Ketogenic Diet and Seizure Susceptibility in a Whole-Animal Drosophila melanogaster Model: Effects and Mechanisms

Abstract

Seizures are abnormal epochs of neuronal hyperexcitability. The lowcarbohydrate, high-fat ketogenic diet (KD) is an effective treatment for epilepsy in juveniles especially for drug-resistant seizures. KD produces ketone bodies (KB, e.g. β- hydroxybutyrate, or βHB) that are thought to have anticonvulsant properties, however, their exact mechanism of action is unknown. In vitro, presumably anticonvulsant KB effects appear to be mediated by KATP channels and GABAB signaling. In order to study the role of GABAB signaling and KATP channels, the eas bang-sensitive mutant strain, which exhibits seizures upon mechanical stimulation, was used. This strain is expected to have reduced seizure like activity (SLA) in the presence of βHB after mechanical shock. Fly SLA was examined under various conditions of diet and pharmacological treatment. Using automated computer scoring of behavior, eas flies fed the βHB supplemented diet exhibited significantly fewer “jumps” (interpreted as SLA’s) compared with the control diet. Application of CGP55485 (a GABAB blocker), or tolbutamide (a KATP blocker) partially reversed these KB effects in this whole-animal model, validating its use for further study of seizure disorders.