Glucose reduces the anticonvulsant effects of the ketogenic diet in EL mice

• Ketogenic diet (KD) controls seizures in EL mice.
• Calorie restricting the KD further increases seizure threshold in EL mice.
• Glucose supplementation decreases seizure threshold in EL mice on KD.
• Glucose decreases the anticonvulsant action of the KD.

SummaryThe ketogenic diet (KD) is known to be anticonvulsant and anti-epileptogenic. While the mechanism behind this therapeutic benefit is unclear, a reduction of circulating glucose levels through calorie restriction (CR) has been implicated. Foods or drinks that elevate blood glucose are known to compromise the therapeutic benefit of the KD in some children with epilepsy. We therefore evaluated the effect of a calorie restricted KD (KD-R) with supplementation of glucose in the drinking water of EL mice, a natural model of idiopathic generalized epilepsy, prior to seizure testing to assess the effect of glucose on seizure generation. Mice were fed either a standard diet or the KD unrestricted (SD-UR and KD-UR, respectively), or the KD restricted (KD-R). d-Glucose (25 mM) was supplemented in the drinking water of KD-R fed mice for 0.5 h or for 2.5 h prior to seizure testing. Each restricted mouse served as its own body weight control to achieve a 15–18% body weight reduction. Seizure susceptibility, body weights, and plasma glucose and β-hydroxybutyrate levels were measured over a nine-week treatment period. Body weights and glucose levels remained high over the testing period in both the SD-UR and the KD-UR groups, but were significantly reduced in all R-fed groups. A significant increase in β-hydroxybutyrate levels was observed in all KD groups. Seizure susceptibility remained highest in the SD-UR group, was slightly reduced in the KD-UR group, and was significantly reduced after three weeks in all R-fed groups. Supplementation of glucose prior to seizure testing resulted in a decrease of seizure threshold for R-fed mice, but did not alter bodyweight or circulating glucose levels. The KD has both an anticonvulsant and antiepileptogenic effect in EL mice. Here we confirm that CR enhances the anticonvulsant action of the KD in EL mice. Additionally, we show for the first time that supplementation of glucose decreases the anticonvulsant action of the KD, which further supports the hypothesis that CR works through transitioning metabolism from glucose to ketone utilization for energy.