Inhibition of adenosine A1 receptors abolished the nutritional ketosis-evoked delay in the onset of isoflurane-induced anesthesia in Wistar Albino Glaxo Rijswijk rats

Abstract

Background: It has been demonstrated that administration of exogenous ketone supplement ketone salt (KS) and ketone ester (KE) increased blood ketone level and delayed the onset of isoflurane-induced anesthesia in different rodent models, such as Wistar Albino Glaxo Rijswijk (WAG/Rij) rats. The modulatory effect of adenosinergic system may have a role in the ketone supplementation-evoked effects on isoflurane-generated anesthesia. Thus, we investigated whether adenosine receptor antagonists can modulate the effect of exogenous ketone supplements on the onset of akinesia induced by isoflurane. Methods: To investigate the effect of exogenous ketone supplements on anesthetic induction we used ketone supplement KE, KS, KEKS (1:1 mix of KE and KS), KSMCT and KEMCT (1:1 mix of KS and KE with medium chain triglyceride/MCT oil, respectively) in WAG/Rij rats. Animals were fed with standard diet (SD), which was supplemented by oral gavage of different ketone supplements (2.5 g/kg/day) for 1 week. After 7 days, isoflurane (3%) was administered for 5 min and the time until onset of isoflurane-induced anesthesia (time until immobility; light phase of anesthesia: loss of consciousness without movement) was measured. Changes in levels of blood β-hydroxybutyrate (βHB), blood glucose and body weight of animals were also recorded. To investigate the putative effects of adenosine receptors on ketone supplements-evoked influence on isoflurane-induced anesthesia we used a specific adenosine A1 receptor antagonist DPCPX (intraperitoneally/i.p. 0.2 mg/kg) and a selective adenosine A2A receptor antagonist SCH 58261 (i.p. 0.5 mg/kg) alone as well as in combination with KEKS. Results: Significant increases were demonstrated in both blood βHB levels and the number of seconds required before isoflurane-induced anesthesia (immobility) after the final treatment by all exogenous ketone supplements. Moreover, this effect of exogenous ketone supplements positively correlated with blood βHB levels. It was also demonstrated that DPCPX completely abolished the effect of KEKS on isoflurane-induced anesthesia (time until immobility), but not SCH 58261.Conclusions: These findings strengthen our previous suggestion that exogenous ketone supplements may modulate the isoflurane-induced onset of anesthesia (immobility), likely through A1Rs.

Age- and Sex-Dependent Modulation of Exogenous Ketone Supplement-Evoked Effects on Blood Glucose and Ketone Body Levels in Wistar Albino Glaxo Rijswijk Rats

“…We demonstrated previously that intragastric gavage of not only KE and MCT oil but also KEMCT (mix of KE and MCT oil in a 1:1 ratio; ad libitum access to normal rat chow + 2.5g/kg body weight KEMCT) effectively induced and maintained ketosis without causing side effects ( Ari et al, 2016 ; Kesl et al, 2016 ; Kovács et al, 2020 ). Therefore, in this study, 2.5 g/kg dosage of KEMCT was administered once a month by intragastric gavage for 17 months.…”

“…Similar to our previous studies ( Kovács et al, 2018 , 2020 ), blood was taken from the tail vein of rats about 60 min after the gavage, and βHB and glucose levels were measured by a commercially available glucose and ketone monitoring system (Precision Xtra TM , Abbott Laboratories, Abbott Park, IL, United States). This instrument only measures blood levels of R-βHB.…”

“…It has been demonstrated previously that EKS-evoked ketosis can generate beneficial (modulatory) effects on absence epilepsy ( Kovács et al, 2017 , 2019b ), anxiety ( Ari et al, 2016 ; Kovács et al, 2018 ), sleep-like effects ( Ari et al, 2018 ; Kovács et al, 2020 ), and motor performance ( Ari et al, 2020 ) in a well-investigated model animal of human absence epilepsy Wistar Albino Glaxo Rijswijk (WAG/Rij) rats ( Coenen and Van Luijtelaar, 2003 ). Theoretically, these beneficial influences of EKSs, which are likely generated through ketosis ( Ari et al, 2016 , 2018 , 2020 ; Kovács et al, 2017 ), can be modulated by age and gender, but systematic investigation of the putative influences of age and gender on EKS-evoked effects through several months was not carried out previously.…”

“…Therefore, this study extends our previous results on EKS-evoked effects in WAG/Rij rats in order to obtain further understanding of how age and sex regulate EKS-generated changes in blood βHB and glucose levels. We investigated the alteration of EKS-evoked changes in these parameters in WAG/Rij rats of both sexes between 1 and 17 months of age, using a previously established effective dose of a ketone supplement mix (KE and MCT oil in a 1:1 ratio: KEMCT; 2.5 g/kg, gavage) ( Ari et al, 2020 ; Kovács et al, 2020 ).…”

Supplementation of Regular Diet With Medium-Chain Triglycerides for Procognitive Effects: A Narrative Review

“…In both studies, KSMCT treatment significantly elevated the blood level of βHB. In another study, they showed that the same KSMCT supplementation protocol alleviated isoflurane-induced anesthesia (immobility), and this effect was mediated through A 1 R but not A 2 R receptors (109). This observation was further confirmed in yet another study by the same group, where KEKS food [standard chow with mixed in ketone esters and ketone salts (110)] supplementation decreased the lipopolysaccharideinduced elevation of SWD in the same rat model, while A 1 R, but not A 2A R antagonism abolished the anti-seizure effect of KEKS supplementation (111).…”