Abstracts

Rationale: Cognitive dysfunction is an important comorbidity of temporal lobe epilepsy (TLE). However, the mechanisms underlying cognitive impairment, specifically deficits in learning and memory associated with TLE remain unclear. Metabolic dysfunction is emerging as an important mechanism in the pathogenesis of TLE but to what degree metabolic dysfunction and cognitive impairment are related has yet to be determined. We hypothesize that injury-mediated oxidative stress induces mitochondrial dysfunction and neuronal death which leads to cognitive decline associated with epileptogenesis. Methods: Using a synthetic catalytic antioxidant (AEOL10150), we determined if pharmacological scavenging of reactive oxygen species (ROS) prevents 1) oxidative stress parameters, 2) deficits in mitochondrial oxygen consumption rates (OCR), 3) hippocampal neuronal loss and 4) cognitive dysfunction in a rat model of TLE. Adult male Sprague-Dawley rats were treated with pilocarpine to induce status epilepticus (SE) or saline in control groups. All rats were injected with scopolamine (1mg/kg) 30 minutes prior to pilocarpine (340mg/kg) to limit peripheral cholinergic effects and diazepam (10mg/kg) 90 minutes after pilocarpine to terminate SE. The drug treatment group received AEOL10150 (AEOL150; 5mg/kg) starting 1 hour after pilocarpine and maintained on a q4 dosing schedule for 24-48 hours for all acute experiments. A separate cohort of rats received q4 injections for the first 48 hours followed by a gradual tapering of doses over 3 days and subsequently tested following drug discontinuation in the novel object recognition (NOR) task one week after SE. Results: At the 24 hour time point, treatment with AEOL150 significantly inhibited 1) indices of oxidative stress (glutathione depletion (p>0.01) and 3-nitrotyrosine accumulation (p>0.01) detected by HPLC methods), 2) deficits in hippocampal synaptosomal mitochondrial respiration (OCR (p>0.05) as detected by an extracellular flux analysis) and 3) neuronal death in brain regions (p>0.01) (detected by Fluoro-Jade B labeling of degenerating neurons). Deficits in memory performance (p>0.01) on the NOR task were also significantly attenuated by treatment with AEOL150 one week after SE. Continuous video-EEG analysis in a separate cohort of rats indicated that AEOL10150 did not alter SE parameters. Conclusions: The data demonstrates that catalytic removal of ROS preserves cognitive function while ameliorating SE-induced oxidative stress, mitochondrial deficits and neuronal death. The data further suggest that pharmacological scavenging of ROS with a catalytic antioxidant can exert a disease-modifying effect against cognitive dysfunction in the pilocarpine rat model of experimental TLE and point to mitochondrial dysfunction as a shared underlying mechanism. Funding: R21NS072099-01(M.P.), 1RO1NS086423-01 (M.P.), R01NS39587 (M.P.), U01NS083422 (M.P.), F31NS086405 (J.N.P), F31NS077739-03 (S.R.)