Role of nitric oxide in the secondary expansion of a cortical brain lesionfrom cold injury

We have investigated the role of nitric oxide (NO) as mediator of the secon dary growth of a traumatic cortical necrosis. For this purpose, a highly st andardized focal lesion of the brain was induced in 46 Sprague-Dawley rats by cold injury. Twenty-four hours later-the timepoint of maximal lesion spr ead-the animals were sacrificed and brains were removed for histomorphometr y of the maximal necrosis area and volume. The animals were divided into fi ve experimental groups. Group I received the NO donor L-arginine as i.v. bo lus 10 min prior to trauma (300 mg/kg body weight; n = 10) and a second bol us of the same dosage intraperitoneally 1 h after trauma. Group II (n = 10) -serving as control of group I-was infused with an i.v. bolus of 1 mL/kg is otonic saline 10 min prior to and a subsequent bolus i.p. 1 h after trauma. Group III (n = 8) received 100 mg/kg b.w. of the inducible NOS (iNOS) inhi bitor aminoguanidine (AG) 1 h before and 8 1 1 after trauma by intraperiton eal route. Group IV was administered with the nitric oxide synthase (NOS) i nhibitor N-G-nitro-L-arginine (L-NNA; 100 mg/kg b.w., i.p.; n = 8); group V -the controls of group III and IV-was administered with isotonic saline (1 mL/kg b.w, i.p.; n = 10) 1 h before and 8 h after trauma. In the control gr oup with i.v./i.p. sham treatment (II), the focal lesion led to a cortical necrosis with a maximum area of 3.1 +/- 0.3 mm(2) and a lesion volume of 5. 7 +/- 0.5 mm(3) at 24 h after trauma. In animals with administration of L-a rginine, the focal lesion had a maximum area of 3.1 +/- 0.3 mm(2) and a vol ume of 5.3 +/- 0.5 mm3. Hence, the NO donor did not affect the secondary gr owth of necrosis. Animals with i.p. sham treatment (group V) had a maximal lesion area of 3.6 +/- 0.2 mm(2) and lesion volume of 6.2 +/- 0.4 mm(3). Ad ministration of aminoguanidine afforded significant attenuation of the lesi on growth. Accordingly, the maximal area of necrosis spread only to 2.8 +/- 0.2 mm(2) with a volume of 4.5 +/- 0.5 mm(3), respectively, at 24 h after trauma (p < 0.01 vs group V). On the other hand, administration of L-NNA di d not influence the maximal lesion area (3.7 +/- 0.2 mm(2)) or lesion volum e (6.5 +/- 0.5 mm(3)) evolving at 24 h after trauma. Thus, neither the enha ncement of the formation of NO by L-arginine nor gross inhibition of the sy nthesis of NO by L-NNA did affect the secondary spread of the necrosis from a focal trauma. The marked attenuation of the posttraumatic necrosis growt h by the iNOS inhibitor aminoguanidine strongly indicates an important role of iNOS product in this phenomenon. These findings, thus, demonstrate that the expansion of a primary necrotic focal lesion is a secondary process wh ich can be therapeutically inhibited. Thereby, the growth of a focal tissue necrosis from trauma is clearly identified as a manifestation of secondary brain damage. This information is deemed important for the better understa nding of the pathophysiology of traumatic brain injury and for the targeted development of specific treatment modalities.