Dataset Information

Exogenous Ketone Supplementation Decreased the Lipopolysaccharide-Induced Increase in Absence Epileptic Activity in Wistar Albino Glaxo Rijswijk Rats.

ABSTRACT: It has been demonstrated previously that exogenous ketone supplements such as ketone ester (KE) decreased absence epileptic activity in a well-studied animal model of human absence epilepsy, Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. It is known that lipopolysaccharide (LPS)-generated changes in inflammatory processes increase absence epileptic activity, while previous studies show that ketone supplement-evoked ketosis can modulate inflammatory processes. Thus, we investigated in the present study whether administration of exogenous ketone supplements, which were mixed with standard rodent chow (containing 10% KE + 10% ketone salt/KS, % by weight, KEKS) for 10 days, can modulate the LPS-evoked changes in absence epileptic activity in WAG/Rij rats. At first, KEKS food alone was administered and changes in spike-wave discharge (SWD) number, SWD time, discharge frequency within SWDs, blood glucose, and beta-hydroxybutyrate (?HB) levels, as well as body weight and sleep-waking stages were measured. In a separate experiment, intraperitoneal (i.p.) injection of LPS (50 ?g/kg) alone and a cyclooxygenase 1 and 2 (COX-1 and COX-2) inhibitor indomethacin (10 mg/kg) alone, as well as combined IP injection of indomethacin with LPS (indomethacin + LPS) were applied in WAG/Rij rats to elucidate their influences on SWD number. In order to determine whether KEKS food can modify the LPS-evoked changes in SWD number, KEKS food in combination with IP LPS (50 ?g/kg) (KEKS + LPS), as well as KEKS food with IP indomethacin (10 mg/kg) and LPS (50 ?g/kg) (KEKS + indomethacin + LPS) were also administered. We demonstrated that KEKS food significantly increased blood ?HB levels and decreased not only the spontaneously generated absence epileptic activity (SWD number), but also the LPS-evoked increase in SWD number in WAG/Rij rats. Our results suggest that administration of exogenous ketone supplements (ketogenic foods) may be a promising therapeutic tool in the treatment of epilepsy.

SUBMITTER: Kovacs Z

PROVIDER: S-EPMC6427924 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Exogenous Ketone Supplementation Decreased the Lipopolysaccharide-Induced Increase in Absence Epileptic Activity in Wistar Albino Glaxo Rijswijk Rats.

Kovács Zsolt Z D'Agostino Dominic P DP Diamond David M DM Ari Csilla C

Frontiers in molecular neuroscience 20190228

It has been demonstrated previously that exogenous ketone supplements such as ketone ester (KE) decreased absence epileptic activity in a well-studied animal model of human absence epilepsy, Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. It is known that lipopolysaccharide (LPS)-generated changes in inflammatory processes increase absence epileptic activity, while previous studies show that ketone supplement-evoked ketosis can modulate inflammatory processes. Thus, we investigated in the present s ...[more]

PMID: 30930744

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Project description:AimsRecent evidence has demonstrated that ketone bodies, particularly β-hydroxybutyrate (BHB), are beneficial to the failing heart due to their potential as an alternative energy substrate as well as their anti-inflammatory and anti-oxidative properties. Exogenous supplementation of ketones also helps prevent heart failure (HF) development in rodent models, but whether ketones can be used to treat HF remains unexplored. Herein, we investigated whether chronic supplementation of ketones is beneficial for the heart in a mouse model of established HF.Methods and resultsTo elevate circulating ketone levels, we utilized (R)-3-hydroxybutyl-(R)-3-hydroxybutyrate [ketone ester (KE)]. C57Bl/6N male mice were subjected to transverse aortic constriction (TAC) surgery. After developing HF, mice were treated with either 20% KE or vehicle via drinking water for 2 weeks. In another cohort, mice 3-4 weeks post-TAC received acute intravenous infusions of BHB or saline for 1 h and their cardiac function was measured. 20% KE significantly elevated blood BHB in mice (P < 0.01) without inducing ketoacidosis or altering other metabolic parameters. Mice with overt HF (30-45% ejection fraction) treated with 20% KE displayed significantly elevated circulating ketone levels compared with vehicle-treated mice (P < 0.05). The significant cardiac dysfunction in mice with HF continued to worsen after 2 weeks of vehicle treatment, whereas this decline was absent in KE-treated mice (mean difference 4.7% ejection fraction; P < 0.01). KE treatment also alleviated TAC-induced cardiomyocyte hypertrophy (P < 0.05) and reduced the TAC-induced elevated cardiac periostin (P < 0.05), a marker of activated fibroblasts. Cardiac fibrosis was also significantly reduced with KE treatment in TAC mice (P < 0.01). In another cohort, acute BHB infusion significantly increased the cardiac output of mice with HF (P < 0.05), providing further support that ketone therapy can be used to treat HF.ConclusionsWe show that chronic treatment of exogenous ketones is of benefit to the failing heart and that chronic ketone elevation may be a therapeutic option for HF. Further investigations to elucidate the underlying mechanism(s) are warranted.

Project description:Recently developed ketone (monoester or salt) supplements acutely elevate blood β-hydroxybutyrate (BHB) exogenously without prolonged periods of fasting or carbohydrate restriction. Previous (small-scale) studies have found a blood glucose-lowering effect of exogenous ketones. This study aimed to systematically review available evidence and conduct meta-analyses of studies reporting on exogenous ketones and blood glucose. We searched 6 electronic databases on 13 December 2021 for randomized and nonrandomized trials of any length that reported on the use of exogenous ketones. We calculated raw mean differences (MDs) in blood BHB and glucose in 2 main analyses: 1) after compared with before acute ingestion of exogenous ketones and 2) following acute ingestion of exogenous ketones compared with a comparator supplement. We pooled effect sizes using random-effects models and performed prespecified subgroup analyses to examine the effect of potential explanatory factors, including study population, exercise, blood BHB, and supplement type, dosing, and timing. Risk of bias was examined using Cochrane's risk-of-bias tools. Studies that could not be meta-analyzed were summarized narratively. Forty-three trials including 586 participants are summarized in this review. Following ingestion, exogenous ketones increased blood BHB (MD = 1.73 mM; 95% CI: 1.26, 2.21 mM; P < 0.001) and decreased mean blood glucose (MD = -0.54 mM; 95% CI: -0.68, -0.40 mM; P < 0.001). Similarly, when compared with placebo, blood BHB increased (MD = 1.98 mM; 95% CI: 1.52, 2.45 mM; P < 0.001) and blood glucose decreased (MD = -0.47 mM; 95% CI: -0.57, -0.36 mM; P < 0.001). Across both analyses, significantly greater effects were seen with ketone monoesters compared with salts (P < 0.001). The available evidence indicates that acute ingestion of exogenous ketones leads to increased blood BHB and decreased blood glucose. Limited evidence on prolonged ketone supplementation was found.

Project description:Exogenous ketone ester and ketone ester mixed with ketone free acid formulations are rapidly entering the commercial marketspace. Short-term animal and human studies using these products suggest significant potential for primary or secondary prevention of a number of chronic disease conditions. However, a number of questions need to be addressed by the field for optimal use in humans, including variable responses among available exogenous ketones at different dosages; frequency of dosing; and their tolerability, acceptability, and efficacy in long-term clinical trials. The purpose of the current investigation was to examine the tolerability, acceptability, and circulating R-beta-hydroxybutyrate (R-βHB) and glucose responses to a ketone monoester (KME) and ketone monoester/salt (KMES) combination at 5 g and 10 g total R-βHB compared with placebo control (PC). Fourteen healthy young adults (age: 21 ± 2 years, weight: 69.7 ± 14.2 kg, percent fat: 28.1 ± 9.3%) completed each of the five study conditions: placebo control (PC), 5 g KME (KME5), 10 g KME (KME10), 5 g (KMES5), and 10 g KMES (KMES10) in a randomized crossover fashion. Circulating concentrations of R-βHB were measured at baseline (time 0) following an 8-12 h overnight fast and again at 15, 30, 60, and 120 min following drink ingestion. Participants also reported acceptability and tolerability during each condition. Concentrations of R-βHB rose to 2.4 ± 0.1 mM for KME10 after 15 min, whereas KMES10 similarly peaked (2.1 ± 0.1 mM) but at 30 min. KME5 and KMES5 achieved similar peak R-βHB concentrations (1.2 ± 0.7 vs. 1.1 ± 0.5 mM) at 15 min. Circulating R-βHB concentrations were similar to baseline for each condition by 120 min. Negative correlations were observed between R-βHB and glucose at the 30 min time point for each condition except KME10 and PC. Tolerability was similar among KME and KMES, although decreases in appetite were more frequently reported for KMES. Acceptability was slightly higher for KMES due to the more frequently reported aftertaste for KME. The results of this pilot investigation illustrate that the KME and KMES products used increase circulating R-βHB concentrations to a similar extent and time course in a dose-dependent fashion with slight differences in tolerability and acceptability. Future studies are needed to examine variable doses, frequency, and timing of exogenous ketone administration for individuals seeking to consume ketone products for health- or sport performance-related purposes.

Project description:BackgroundInterest in therapeutic applications of exogenous ketones has grown significantly, spanning patients with heart failure to endurance athletes. Exogenous ketones engender significant effects on cardiac function in heart failure and provide an ergogenic benefit in athletes. The aim of this study was to assess the effects of exogenous ketones on cardiac function in healthy participants.MethodsIn a single-arm intervention study, 20 fasting, healthy participants underwent comprehensive echocardiography (two-dimensional, Doppler, and strain) before and 30 min after weight-based oral ketone ester administration. The relationship between changes in log-transformed biomarker levels and change in absolute global longitudinal strain (GLS) was assessed using linear regression.ResultsThe mean age was 30 ± 7 years, 50% were women, 45% were nonwhite, and the average body mass index was 24.3 ± 3.1 kg/m2. Ketone ingestion acutely elevated β-hydroxybutyrate levels from a median of 0.13 mmol/L (interquartile range, 0.10-0.37 mmol/L) to 3.23 mmol/L (interquartile range, 2.40-4.97 mmol/L) (P < .001). After ketone ester consumption, systolic blood pressure, heart rate, biventricular function, left ventricular GLS, and left atrial (LA) strain all augmented, while systemic vascular resistance decreased. Displayed as mean change, increases in ejection fraction (3.1%; 95% CI, 2.0%-4.2%; P < .001), GLS (2.0%; 95% CI, 1.4%-2.7%; P < .001), right ventricular S' (1.1 cm/sec; 95% CI, 0.4-1.8 cm/sec; P = .004), LA reservoir strain (7%; 95% CI, 3%-12%; P = .005), and LA contractile strain (4%; 2%-6%; P = .001) were observed. During robustly achieved ketosis, change in GLS was inversely associated with change in nonesterified fatty acids (P = .019).ConclusionsIn a single-arm study, systolic blood pressure, heart rate, biventricular function, and LV and LA strain acutely augmented after ketone ester ingestion in healthy, fasting participants, similar to several effects observed in the failing heart. These data may provide supporting data for the ergogenic benefits observed in athletes and may become increasingly relevant with exogenous ketone consumption across a variety of cardiovascular and noncardiovascular applications.

Dataset Information

Exogenous Ketone Supplementation Decreased the Lipopolysaccharide-Induced Increase in Absence Epileptic Activity in Wistar Albino Glaxo Rijswijk Rats.

Publications

Exogenous Ketone Supplementation Decreased the Lipopolysaccharide-Induced Increase in Absence Epileptic Activity in Wistar Albino Glaxo Rijswijk Rats.

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