Early treatment with a novel inhibitor of lipid peroxidation (LY341122) improves histopathological outcome after moderate fluid percussion brain injury in rats

OBJECTIVE: Reactive oxygen species are thought to participate in the pathob iology of traumatic brain injury (TBI). This study determined whether treat ment with LY341122, a potent inhibitor of lipid peroxidation and an antioxi dant, would provide neuroprotection in a rat model of TBI. METHODS: To investigate the efficacy of LY341122 in this parasagittal fluid percussion model (1.8-2.1 atm), the rats received oval administration of L Y341122 (100 mg/kg) or vehicle 2 hours before and 4 hours after TBI teach g roup, n = 7). To investigate the therapeutic window for treatment, rats wer e treated with LY341122 or vehicle for 20 hours by femoral vein infusion st arting at 5 minutes, 30 minutes, or 3 hours after TBI teach group, n = 5). Three days after injury, analysis of contusion volumes and the frequency of damaged cortical neurons was conducted. RESULTS: Oral administration of LY341122 before and after TBI led to a sign ificant reduction in overall contusion volume (3.28 mm(3) +/- 0.75 mm(3) [m ean +/- standard error of the mean] versus 1.32 mm(3) +/- 0.33 mm(3); P < 0 .05) and also reduced the frequency of damaged cortical neurons (1191.7 +/- 267.1 versus 474.6 +/- 80.2; P < 0.05). In the second experiment, rats tre ated with LY341122 at 5 minutes or 30 minutes after TBI also demonstrated a significant reduction (P < 0.05) in contusion volume (1.92 mm(3) +/- 0.64 mm(3) or 1.59 mm(3) +/- 0.50 mm(3), respectively) compared with vehicle-tre ated rats (4.32 mm(3) +/- 1.15 mm(3)). A significant reduction in total cor tical necrotic neuron counts was also demonstrated in the 5-minute group (2 243.8 +/- 265.3 versus 1457.8 +/- 265.3; P < 0.05). In contrast, histopatho logical outcome was not significantly improved when treatment was delayed u ntil 3 hours after TBI. CONCLUSION: These data reinforce the hypothesis that lipid peroxidation and reactive oxygen species participate in the acute pathogenesis of TBI. Trea tment delayed until 3 hours after TBI did not provide significant histopath ological protection.