Adenosine Receptors Modulate the Exogenous Ketogenic Supplement-Evoked Alleviating Effect on Lipopolysaccharide-Generated Increase in Absence Epileptic Activity in WAG/Rij Rats.

Brigitta Brunner,Csilla Ari,Dominic P D’Agostino,Zsolt Kovács

doi:10.3390/nu13114082

Abstract

It has been previously demonstrated that KEKS food containing exogenous ketogenic supplement ketone salt (KS) and ketone ester (KE) decreased the lipopolysaccharide (LPS)-generated increase in SWD (spike-wave discharge) number in Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats, likely through ketosis. KEKS-supplemented food-generated ketosis may increase adenosine levels, and may thus modulate both neuroinflammatory processes and epileptic activity through adenosine receptors (such as A1Rs and A2ARs). To determine whether these adenosine receptors are able to modify the KEKS food-generated alleviating effect on LPS-evoked increases in SWD number, an antagonist of A1R DPCPX (1,3-dipropyl-8-cyclopentylxanthine; 0.2 mg/kg) with LPS (50 µg/kg) and an antagonist of A2AR SCH58261 (7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine; 0.5 mg/kg) with LPS were co-injected intraperitoneally (i.p.) on the ninth day of KEKS food administration, and their influence not only on the SWD number, but also on blood glucose, R-beta-hydroxybutyrate (R-βHB) levels, and body weight were measured. We showed that inhibition of A1Rs abolished the alleviating effect of KEKS food on LPS-generated increases in the SWD number, whereas blocking A2ARs did not significantly modify the KEKS food-generated beneficial effect. Our results suggest that the neuromodulatory benefits of KEKS-supplemented food on absence epileptic activity are mediated primarily through A1R, not A2AR.

Highlights

Digestion of administered exogenous ketogenic supplements (EKSs), such as ketone salts and ketone esters (KSs and KEs, respectively) can liberate ketone bodies, such as beta-hydroxybutyrate and acetoacetate (AcAc) [1]
LPS (50 μg/kg) alone significantly enhanced the spike-wave discharge. * (SWD) number between 30 and 150 min compared to the control
We further validated our previous result that KEKS‐supplemented food (KEKS food) is able to decrease the LPS‐induced increase in SWD number [19] and pro‐ vided new evidence that this alleviating effect of KEKS food may be mediated by the adenosinergic system, likely through A1Rs

Summary

Introduction

Digestion of administered exogenous ketogenic supplements (EKSs), such as ketone salts and ketone esters (KSs and KEs, respectively) can liberate ketone bodies, such as beta-hydroxybutyrate (βHB) and acetoacetate (AcAc) [1]. These molecules can transport to the bloodstream and are able to evoke an increase in ketone body levels (therapeutic ketosis) without dietary restriction, such as a ketogenic diet [2,3]. It is widely accepted that ketone bodies (e.g., βHB), are a potential energy source for different tissues of the body, and signaling molecules for the central nervous system’s processes [4,5]. Despite the potential beneficial effects of EKS administration in the treatment of central nervous system disorders, their mechanism(s) of action are largely unknown

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