Abstracts

Rationale: The ketogenic diet was designed to mimic the beneficial effects of fasting. The ketogenic diet received its name based on the finding that its consumption led to the appearance of ketone bodies in the blood and urine. Despite a widely held assumption that the ketogenic diet and fasting share anticonvulsant mechanisms, our lab recently found that these diets have opposite patterns in some acute seizure tests (Hartman et al., 2010). In particular, mice fed a ketogenic diet are protected against seizures in the 6 Hz electroshock test, whereas mice fed intermittently are more susceptible to these seizures the day after a feeding. The converse was true in the kainic acid test, where intermittently fasted mice were protected against kainic acid-induced seizures and those fed a ketogenic diet were not. However, intermittently fasted mice were not ketotic, since they were tested the day after a feeding. One conclusion from the prior study is that ketosis may be responsible for the anticonvulsant effect in the 6 Hz test. The purpose of this study was to determine whether intermittently fasted mice were protected against 6 Hz-induced seizures on the day after a fast, when they would be expected to be in ketosis. This is one means of testing seizure protection due to endogenous ketone body production.Methods: After weaning at 3 weeks of age, male NIH Swiss mice were fasted overnight then divided into one of four dietary schemes: (1) a 6.5:1 ketogenic diet (KD), (2) an unrestricted control diet matched to the ketogenic diet in protein content, vitamins, and minerals (CD), (3) control diet fed by intermittent fasting (i.e., ad lib every other day), tested the day after feeding (CD-IF-feed), and (4) control diet fed by intermittent fasting, tested the day after fasting (CD-IF-fast). Each dietary scheme was implemented for 11-13 days. Body weights were recorded daily. Blood glucose and beta-hydroxybutyrate (BHB) levels were performed just prior to seizure testing. 6 Hz current-response curves derived for each dietary scheme were compared using a probit analysis. Other comparisons included maximum seizure score and duration.Results: Mice fed the ketogenic diet were protected against 6 Hz-induced seizures; conversely, those fasted intermittently, regardless of the day of testing (i.e., post-feed or post-fast), were more susceptible. Blood BHB levels were significantly higher in mice fed a ketogenic diet and in CD-IF-fast mice than the other two groups. However, blood glucose levels were significantly lower in both the ketogenic diet and CD-IF-fast group than the others (but the CD-IF-fast group was significantly lower than the ketogenic diet group).Conclusions: Ketosis is necessary but not sufficient to protect against 6 Hz-induced seizures in these metabolism-based models. The role of concomitant low blood glucose levels is unclear, as both CD-IF-fast and ketogenic diets resulted in low blood glucose levels.