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. 2021 Nov 15;13(11):4082.
doi: 10.3390/nu13114082.

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

Brigitta Brunner  1   2 , Csilla Ari  3   4 , Dominic P D'Agostino  3   5   6 , Zsolt Kovács  2
Affiliations

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

Brigitta Brunner et al. Nutrients. .

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.

Keywords: LPS; WAG/Rij rats; absence epilepsy; adenosine receptors; ketogenic supplements; ketosis.

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Conflict of interest statement

International Patent # PCT/US2014/031237, University of South Florida, D.P. D’Agostino, S. Kesl, P. Arnold, “Compositions and Methods for Producing Elevated and Sustained Ketosis”. Patent: US 10,980,764 B1, C. Ari, D.P.D’Agostino, “Exogenous ketone supplements for reducing anxiety-related behavior”; Ari, C., Arnold P., D’Agostino, D.P. Technology Title: “Exogenous Ketone Supplementation Improved Motor Function in Sprague-Dawley Rats.” USF Ref. No: 16A019; Ari, C., Arnold P., D’Agostino, D.P. Technology Title: “Lowering of Blood Glucose in Exercising and Non-Exercising Rats Following Administration of Exogenous Ketones and Ketone Formulas.” USF Ref. No: 16A049; Ari, C., Arnold P., D’Agostino, D.P. Technology Title: “Neuroregeneration improved by ketone.” USF Ref. No: 16B128 (provisional patent); Patent: US 10,945,975 B2:Ari, C., D’Agostino, D.P. Dean, J.B. Technology Title: “Delaying latency to seizure by combinations of ketone supplements.” D.P. D’Agostino and C. Ari are co-owners of the company Ketone Technologies LLC, and C. Ari is owner of Fortis World LLC. These interests have been reviewed and managed by the University in accordance with its Institutional and Individual Conflict of Interest policies. All authors declare that there are no additional conflict of interest.

Figures

Figure 1
Figure 1
Experimental design. Abbreviations: DMSO, dimethyl sulfoxide; DPCPX, 1,3-dipropyl-8-cyclopentylxanthine; i.p., intraperitoneal; KEKS days, days KEKS food (10% ketone ester/KE, 10% ketone salt/KS and 1% saccharin in paste-like standard rodent chow) administration; LPS, lipopolysaccharide; sal. + sal.: i.p. 0.3 mL saline/100 g body weight (first injection) + 0.3 mL saline/100 g body weight (second injection; 30 min later); SCH582361, 7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine.
Figure 2
Figure 2
Effect of LPS (50 µg/kg) alone (A) and combined administration of DPCPX (0.2 mg/kg) with LPS (B) and SCH58261 (0.5 mg/kg) with LPS (C) on SWD number (group 1, group 2 and group 3, respectively). Abbreviations: DPCPX, 1,3-dipropyl-8-cyclopentylxanthine; i.p., intraperitoneal; LPS, lipopolysaccharide; SCH582361, 7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine; SWD, spike-wave discharge. **: p < 0.01, ***: p < 0.001 and ****: p < 0.0001.
Figure 3
Figure 3
Influence of combined administration of KEKS-supplemented food (paste-like standard rodent chow containing 10% ketone ester/KE, 10% ketone salt/KS and 1% saccharin) with LPS (50 µg/kg) (A), with DPCPX (0.2 mg/kg) and LPS (B) and with SCH58261 (0.5 mg/kg) and LPS (C) on SWD number (groups 4, 5, and 6, respectively). Abbreviations: 1K, first day of KEKS food administration, 2K, second day of KEKS food administration and so on; 9K + D + L, 9th day of KEKS food administration and co-administration of i.p. DPCPX (0.2 mg/kg) and LPS (50 µg/kg); 9K + L, 9th day of KEKS food administration and co-administration of i.p. LPS (50 µg/kg); 9K + S + L, 9th day of KEKS food administration and co-administration of i.p. SCH58261 (0.5 mg/kg) and LPS (50 µg/kg); CON, control; SWD, spike-wave discharge. *: p < 0.05, **: p < 0.01, ***: p < 0.001 and ****: p < 0.0001.
Figure 4
Figure 4
Changes in blood R-βHB and glucose levels on the first day of KEKS-supplemented food (10% ketone ester/KE, 10% ketone salt/KS and 1% saccharin in paste-like standard rodent chow) administration (1K; (A–F)) and on the ninth day of KEKS food administration combined with i.p. LPS (50 µg/kg) (9K + L; A,B), with i.p. DPCPX (0.2 mg/kg) and LPS (9K + D + L; C,D) and with i.p. SCH58261 (0.5 mg/kg) and LPS (9K + S + L; E and F), compared to the control (CON; groups 4, 5, and 6, respectively). ***: p < 0.001 and ****: p < 0.0001.
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