U83836E REDUCES SECONDARY BRAIN INJURY IN A RABBIT MODEL OF CRYOGENICTRAUMA

Oxygen-derived free radicals have been implicated in secondary brain i njury after head trauma. Although oxygen-free radicals may be derived from multiple sources, the activation and accumulation of neutrophils in areas of brain injury is a potential source of deleterious inflamma tory mediators, including free radicals, which may exacerbate the prim ary insult. Neutrophils may also impede the cerebral microcirculation by congestion and occlusion of postcapillary venules. The lazaroid U83 836E is a potent-free radical scavenger that inhibits lipid peroxidati on. US3836E was studied in a cryogenic model of cerebral injury in pre treatment paradigm. Fifteen rabbits received a unilateral cryogenic br ain lesion. Six animals received U83836E, and nine animals received ve hicle only. Arterial blood gases, hematocrit, temperature, and mean ar terial pressure were controlled in physiologic range throughout the ex periment. Intracranial pressure was continuously monitored. Lesion siz e was determined by triphenyltertrazolium chloride staining and planim etric image analysis. Neutrophil aggregation and oxygen-free radical g eneration was assessed in whole blood by impedance aggregometry and si multaneous luminol-mediated chemiluminescence, respectively. Myelopero xidase assay was used to determine neutrophil accumulation within the brain. Elevations in intracranial pressure from baseline values were s ignificantly greater in the untreated (control) animals at all time po ints (p < 0.0001). Mean lesion size (%hemisphere +/- SEM) was signific antly reduced in animals receiving U83836E (4.41 +/- 0.64, n = 6) when compared with controls (15.09 +/- 2.28, n = 9, p < 0.001). A reductio n in both the release of oxygen-free radicals and in neutrophil aggreg ation following the cryogenic injury in the U83836E animals correlated with a smaller lesion volume. Myeloperoxidase assay and histologic ex amination demonstrated a reduction in neutrophil accumulation in the l esion penumbra in the U83836E group. This study suggests that U83836E limits secondary brain injury after a cryogenic lesion. The study also suggests that part of the salutary effect of the antioxidant U83836E may be related to neutrophil inhibition.