Triheptanoin reduces seizure susceptibility in a syndrome-specific mouse model of generalized epilepsy

Triheptanoin is a triglyceride containing heptanoate, an odd-chained medium fatty acid that is metabolized to produce propionyl-CoA and subsequently C4 intermediates of the citric acid cycle and therefore capable of anaplerosis. These metabolic products are believed to underlie triheptanoin's anticonvulsant effects in rodent seizure models. Here we investigate the anticonvulsive effects of oral triheptanoin in a syndrome-specific genetic mouse model of generalized epilepsy based on the GABA(A)γ2(R43Q) mutation. Mice were fed a diet supplemented with triheptanoin from weaning for three weeks prior to electrocortical recordings. Occurrence and durations of spike and wave discharges (SWDs) were measured. Triheptanoin did not alter body weight or basal blood glucose levels suggesting that it was well tolerated. Triheptanoin supplementation halved the time spent in seizures due to a reduction in both SWD occurrence and duration. An injection of insulin was used to reduce blood glucose, a metabolic stress known to precipitate seizures in the GABA(A)γ2(R43Q) mouse. The reduction in seizure count was also evident following insulin induced hypoglycemia with the triheptanoin treated group having significantly less SWDs than control animals under similar low blood glucose conditions. In summary, triheptanoin may be an effective and well tolerated dietary therapy for generalized epilepsy.