Role of nitric oxide in traumatic brain injury in the rat

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.