Abstracts

Rationale: Traumatic brain injury (TBI)-related oxidative stress occurs in both human and rodent brains and is associated with TBI-related hemorrhage/brain iron deposition, a clear risk factor for the development of posttraumatic epilepsy (PTE). The cys-leukotrienes (cys-LTs) are a class of arachidonic acid-derived lipid mediators of inflammation produced in the brain in response to TBI. In the brain, these compounds are synthesized via a transcellular biosynthetic pathway that is facilitated by TBI-related blood-brain barrier breakdown and hemorrhage. Pharmacological blockade of the production or end-organ effect of the cys-LTs has been shown to ameliorate oxidative stress in lymphocytes and to improve functional outcome in a rat model of spinal cord injury. The aim of this study was to test the effect of pharmacological blockade of cys-LT synthesis on post-injury oxidative stress in the rat fluid percussion injury (FPI) model of posttraumatic epilepsy. Methods: To establish the time course of changes in redox balance after TBI, 19 rats underwent moderate FPI (2.5 to 3 atm). 5 animals were used as sham-injured controls. Tissue samples of injured cortex (Cx) and the ipsilateral hippocampus (HC) were collected and used for measurements of reduced glutathione (GSH) and its disulfide (GSSG) at multiple time points after injury. Subsequently, six rats received 6mg/kg MK-886 (a 5-lipoxygenase activating protein inhibitor) or the same volume of DMSO/saline vehicle intravenously 30 minutes prior to moderate FPI. Cx and HC tissue samples were again collected and used for measurements of GSH and GSSG levels at 48 hours after injury. Results: Significant increases in GSSG and significant decreases in GSH/GSSG ratios and total glutathione were seen in both the injured cortex and the ipsilateral hippocampus at multiple time points during the week post-injury, suggestive of sustained redox derangement after FPI. Pretreatment with MK-886 resulted in a significant normalization of all three markers in the ipsilateral hippocampus and in a significant normalization of GSSG and GSH/GSSG in the injured cortex at 48 hours after injury, compared to vehicle-treated animals (GSSG: Cx: 4.93+/-0.50 vs. 12.72+/-1.59 nmol/g tissue, p<0.001, HC: 6.44+/-0.70 vs. 11.60+/-1.16 nmol/g tissue, p<0.01; GSH/GSSG: Cx: 301.41+/-28.81 vs. 108.27+/-13.22 nmol/g tissue, p<0.001, HC: 267.55+/-42.30 vs. 131.35+/-12.17 nmol/g tissue, p <0.05; Total glutathione: Cx: 1451.08+/-21.74 vs. 1299.04+/-44.88 nmol/g tissue, NS, HC: 1646.14+/-44.64 vs. 1477.50+/-48.80 nmol/g tissue, p<0.05).