Interleukin-1 receptor antagonist attenuates regional neuronal cell death and cognitive dysfunction after experimental brain injury

The effect of systemic administration of human recombinant interleukin-l re ceptor antagonist (rhIL-lra) on behavioral outcome and histopathologic dama ge after lateral fluid-percussion brain injury of moderate severity was eva luated. In study 1, brain-injured Sprague Dawley rats received timed subcut aneous injections beginnings 15 minutes after injury of either 100 mg/kg rh IL-lra (high dose, total dose = 1900 mg/kg), 10 mg/kg rhiIL-lra (low dose, total dose = 190 mg/kg), or vehicle over 7 days. No effect of low-dose rhIL -lra was observed in study 1. High-dose rhIL-lra significantly attenuated p osttraumatic neuronal loss in the injured hippocampal CA, region (P < 0.05) , dentate hilus (P < 0.05), and cortex (P < 0.05) but impaired recovery of motor function at 7 days after trauma (P < 0.05). In study 2, rats were pre trained to learn a visuospatial task in a Morris water maze, subjected to f luid- percussion brain injury or sham treatment, and randomly assigned to r eceive multiple subcutaneous injections at timed intervals of 100 mg/kg rhI L-lra (total dose = 900 mg/kg) or vehicle over 42 hours, followed by contin uous infusion of a lower concentration of rhIL-lra (20 mg/kg/day, total dos e = 100 mg/kg), or vehicle for 5 days using subcutaneously implanted osmoti c minipumps, Postinjury administration of rhIL-Ira significantly attenuated cognitive deficits compared with vehicle-treated animals at 42 hours (P < 0.05) but did not affect motor function at 48 hours, 1 week, and 2 weeks. T hese results suggest that inhibitors of cytokine pathways may be therapeuti cally useful for the treatment of brain trauma.