Role of nitric oxide in the secondary expansion of a cortical brain lesion from cold injury.

We have investigated the role of nitric oxide (NO) as mediator of the secondary growth of a traumatic cortical necrosis. For this purpose, a highly standardized focal lesion of the brain was induced in 46 Sprague-Dawley rats by cold injury. Twenty-four hours later--the timepoint of maximal lesion spread--the animals were sacrificed and brains were removed for histomorphometry of the maximal necrosis area and volume. The animals were divided into five experimental groups. Group I received the NO donor L-arginine as i.v. bolus 10 min prior to trauma (300 mg/kg body weight; n = 10) and a second bolus 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 isotonic 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) inhibitor aminoguanidine (AG) 1 h before and 8 h after trauma by intraperitoneal route. Group IV was administered with the nitric oxide synthase (NOS) inhibitor 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 group 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 mm2 and a lesion volume of 5.7 +/- 0.5 mm3 at 24 h after trauma. In animals with administration of L-arginine, the focal lesion had a maximum area of 3.1 +/- 0.3 mm2 and a volume of 5.3 +/- 0.5 mm3. Hence, the NO donor did not affect the secondary growth of necrosis. Animals with i.p. sham treatment (group V) had a maximal lesion area of 3.6 +/- 0.2 mm2 and lesion volume of 6.2 +/- 0.4 mm3. Administration of aminoguanidine afforded significant attenuation of the lesion growth. Accordingly, the maximal area of necrosis spread only to 2.8 +/- 0.2 mm2 with a volume of 4.5 +/- 0.5 mm3, respectively, at 24 h after trauma (p < 0.01 vs group V). On the other hand, administration of L-NNA did not influence the maximal lesion area (3.7 +/- 0.2 mm2) or lesion volume (6.5 +/- 0.5 mm3) evolving at 24 h after trauma. Thus, neither the enhancement of the formation of NO by L-arginine nor gross inhibition of the synthesis of NO by L-NNA did affect the secondary spread of the necrosis from a focal trauma. The marked attenuation of the posttraumatic necrosis growth 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 which 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 understanding of the pathophysiology of traumatic brain injury and for the targeted development of specific treatment modalities.