Abstract
The state of therapeutic ketosis can be achieved by using the ketogenic diet (KD) or exogenous ketone supplementation. It was suggested previously that the adenosinergic system may be involved in the mediating effect of KD on suppressing seizure activity in different types of epilepsies, likely by means of adenosine A1 receptors (A1Rs). Thus, we tested in the present study whether exogenous ketone supplements (ketone ester: KE, 2.5 g/kg/day; ketone salt/KS + medium chain triglyceride/MCT: KSMCT, 2.5 g/kg/day) applied sub-chronically (for 7 days) by intragastric gavage can modulate absence epileptic activity in genetically absence epileptic Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. The number of spike-wave discharges (SWDs) significantly and similarly decreased after both KE and KSMCT treatment between 3rd and 7th days of gavage. Moreover, blood beta-hydroxybutyrate (βHB) levels were significantly increased alike after KE and KSMCT gavage, compared to control levels. The SWD number and βHB levels returned to the baseline levels on the first day without ketone supplementation. To determine whether A1Rs can modify ketone supplement-evoked changes in absence epileptic activity, we applied a non-pro-epileptic dose of a specific A1R antagonist DPCPX (1,3-dipropyl-8-cyclopentylxanthine) (intraperitoneal/i.p. 0.2 mg/kg) in combination with KSMCT (2.5 g/kg/day, gavage). As expected, DPCPX abolished the KSMCT-evoked decrease in SWD number. Thus, we concluded that application of exogenous ketone supplements may decrease absence epileptic activity in WAG/Rij rats. Moreover, our results suggest that among others the adenosinergic system, likely via A1Rs, may modulate the exogenous ketone supplements-evoked anti-seizure effects.
Highlights
Ketogenic diet and ketone supplementation may evoke nutritional ketosis (Kwiterovich et al, 2003; Poff et al, 2015; Kesl et al, 2016), which enhances conversion of ketone bodies such as beta-hydroxybutyrate and acetoacetate (AcAc) into acetyl-CoA to support adenosine triphosphate (ATP) production (Yudkoff et al, 2007)
As we have no data on the putative effects of intraperitoneally (i.p.) injected specific adenosine A1 receptor (A1R) antagonist DPCPX on absence epileptic activity in Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats, we investigated the effect of two doses (i.p. 0.2 and 0.5 mg/kg alone) on spike-wave discharge (SWD) number
We demonstrated that exogenous ketone supplements increased blood βHB levels and decreased SWD number when given sub-chronically and inhibition of A1Rs abolished the exogenous ketone supplementsevoked changes in SWD number in WAG/Rij rats
Summary
Ketogenic diet (high-fat, adequate protein, and low carbohydrate diet) and ketone supplementation (exogenous ketone supplement and/or MCT) may evoke nutritional ketosis (Kwiterovich et al, 2003; Poff et al, 2015; Kesl et al, 2016), which enhances conversion of ketone bodies such as beta-hydroxybutyrate and acetoacetate (AcAc) into acetyl-CoA to support ATP production (Yudkoff et al, 2007). Under this condition, the cells utilize ketone bodies as an alternative fuel to enhance brain energy metabolism. Absence epileptic WAG/Rij rats spontaneously generate absence-like seizures, and manifest spike-wave asymmetric discharges (SWDs) on the EEG. It was demonstrated that the hyperexcitable neurons of cortical focus in the somatosensory cortex initiate SWDs (cortical focus theory) (Meeren et al, 2002)
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