Enhancement of Ketone Supplements-Evoked Effect on Absence Epileptic Activity by Co-Administration of Uridine in Wistar Albino Glaxo Rijswijk Rats.

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

doi:10.3390/nu13010234

Abstract

Both uridine and exogenous ketone supplements decreased the number of spike-wave discharges (SWDs) in a rat model of human absence epilepsy Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. It has been suggested that alleviating influence of both uridine and ketone supplements on absence epileptic activity may be modulated by A1 type adenosine receptors (A1Rs). The first aim was to determine whether intraperitoneal (i.p.) administration of a specific A1R antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; 0.2 mg/kg) and a selective adenosine A2A receptor antagonist (7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo [1,5-c]pyrimidine) (SCH 58261; 0.5 mg/kg) have a modulatory influence on i.p. 1000 mg/kg uridine-evoked effects on SWD number in WAG/Rij rats. The second aim was to assess efficacy of a sub-effective dose of uridine (i.p. 250 mg/kg) combined with beta-hydroxybutyrate salt + medium chain triglyceride (KSMCT; 2.5 g/kg, gavage) on absence epilepsy. DPCPX completely abolished the i.p. 1000 mg/kg uridine-evoked alleviating effect on SWD number whereas SCH 58261 was ineffective, confirming the A1R mechanism. Moreover, the sub-effective dose of uridine markedly enhanced the effect of KSMCT (2.5 g/kg, gavage) on absence epileptic activity. These results demonstrate the anti-epilepsy benefits of co-administrating uridine and exogenous ketone supplements as a means to treat absence epilepsy.

Highlights

It has been demonstrated that nucleoside levels and metabolic enzymes, transporters, and receptors of nucleosides are unevenly distributed in the central nervous system (CNS)
It was recently demonstrated that uridine has an anticonvulsant and anti-epileptic effect on different animal models [3,5,6] such as a model of human absence epilepsy Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats [7,8], but our knowledge relating to its mechanism of action is far from complete
Uridine may be metabolized to uridine nucleotides such as uridine triphosphate (UTP) in brain cells [15], which is involved in synthesis of RNA and glycogen molecules as well as membrane lipid phosphatidylcholine [12,16]

Summary

Introduction

It has been demonstrated that nucleoside levels and metabolic enzymes, transporters, and receptors of nucleosides are unevenly distributed in the central nervous system (CNS)of animals and humans suggesting region-dependent roles of nucleosidergic system in the brain [1]. It has been demonstrated that nucleoside levels and metabolic enzymes, transporters, and receptors of nucleosides are unevenly distributed in the central nervous system (CNS). As de novo synthesis of pyrimidines in the brain is limited [13] brain utilization is mostly plasma uridine to generate and maintain proper uridine levels for different physiological processes [12]. Uridine molecules can be transported from liver cells to the circulatory system, subsequently enter the brain through the blood–brain barrier and transported through nucleoside transporters into brain cells [14]. UTP can be released from brain cells and metabolized extracellularly by ectonucleotidase enzyme cascade to uridine, which uridine can be transported again into the brain cells. It was suggested that uridine can modulate different neurotransmitter systems, such as the adenosinergic system, likely via interaction with A1 type adenosine receptors (A1 Rs) [9,11]

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