Abstracts

Rationale: Mitochondrial dysfunction, including impairment of respiratory capacity and ATP production, excessive free radical generation and lowered mitochondrial permeability transition occurs in seizure-genic regions such as the hippocampus in animal models of epilepsy. We examined whether the antiepileptic and neuroprotective drug carbamazepine (CBZ) directly influences mitochondria function. Methods: Mitochondria were isolated from the hippocampus of normal wild-type and chronically epileptic Kcna1-null mice. Respiratory capacity, calcium sequestration and reactive oxygen species production were assessed using standard oxygen polarography with a Clark-type electrode and spectrofluorescence assays. Results: Hippocampal mitochondria was dysfunctional in Kcna1-null mice, specifically, state III respiration was impaired when compared to that of wild-type control mice. Application of CBZ attenuated state III respiration in wild-type hippocampus in a concentration dependent manner (IC50: 129.2 M). In contrast, CBZ failed to influence the respiratory capacity of hippocampal mitochondria isolated from epileptic mice at all concentrations examined (50-300 M). Furthermore, CBZ differentially influenced the ability of wild-type and pathologic mitochondria to sequester calcium and generate free radicals. Conclusions: These data indicate that CBZ directly influences mitochondria function and suggest novel anti-epileptic mechanisms in its ability to influence energy regulation and neuroprotective signaling cascades. In addition, the lack of effect of CBZ in epileptic mitochondria supports the notion that dysregulation of mitochondrial proteins will impede normal function and may contribute to the ineffectiveness of CBZ in certain medically refractory epilepsies.