Abstracts

Rationale: The ketogenic diet’s (KD) anticonvulsant mechanism is not yet understood. Here, we assessed 1) anticonvulsant effects of 4:1 and 6:1 balanced KDs in acute mouse seizure models, and 2) potential changes in brain metabolism by analyzing the brain extracellular fluid using in vivo microdialysis. Methods: Vitamin and mineral contents were matched in control diet, 4:1 and 6:1 KDs relative to their caloric densities. The anticonvulsant profile of the diet was assessed in four acute seizure models. In vivo microdialysis of the hippocampus was used to quantify extracellular fluid composition changes at baseline and after stimulation with 60 mM KCl perfused through the microdialysis probe. Results: Feeding 4:1 and 6:1 KDs ad lib to three week old (adolescent) male mice resulted in 1.2-2.2 mM D-BHB in plasma, but did not consistently change glucose levels. Feeding 6:1 KD to adolescent CD1 mice for 14-21 days repeatedly elevated the CC50 (current that initiates seizures in 50% mice tested) in the 6 Hz model, while the 4:1 KD showed no consistent effect. Higher plasma D-BHB levels correlated with an anticonvulsant effect. Despite ketosis, no consistent anticonvulsant effects of KDs were found in the fluorothyl, pentylenetetrazole, and kainate models. In hippocampal extracellular fluid, no significant differences in baseline concentrations of glucose, lactate and glutamate of control and KD-fed mice were found. Extracellular lactate and glucose showed similar concentration changes in KD- and control diet-fed mice after stimulation with 60 mM KCl. In KD-fed mice, the average hippocampal extracellular D-BHB concentration was 45 ± 9 μM (n=9). Conclusions: Our balanced KD can be used to study the mechanism of the anticonvulsant effect of the KD. This effect was limited to the 6 Hz model, required chronic feeding with 6:1 fat content, and was independent from lowering plasma glucose. Except for higher D-BHB content there were no apparent changes in the extracellular fluid concentrations of lactate and glucose before and after stimulation, indicating that there may be only slight changes in neuronal environment in the KD-induced anticonvulsant state. Further studies are needed to elucidate the KD’s anticonvulsant mechanism. This study was funded by the Epilepsy Foundation.