Abstracts

Rationale: Epileptic seizures are the most common feature observed in children with inherited mitochondrial diseases. Work in this laboratory suggests an emerging role of mitochondrial oxidative stress and resultant dysfunction in seizure-induced brain injury. The objective of this study was to determine the ability of a lipophilic metalloporphyrin antioxidant identified from an in vitro screening model to modulate seizures in a mouse model of acute mitochondrial dysfunction. The model utilizes cross-bred C57BL6XDBA2F2 (B6D2) mutant mice lacking manganese superoxide dismutase (MnSOD or Sod2), a critical mitochondrial antioxidant. In the second week of postnatal life (P14-P21) B6D2 Sod2-/- mice exhibit frequent episodes of spontaneous tonic-clonic seizures, allowing their use as a model of epilepsy associated with mitochondrial disease for testing therapeutic interventions. Methods: The effect of a lipophilic potent catalytic antioxidant, AEOL 11207, was determined on the lifespan and behavioral seizure characteristics of Sod2-/- mice during the second to third week of post-natal life. Mice were genotyped on P5 and positively identified Sod2-/- mice received daily subcutaneous injections thereafter of either AEOL 11207 (5 mg/kg) or saline. All Sod2-/- mice were video recorded for a minimum of 6 hours a day starting on P16 and reviewed for seizure number, frequency, duration, and severity by an observer blind to treatments. Results: Sod2-/- mice treated with AEOL 11207 showed a decrease in the total number and frequency of behavioral seizures, but no significant changes in seizure duration or severity. AEOL 11207 treated Sod2-/- mice had a significant increase in average lifespan compared to saline treated controls from 14.01± 3.95 days to 20.33 ± 2.00 days. Conclusions: These results indicate the ability of a synthetic lipophilic metalloporphyrin to attenuate behavioral seizures and increase lifespan in a model of acute mitochondrial oxidative stress and epilepsy. This suggests that mitochondrial oxidative stress may be a novel therapeutic target for the treatment of epilepsies associated with mitochondrial disease.