Abstracts

Rationale: Ongoing studies in our laboratory suggest that status epilepticus (SE) results in profound oxidative stress and mitochondrial dysfunction. Reactive oxygen species are mediators of mitochondrial dysfunction that may be active in promoting neuronal death associated with the development of temporal lobe epilepsy (TLE). The goal of this study was to determine if mitochondrial oxidative stress contributes to hippocampal neuronal death following SE and whether a synthetic catalytic antioxidant administered post-SE would provide neuroprotection in two chemoconvulsant models. Methods: Adult Sprague-Dawley rats were injected with vehicle, kainate (11 mg/kg) or pilocarpine (340 mg/kg) to initiate SE followed by treatment with vehicle or a synthetic metalloporphyrin catalytic antioxidant, AEOL 10150 (5 mg/kg, s.c.), beginning 60-90 min post-SE onset and every 4-6 hr until sacrifice at 48 h. Evidence for neuroprotection in the hippocampus of chemoconvulsant/AEOL 10150-treated rats was measured at 48 h post-SE using Fluoro-Jade B staining, a marker of degenerating neurons, and Image J analysis. Oxidative damage was assessed 24 h post-SE by measurement of 3-nitrotyrosine/tyrosine (3NT/tyr) and reduced/oxidized glutathione (GSH/GSSG) ratios, respectively by HPLC methods. The concentrations of AEOL 10150 in the rat brain were also determined. Results: Fluoro-Jade B staining indicative of cell injury was prevalent throughout the hippocampus of pilocarpine and kainate-treated rats at 48 h post-SE. In pilocarpine-treated rats receiving AEOL 10150, cell injury decreased by approximately 40% in CA1, and 60% in CA3 and hilus. In kainate-treated rats receiving AEOL 10150, cell injury decreased by approximately 40% in CA3 and hilus. AEOL 10150 significantly decreased oxidative stress indices (3-NT/tyr and GSH/GSSG ratios) in the hippocampus of pilocarpine-treated rats. Measurement of AEOL 10150 levels in the brain revealed its ability to achieve neuroprotective concentrations in the hippocampus and cortex following systemic administration. Conclusions: These data demonstrate the ability of a catalytic metalloporphyrin antioxidant to inhibit oxidative damage and provide neuroprotection in the hippocampus when administered 60-90 minutes following SE onset. The results suggest that oxidative stress may be a potential target for neuroprotection following SE.