injury in a time-dependent manner. Inhibition of activated neuronal NOS and/or enhanced endothelial NOS activation may represent a potential therapeutic strategy for the treatment of TBI.
尽管一氧化氮（NO）已被证明在脑缺血的病理生理过程中起重要作用，但其在创伤性脑损伤（TBI）发病机制中的作用仍有待阐明。作者研究了TBI后组成型一氧化氮合酶（NOS）活性的变化以及对NO进行药物干预后的组织病理学反应。
雄性Sprague-Dawley大鼠接受中度（1.7 - 2.2个大气压）矢状旁流体冲击性脑损伤。TBI发生后5分钟，在同侧顶叶大脑皮质（即组织病理学易损部位），组成型NOS活性显著增加（为对侧值的234.5±60.2%[平均值±平均标准误（SEM）]，p<0.05），30分钟时恢复至对照值（114.1±17.4%），TBI后1天降低（50.5±13.1%，p<0.01）。组成型NOS活性的降低在TBI后持续长达7天（3天时为31.8±6.0%，p<0.05；7天时为20.1±12.7%，p<0.01）。用3 - 溴 - 7 - 硝基吲唑（7 - NI）（25 mg/kg）预处理，一种相对特异性的神经元NOS抑制剂，与对照组相比，显著降低了挫伤体积（1.27±0.17 mm³[平均值±SEM]，p<0.05）（对照组为2.52±0.35 mm³）。然而，用7 - NI进行后处理或用硝基 - L - 精氨酸甲酯（L - NAME）（15 mg/kg）进行预处理或后处理，一种NOS的非特异性抑制剂，与对照动物相比，未影响挫伤体积（分别为1.87±0.46 mm³、2.13±0.43 mm³和2.18±0.53 mm³）。用L - 精氨酸进行后处理（1.1±0.3 mm³，p<0.05），但不是3 - 吗啉代 - 西多胺（SIN - 1）（2.48±0.37 mm³），与对照动物相比，显著降低了挫伤体积。
这些数据表明，中度矢状旁流体冲击性脑损伤后，组成型NOS活性呈时间依赖性受到影响。抑制活化的神经元NOS和/或增强内皮型NOS活化可能代表一种治疗TBI的潜在治疗策略。
