Exogenous Ketone Supplementation Decreased the Lipopolysaccharide-Induced Increase in Absence Epileptic Activity in Wistar Albino Glaxo Rijswijk Rats.

Zsolt Kovács,Csilla Ari,Dominic P D'Agostino,David M Diamond

doi:10.3389/fnmol.2019.00045

Abstract

It has been demonstrated previously that exogenous ketone supplements such as ketone ester (KE) decreased absence epileptic activity in a well-studied animal model of human absence epilepsy, Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. It is known that lipopolysaccharide (LPS)-generated changes in inflammatory processes increase absence epileptic activity, while previous studies show that ketone supplement-evoked ketosis can modulate inflammatory processes. Thus, we investigated in the present study whether administration of exogenous ketone supplements, which were mixed with standard rodent chow (containing 10% KE + 10% ketone salt/KS, % by weight, KEKS) for 10 days, can modulate the LPS-evoked changes in absence epileptic activity in WAG/Rij rats. At first, KEKS food alone was administered and changes in spike-wave discharge (SWD) number, SWD time, discharge frequency within SWDs, blood glucose, and beta-hydroxybutyrate (βHB) levels, as well as body weight and sleep-waking stages were measured. In a separate experiment, intraperitoneal (i.p.) injection of LPS (50 μg/kg) alone and a cyclooxygenase 1 and 2 (COX-1 and COX-2) inhibitor indomethacin (10 mg/kg) alone, as well as combined IP injection of indomethacin with LPS (indomethacin + LPS) were applied in WAG/Rij rats to elucidate their influences on SWD number. In order to determine whether KEKS food can modify the LPS-evoked changes in SWD number, KEKS food in combination with IP LPS (50 μg/kg) (KEKS + LPS), as well as KEKS food with IP indomethacin (10 mg/kg) and LPS (50 μg/kg) (KEKS + indomethacin + LPS) were also administered. We demonstrated that KEKS food significantly increased blood βHB levels and decreased not only the spontaneously generated absence epileptic activity (SWD number), but also the LPS-evoked increase in SWD number in WAG/Rij rats. Our results suggest that administration of exogenous ketone supplements (ketogenic foods) may be a promising therapeutic tool in the treatment of epilepsy.

Highlights

Ketone bodies are produced mainly in the liver, which may serve as an energy source for different tissues under circumstances when glucose supply is insufficient, such as fasting or after following a ketogenic diet (Hashim and VanItallie, 2014; Achanta and Rae, 2017)
These results suggest the role of the Toll-like receptor 4 (TLR4)/COX-2/prostaglandin E2 (PGE2) system in the LPS-induced processes leading to PGE2 synthesis, which may enhance spike-wave discharge (SWD) generator mechanisms (Kovács et al, 2006, 2011, 2014a)
Because average SWD duration did not change after treatment by KEKS, but SWD number decreased (Figure 2; group 1), changes in the total time of SWDs were similar to the change in SWD number

Summary

Introduction

Ketone bodies (beta-hydroxybutyrate/βHB, acetoacetate, and acetone) are produced mainly in the liver, which may serve as an energy source for different tissues under circumstances when glucose supply is insufficient, such as fasting or after following a ketogenic diet (Hashim and VanItallie, 2014; Achanta and Rae, 2017). Prostaglandins may decrease the seizure threshold and prostaglandin E2 (PGE2) showed a proconvulsant effect (Sayyah et al, 2003) These effects of LPS may enhance cortical excitability for example via modulation of GABAergic, glutamatergic, and adenosinergic systems (Wang and White, 1999; Coenen and Van Luijtelaar, 2003; Kovács et al, 2015b) and, as a consequence, augment absence epileptic activity in WAG/Rij rats (Kovács et al, 2006, 2011, 2014a). The LPS-evoked increase in spike-wave discharge (SWD) number was abolished by a potent inhibitor of prostaglandin synthesis, a cyclooxygenase 1 (COX-1) and COX-2 inhibitor indomethacin These results suggest the role of the TLR4/COX-2/PGE2 system in the LPS-induced processes leading to PGE2 synthesis, which may enhance SWD generator mechanisms (Kovács et al, 2006, 2011, 2014a)

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Results

Conclusion