Exogenous Ketone Supplementation Enhances the Anti-Epileptic Effect of Levetiracetam in Wistar Albino Glaxo/Rijswijk Rats.

Background: It has been demonstrated that levetiracetam can decrease absence epileptic activity in both human patients and different types of animal models of absence epilepsy, such as the genetically absence epileptic Wistar Albino Glaxo/Rijswijk (WAG/Rij) rat. It was also suggested previously that exogenous ketone supplements (EKSs)-evoked ketosis not only decreases the number of spike-wave discharges (SWDs) but also enhances the anti-absence epileptic effect of pyrimidine nucleoside uridine in WAG/Rij rats. These findings suggest that EKSs may enhance the efficacy of clinically used anti-epileptic drugs, such as levetiracetam. Methods: We investigated the effect of not only levetiracetam (intraperitoneal/i.p. 200 mg/kg) alone and KEKS supplemented food (containing 10% ketone ester/KE and 10% ketone salt/KS in a normal rat chow) alone, but also the combination of levetiracetam and KEKS supplemented food on SWD number and SWD time for 5 days in WAG/Rij rats. For evaluation of SWDs, electroencephalographic (EEG) recordings were performed every day. Moreover, for the measurement of blood glucose and R-beta-hydroxybutyrate (R-βHB) levels, the blood was taken from the tail vein of rats after EEG registration. Results: It was demonstrated that the administration of both levetiracetam alone and KEKS food alone decreased the SWD number and time spent in SWD, compared to control. Moreover, after combined administration of levetiracetam with KEKS food, enhanced anti-absence epileptic effect was observed, compared to levetiracetam alone. Blood R-βHB level significantly increased after administration of both KEKS food alone and KEKS food in combination with levetiracetam. Nevertheless, these treatments did not significantly change the blood glucose levels. Conclusions: We can conclude that EKSs may be able to enhance the anti-epileptic effect of different drugs, and this combined treatment method may represent a promising new approach and effective therapy against epileptic seizures, especially in treatment-resistant patients.