INCREASE IN IL-6, IL-1 AND TNF LEVELS IN RAT-BRAIN FOLLOWING TRAUMATIC LESION - INFLUENCE OF PRE-TRAUMATIC AND POSTTRAUMATIC TREATMENT WITH RO5 4864, A PERIPHERAL-TYPE (P-SITE) BENZODIAZEPINE LIGAND

The effects of fluid percussion trauma on brain interleukin (IL)-6, IL-1 and tumor necrosis factor-alpha (TNF-alpha) levels have been studied. In the cortex and hippocampus of control and sham-operated rats, the levels of these cytokines were very low (below 4 units/mg protein) and constant. IL-6 and IL-1 levels in the ipsilateral cortex increased rapidly following trauma to reach a maximum of 350 and 16 units/mg protein, respectively, 8 h after the lesion, remained elevated until 18 h and decreased thereafter to basal values. TNF-alpha levels were maximally elevated (12 units/mg protein) at 3 h and 8 h and returned to basal values by 18 h. Qualitatively similar changes, but with 25-80-fold smaller amplitude, were seen in the contralateral cortex and in the ipsi- and contralateral hippocampus. The levels of IL-6 in the plasma of sham-operated and lesioned rats were only slightly elevated, whereas IL-1 and TNF-alpha were undetectable. Histological studies of brain tissue at early stages after trauma demonstrated an acute hemorrhage associated with neutrophil invasion. The administration of Ro5 4864 (0.5 mg/kg i.p.), a specific ligand of p (peripheral-type benzodiazepine) binding sites, did not result in any significant effect on the levels of IL-6, IL-1 or TNF-alpha in the brain of control or sham-operated animals. However, when administered 24 h before or 15 min after trauma, this benzodiazepine enhanced the increase of these cytokines by 2-4-fold in the ipsilateral cortex. The global effect of Ro5 4864 on IL-6 levels was of greater amplitude than those on IL-1 or TNF-alpha. Ro5 4864 had no effect on IL-6 levels in the plasma of lesioned rats. The activation of p sites by specific benzodiazepine ligands might, by increasing the trauma-induced production of these cytokines, modulate the inflammatory reaction at the site of brain injury.