Abstracts

Rationale: The ketogenic diet (KD) is an effective treatment for medically refractory epilepsy, but the anticonvulsant mechanisms remain largely unknown. Here, we focused on examining the effects of the KD on neuronal and mitochondrial damage following acute and chronic seizures. Methods: Kainic-acid (KA) was used to induce acute seizures, whereas chronic seizures were examined in Kcna1-null mice (a potassium channel deletion which causes mice to have recurrent, spontaneous limbic-like seizures). Adult wild-type and Kcna1-null mice maintained on the ketogenic diet (6:1 ratio of fats to carbohydrates and protein) were compared to littermates fed a standard rodent chow diet. KD-induced effects on behavioral seizures (Racine scale), EEG seizure detection, and hippocampal neuronal injury (Fluoro-Jade B) were determined. Also, hippocampal and cortical mitochondria were isolated and oxidative damage assessed by immunoblot analysis of lipid peroxidation, protein oxidation and protein nitration. Results: Even though the diet did not influence the cumulative behavioral seizure scores, the KD protected mice against neuronal damage in the CA1 hippocampal region and mitochondrial oxidative damage 72h after KA-induced acute seizures. In the chronic seizure model, the life-span of Kcna1-null mice increased from 51 ± 9 days when fed a standard diet to 66 ± 14 days while given a KD (mean ± standard deviation; P < 0.0001) indicating possible neuroprotective effects. Compared to standard diet fed null mice, KD-treated null mice had fewer, although not significant, limbic seizures per day (5.3 ± 1.5 and 12.0 ± 6.3, respectively; mean ± standard deviation; P < 0.138) and lower overall behavioral seizure scores. In addition, KD fed Kcna1-null mice had reduced mitochondrial oxidative damage compared to standard diet fed null mice. Conclusions: These data support a mitochondrial site of action for the KD, either by enhancing mitochondrial capacity to withstand the high-energy demand caused by seizures or assisting in the reduction of mitochondrial oxidative damage.