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

Brunner, Brigitta; Rauch, E.; Ari, Csilla; D’Agostino, Dominic P.; Kovács, Zsolt

doi:10.3390/nu13010234

Cited by 7 publications

(8 citation statements)

References 67 publications

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“…β-OHB infusion in patients with HFrEF can significantly improve cardiac output and reduce systemic vascular resistance in a dosedependent manner without impairing the myocardial external energy efficiency (Nielsen et al, 2019). Oral forms of β-OHB include 1,3-butanediol (Scott et al, 2019), medium-chain triglyceride (MCT) supplementation (Brunner et al, 2021), KEs, and ketone salts (Stubbs et al, 2017). Among them, KEs are the most promising therapeutics, with smaller effective doses and fewer side effects.…”

Section: Potential Therapeutic Applications Of β-Ohbmentioning

confidence: 99%

Beta-Hydroxybutyrate, Friend or Foe for Stressed Hearts

2021

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One of the characteristics of the failing human heart is a significant alteration in its energy metabolism. Recently, a ketone body, β-hydroxybutyrate (β-OHB) has been implicated in the failing heart’s energy metabolism as an alternative “fuel source.” Utilization of β-OHB in the failing heart increases, and this serves as a “fuel switch” that has been demonstrated to become an adaptive response to stress during the heart failure progression in both diabetic and non-diabetic patients. In addition to serving as an alternative “fuel,” β-OHB represents a signaling molecule that acts as an endogenous histone deacetylase (HDAC) inhibitor. It can increase histone acetylation or lysine acetylation of other signaling molecules. β-OHB has been shown to decrease the production of reactive oxygen species and activate autophagy. Moreover, β-OHB works as an NLR family pyrin domain-containing protein 3 (Nlrp3) inflammasome inhibitor and reduces Nlrp3-mediated inflammatory responses. It has also been reported that β-OHB plays a role in transcriptional or post-translational regulations of various genes’ expression. Increasing β-OHB levels prior to ischemia/reperfusion injury results in a reduced infarct size in rodents, likely due to the signaling function of β-OHB in addition to its role in providing energy. Sodium-glucose co-transporter-2 (SGLT2) inhibitors have been shown to exert strong beneficial effects on the cardiovascular system. They are also capable of increasing the production of β-OHB, which may partially explain their clinical efficacy. Despite all of the beneficial effects of β-OHB, some studies have shown detrimental effects of long-term exposure to β-OHB. Furthermore, not all means of increasing β-OHB levels in the heart are equally effective in treating heart failure. The best timing and therapeutic strategies for the delivery of β-OHB to treat heart disease are unknown and yet to be determined. In this review, we focus on the crucial role of ketone bodies, particularly β-OHB, as both an energy source and a signaling molecule in the stressed heart and the overall therapeutic potential of this compound for cardiovascular diseases.

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Section: Potential Therapeutic Applications Of β-Ohbmentioning

confidence: 99%

Beta-Hydroxybutyrate, Friend or Foe for Stressed Hearts

2021

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“…Electrode implantation for EEG recording was carried out under isoflurane anesthesia (Isoflurane was 2.0-2.5% in an Isoflurane-air mixture) [31]. Stainless steel screw electrodes were implanted epidurally above the frontal cortex and parietal cortex (based on stereotaxic coordinates: AP 2.0 mm, L 2.1 mm and AP −6.5 mm, L 2.1 mm, respectively) [32].…”

Section: Electrode Implantationmentioning

confidence: 99%

“…Consequently, we fed the animals with KEKS food for nine days. Moreover, based on our previous results [11,23,31,34] on WAG/Rij rats, we intraperitoneally (i.p.) administered the effective and well-tolerated dose of LPS (50 µg/kg; Sigma-Aldrich, Inc., Hungary) alone; LPS with both a non-proepileptic dose of an A1R antagonist DPCPX (0.2 mg/kg; Sigma-Aldrich, Inc., Hungary) (DPCPX + LPS) and non-antiepileptic dose of an A2AR antagonist SCH58261 (0.5 mg/kg; Sigma-Aldrich, Inc., Hungary) (SCH58261 + LPS); and KEKS food with LPS (KEKS food + LPS), with DPCPX and LPS (KEKS food + DPCPX + LPS) and SCH58261 and LPS (KEKS food + SCH58261 + LPS).…”

Section: Administration Of Exogenous Ketogenic Supplements and Different Drugsmentioning

confidence: 99%

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

et al. 2021

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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.

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“…Brunner and colleagues tested the efficacy of uridine and exogenous ketone supplements in decreasing bilateral, synchronous, spontaneous spike-wave discharges in Wistar Albino Glaxo/Rijswijk rats (WAG/Rij), a model of human absence epilepsy [5]. After implanting EEG electrodes in the rat brains, the authors treated cohorts of animals with type A1 adenosine receptor antagonist (A1R), A2R antagonist, uridine and exogenous ketone supplements plus medium-chain triglycerides as well as combinations of these chemicals prior to measuring spine-wave discharges.…”

mentioning

confidence: 99%