Ketone Supplementation Dampens Subjective and Objective Responses to Alcohol: Evidence From a Preclinical Rat Study and a Randomized, Cross-Over Trial in Healthy Volunteers.

BACKGROUND: Previous preclinical and human studies have shown that a high-fat ketogenic diet and ketone supplements (KS) are efficacious in reducing alcohol craving, alcohol consumption, and signs of alcohol withdrawal. However, the effects of KS on alcohol sensitivity are unknown. METHODS: In this single-blind, cross-over study, 10 healthy participants (3 females) were administered a single, oral dose of a KS (25 g of ketones from D-ß-hydroxybutyric acid and R-1,3-butanediol) or placebo 30 minutes before an oral alcohol dose (0.25 g/kg for women; 0.31 g/kg for men). Assessments of breath alcohol concentration and blood alcohol levels (BAL) and responses on the Drug Effect Questionnaire were repeatedly obtained over 180 minutes after alcohol consumption. In a parallel preclinical study, 8 Wistar rats (4 females) received an oral gavage of KS (0.42 g ketones/kg), water, or the sweetener allulose (0.58 g/kg) followed 15 minutes later by an oral alcohol dose (0.8 g/kg). BAL was monitored for 240 minutes after alcohol exposure. RESULTS: In humans, the intake of KS before alcohol significantly blunted breath alcohol concentration and BAL, reduced ratings of alcohol liking and wanting more, and increased disliking for alcohol. In rats, KS reduced BAL more than either allulose or water. CONCLUSION: KS altered physiological and subjective responses to alcohol in both humans and rats, and the effects were likely not mediated by the sweetener allulose present in the KS drink. Therefore, KS could potentially reduce the intoxicating effects of alcohol.

The Chemistry of the Ketogenic Diet: Updates and Opportunities in Organic Synthesis.

The high-fat, low-carbohydrate (ketogenic) diet has grown in popularity in the last decade as a weight loss tool. Research into the diet's effects on the body have revealed a variety of other health benefits. The use of exogenous ketone supplements to confer the benefits of the diet without strict adherence to it represents an exciting new area of focus. Synthetic ketogenic compounds are of particular interest that has received very little emphasis and is an untapped area of focus for chemical synthesis. In this review, we summarize the chemical basis for ketogenicity and opportunities for further advancement of the field.

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

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 ß-hydroxybutyrate (ßHB), 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 ßHB 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 ßHB 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.

Effects of Ketone Bodies on Brain Metabolism and Function in Neurodegenerative Diseases.

Under normal physiological conditions the brain primarily utilizes glucose for ATP generation. However, in situations where glucose is sparse, e.g., during prolonged fasting, ketone bodies become an important energy source for the brain. The brain's utilization of ketones seems to depend mainly on the concentration in the blood, thus many dietary approaches such as ketogenic diets, ingestion of ketogenic medium-chain fatty acids or exogenous ketones, facilitate significant changes in the brain's metabolism. Therefore, these approaches may ameliorate the energy crisis in neurodegenerative diseases, which are characterized by a deterioration of the brain's glucose metabolism, providing a therapeutic advantage in these diseases. Most clinical studies examining the neuroprotective role of ketone bodies have been conducted in patients with Alzheimer's disease, where brain imaging studies support the notion of enhancing brain energy metabolism with ketones. Likewise, a few studies show modest functional improvements in patients with Parkinson's disease and cognitive benefits in patients with-or at risk of-Alzheimer's disease after ketogenic interventions. Here, we summarize current knowledge on how ketogenic interventions support brain metabolism and discuss the therapeutic role of ketones in neurodegenerative disease, emphasizing clinical data.

The Effect of 1,3-Butanediol on Cycling Time-Trial Performance.

This study investigated the effect of the racemic ß-hydroxybutyrate (ßHB) precursor, R,S-1,3-butanediol (BD), on time-trial (TT) performance and tolerability. A repeated-measures, randomized, crossover study was conducted in nine trained male cyclists (age, 26.7 ± 5.2 years; body mass, 69.6 ± 8.4 kg; height, 1.82 ± 0.09 m; body mass index, 21.2 ± 1.5 kg/m2; VO2peak,63.9 ± 2.5 ml·kg-1·min-1; Wmax, 389.3 ± 50.4 W). Participants ingested 0.35 g/kg of BD or placebo 30 min before and 60 min during 85 min of steady-state exercise, which preceded a ∼25- to 35-min TT (i.e., 7 kJ/kg). The ingestion of BD increased blood D-ßHB concentration throughout exercise (0.44-0.79 mmol/L) compared with placebo (0.11-0.16 mmol/L; all p < .001), which peaked 1 hr following the TT (1.38 ± 0.35 vs. 0.34 ± 0.24 mmol/L; p < .001). Serum glucose and blood lactate concentrations were not different between trials (all p > .05). BD ingestion increased oxygen consumption and carbon dioxide production after 20 min of steady-state exercise (p = .002 and p = .032, respectively); however, no further effects on cardiorespiratory parameters were observed. Within the BD trial, moderate to severe gastrointestinal symptoms were reported in five participants, and low levels of dizziness, nausea, and euphoria were reported in two participants. However, this had no effect on TT duration (placebo, 28.5 ± 3.6 min; BD, 28.7 ± 3.2 min; p = .62) and average power output (placebo, 290.1 ± 53.7 W; BD, 286.4 ± 45.9 W; p = .50). These results suggest that BD has no benefit for endurance performance.

The Effects of Ketogenic Diets and Ketone Supplements on the Aerobic Performance of Endurance Runners: A Systematic Review.

CONTEXT: Ketogenic diets and ketone supplements have gained popularity among endurance runners given their purported effects: potentially delaying the onset of fatigue by enabling the increased utilization of the body's fat reserve or external ketone bodies during prolonged running. OBJECTIVE: This systematic review was conducted to evaluate the effects of ketogenic diets (>60% fat and <10% carbohydrates/<50 g carbohydrates per day) or ketone supplements (ketone esters or ketone salts, medium-chain triglycerides or 1,3-butadiol) on the aerobic performance of endurance runners. DATA SOURCES: A systematic search was conducted in PubMed, Web of Science, Pro Quest, and Science Direct for publications up to October 2023. STUDY SELECTION: Human studies on the effects of ketogenic diets or ketone supplements on the aerobic performance of adult endurance runners were included after independent screening by 2 reviewers. STUDY DESIGN: Systematic review. LEVEL OF EVIDENCE: Level 3. DATA EXTRACTION: Primary outcomes were markers of aerobic performance (maximal oxygen uptake [VO2max], race time, time to exhaustion and rate of perceived exertion). RESULTS: VO2max was assessed by incremental test to exhaustion. Endurance performance was assessed by time trials, 180-minute running trials, or run-to-exhaustion trials; 5 studies on ketogenic diets and 7 studies on ketone supplements involving a total of 132 endurance runners were included. Despite the heterogeneity in study design and protocol, none reported benefits of ketogenic diets or ketone supplements on selected markers of aerobic performance compared with controls. Reduction in bodyweight and fat while preserving lean mass and improved glycemic control were reported in some included studies on ketogenic diets. CONCLUSION: This review did not identify any significant advantages or disadvantages of ketogenic diets or ketone supplements for the aerobic performance of endurance runners. Further trials with larger sample sizes, more gender-balanced participants, longer ketogenic diet interventions, and follow-up on metabolic health are warranted.

Exogenous Ketone Supplementation and Ketogenic Diets for Exercise: Considering the Effect on Skeletal Muscle Metabolism.

In recent years, ketogenic diets and ketone supplements have increased in popularity, particularly as a mechanism to improve exercise performance by modifying energetics. Since the skeletal muscle is a major metabolic and locomotory organ, it is important to take it into consideration when considering the effect of a dietary intervention, and the impact of physical activity on the body. The goal of this review is to summarize what is currently known and what still needs to be investigated concerning the relationship between ketone body metabolism and exercise, specifically in the skeletal muscle. Overall, it is clear that increased exposure to ketone bodies in combination with exercise can modify skeletal muscle metabolism, but whether this effect is beneficial or detrimental remains unclear and needs to be further interrogated before ketogenic diets or exogenous ketone supplementation can be recommended.

Self-Testing of Ketone Bodies, along with Glucose, Using Touch-Based Sweat Analysis.

ß-Hydroxybutyrate (HB) is one of the main physiological ketone bodies that play key roles in human health and wellness. Besides their important role in diabetes ketoacidosis, ketone bodies are currently receiving tremendous attention for personal nutrition in connection to the growing popularity of oral ketone supplements. Accordingly, there are urgent needs for developing a rapid, simple, and low-cost device for frequent onsite measurements of ß-hydroxybutyrate (HB), one of the main physiological ketone bodies. However, real-time profiling of dynamically changing HB concentrations is challenging and still limited to laboratory settings or to painful and invasive measurements (e.g., a commercial blood ketone meter). Herein, we address the critical need for pain-free frequent HB measurements in decentralized settings and report on a reliable noninvasive, simple, and rapid touch-based sweat HB testing and on its ability to track dynamic HB changes in secreted fingertip sweat, following the intake of commercial ketone supplements. The new touch-based HB detection method relies on an instantaneous collection of the fingertip sweat at rest on a porous poly(vinyl alcohol) (PVA) hydrogel that transports the sweat to a biocatalytic layer, composed of the ß-hydroxybutyrate dehydrogenase (HBD) enzyme and its nicotinamide adenine dinucleotide (NAD+) cofactor, covering the modified screen-printed carbon working electrode. As a result, the sweat HB can be measured rapidly by the mediated oxidation reaction of the nicotinamide adenine dinucleotide (NADH) product. A personalized HB dose-response relationship is demonstrated within a group of healthy human subjects taking commercial ketone supplements, along with a correlation between the sweat and capillary blood HB levels. Furthermore, a dual disposable biosensing device, consisting of neighboring ketone and glucose enzyme electrodes on a single-strip substrate, has been developed toward the simultaneous touch-based detection of dynamically changing sweat HB and glucose levels, following the intake of ketone and glucose drinks.

Ketone Monoester Supplementation Does Not Expedite the Recovery of Indices of Muscle Damage After Eccentric Exercise.

Purpose: The purpose of this study was to evaluate the effects of a ketone monoester supplement on indices of muscle damage during recovery after eccentric exercise. Methods: In a randomized, double-blind, independent group design, 20 moderately active healthy young adults consumed 360 mg per kg-1 bodyweight of a ketone monoester (KET) or energy-matched carbohydrate (CON) supplement twice daily following eccentric exercise (drop jumps). Maximal isometric voluntary contraction (MIVC) torque, counter-movement jump (CMJ) height, and muscle soreness were measured before (PRE), and immediately (POST), 24 h and 48 h post-exercise. Blood samples were collected for analysis of ß-hydroxybutyrate (ß-OHB), creatine kinase (CK), and select pro- and anti-inflammatory cytokines. Results: Peak blood ß-OHB concentration after supplement intake was greater (P < 0.001) in KET (4.4 ± 0.8 mM) vs. CON (0.4 ± 0.3 mM). Exercise increased CK concentration at 24 h and 48 h vs. PRE (time: P < 0.001) with no difference between KET and CON. Exercise reduced MIVC (KET: -19.9 ± 14.6; CON: -22.6 ± 11.1%) and CMJ (KET: -11.0 ± 7.5; CON: -13.0 ± 8.7%) at POST relative PRE; however, there was no difference between KET and CON on the recovery of MIVC at 24 h (KET: -15.4 ± 20.4; CON: -18.7 ± 20.1%) or 48 h (KET: -7.2 ± 21.2; CON: -11.8 ± 20.2%), or CMJ at 24 h (KET: -9.2 ± 11.5; CON: -13.4 ± 10.8) or 48 h (KET: -12.5 ± 12.4; CON: -9.1 ± 11.7). Muscle soreness was increased during post-exercise recovery (time: P < 0.001) with no differences between KET and CON. Monocyte chemoattractant protein-1 was greater (group: P = 0.007) in CON (236 ± 11 pg/mL) vs. KET (187 ± 11 pg/mL). Conclusion: In conclusion, twice daily ingestion of a ketone monoester supplement that acutely elevates blood ß-OHB concentration does not enhance the recovery of muscle performance or reduce muscle soreness following eccentric exercise in moderately active, healthy young adults.

Therapeutic Potential of Exogenous Ketone Supplement Induced Ketosis in the Treatment of Psychiatric Disorders: Review of Current Literature.

Globally, psychiatric disorders, such as anxiety disorder, bipolar disorder, schizophrenia, depression, autism spectrum disorder, and attention-deficit/hyperactivity disorder (ADHD) are becoming more prevalent. Although the exact pathological alterations are not yet clear, recent studies have demonstrated that widespread changes of very complex metabolic pathways may partially underlie the pathophysiology of many psychiatric diseases. Thus, more attention should be directed to metabolic-based therapeutic interventions in the treatment of psychiatric disorders. Emerging evidence from numerous studies suggests that administration of exogenous ketone supplements, such as ketone salts or ketone esters, generates rapid and sustained nutritional ketosis and metabolic changes, which may evoke potential therapeutic effects in cases of central nervous system (CNS) disorders, including psychiatric diseases. Therefore, the aim of this review is to summarize the current information on ketone supplementation as a potential therapeutic tool for psychiatric disorders. Ketone supplementation elevates blood levels of the ketone bodies: D-ß-hydroxybutyrate (ßHB), acetoacetate (AcAc), and acetone. These compounds, either directly or indirectly, beneficially affect the mitochondria, glycolysis, neurotransmitter levels, activity of free fatty acid receptor 3 (FFAR3), hydroxycarboxylic acid receptor 2 (HCAR2), and histone deacetylase, as well as functioning of NOD-like receptor pyrin domain 3 (NLRP3) inflammasome and mitochondrial uncoupling protein (UCP) expression. The result of downstream cellular and molecular changes is a reduction in the pathophysiology associated with various psychiatric disorders. We conclude that supplement-induced nutritional ketosis leads to metabolic changes and improvements, for example, in mitochondrial function and inflammatory processes, and suggest that development of specific adjunctive ketogenic protocols for psychiatric diseases should be actively pursued.

Exogenous Ketones Lower Blood Glucose Level in Rested and Exercised Rodent Models.

Diseases involving inflammation and oxidative stress can be exacerbated by high blood glucose levels. Due to tight metabolic regulation, safely reducing blood glucose can prove difficult. The ketogenic diet (KD) reduces absolute glucose and insulin, while increasing fatty acid oxidation, ketogenesis, and circulating levels of ß-hydroxybutyrate (ßHB), acetoacetate (AcAc), and acetone. Compliance to KD can be difficult, so alternative therapies that help reduce glucose levels are needed. Exogenous ketones provide an alternative method to elevate blood ketone levels without strict dietary requirements. In this study, we tested the changes in blood glucose and ketone (ßHB) levels in response to acute, sub-chronic, and chronic administration of various ketogenic compounds in either a post-exercise or rested state. WAG/Rij (WR) rats, a rodent model of human absence epilepsy, GLUT1 deficiency syndrome mice (GLUT1D), and wild type Sprague Dawley rats (SPD) were assessed. Non-pathological animals were also assessed across different age ranges. Experimental groups included KD, standard diet (SD) supplemented with water (Control, C) or with exogenous ketones: 1, 3-butanediol (BD), ßHB mineral salt (KS), KS with medium chain triglyceride/MCT (KSMCT), BD acetoacetate diester (KE), KE with MCT (KEMCT), and KE with KS (KEKS). In rested WR rats, the KE, KS, KSMCT groups had lower blood glucose level after 1 h of treatment, and in KE and KSMCT groups after 24 h. After exercise, the KE, KSMCT, KEKS, and KEMCT groups had lowered glucose levels after 1 h, and in the KEKS and KEMCT groups after 7 days, compared to control. In GLUT1D mice without exercise, only KE resulted in significantly lower glucose levels at week 2 and week 6 during a 10 weeks long chronic feeding study. In 4-month and 1-year-old SPD rats in the post-exercise trials, blood glucose was significantly lower in KD and KE, and in KEMCT groups, respectively. After seven days, the KSMCT group had the most significantly reduced blood glucose levels, compared to control. These results indicate that exogenous ketones were efficacious in reducing blood glucose levels within and outside the context of exercise in various rodent models of different ages, with and without pathology.

Ketogenic Diets and Exercise Performance.

The ketogenic diet (KD) has gained a resurgence in popularity due to its purported reputation for fighting obesity. The KD has also acquired attention as an alternative and/or supplemental method for producing energy in the form of ketone bodies. Recent scientific evidence highlights the KD as a promising strategy to treat obesity, diabetes, and cardiac dysfunction. In addition, studies support ketone body supplements as a potential method to induce ketosis and supply sustainable fuel sources to promote exercise performance. Despite the acceptance in the mainstream media, the KD remains controversial in the medical and scientific communities. Research suggests that the KD or ketone body supplementation may result in unexpected side effects, including altered blood lipid profiles, abnormal glucose homeostasis, increased adiposity, fatigue, and gastrointestinal distress. The purpose of this review article is to provide an overview of ketone body metabolism and a background on the KD and ketone body supplements in the context of obesity and exercise performance. The effectiveness of these dietary or supplementation strategies as a therapy for weight loss or as an ergogenic aid will be discussed. In addition, the recent evidence that indicates ketone body metabolism is a potential target for cardiac dysfunction will be reviewed.

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

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 (ßHB) levels, as well as body weight and sleep-waking stages were measured. In a separate experiment, intraperitoneal (i.p.) injection of LPS (50 µg/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 µg/kg) (KEKS + LPS), as well as KEKS food with IP indomethacin (10 mg/kg) and LPS (50 µg/kg) (KEKS + indomethacin + LPS) were also administered. We demonstrated that KEKS food significantly increased blood ßHB 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.

Nutritional Ketosis Affects Metabolism and Behavior in Sprague-Dawley Rats in Both Control and Chronic Stress Environments.

Nutritional ketosis may enhance cerebral energy metabolism and has received increased interest as a way to improve or preserve performance and resilience. Most studies to date have focused on metabolic or neurological disorders while anecdotal evidence suggests that ketosis may enhance performance in the absence of underlying dysfunction. Moreover, decreased availability of glucose in the brain following stressful events is associated with impaired cognition, suggesting the need for more efficient energy sources. We tested the hypotheses that ketosis induced by endogenous or exogenous ketones could: (a) augment cognitive outcomes in healthy subjects; and (b) prevent stress-induced detriments in cognitive parameters. Adult, male, Sprague Dawley rats were used to investigate metabolic and behavioral outcomes in 3 dietary conditions: ketogenic (KD), ketone supplemented (KS), or NIH-31 control diet in both control or chronic stress conditions. Acute administration of exogenous ketones resulted in reduction in blood glucose and sustained ketosis. Chronic experiments showed that in control conditions, only KD resulted in pronounced metabolic alterations and improved performance in the novel object recognition test. The hypothalamic-pituitary-adrenal (HPA) axis response revealed that KD-fed rats maintained peripheral ketosis despite increases in glucose whereas no diet effects were observed in ACTH or CORT levels. Both KD and KS-fed rats decreased escape latencies on the third day of water maze, whereas only KD prevented stress-induced deficits on the last testing day and improved probe test performance. Stress-induced decrease in hippocampal levels of ß-hydroxybutyrate was attenuated in KD group while both KD and KS prevented stress effects on BDNF levels. Mitochondrial enzymes associated with ketogenesis were increased in both KD and KS hippocampal samples and both endothelial and neuronal glucose transporters were affected by stress but only in the control diet group. Our results highlight the complex relationship between peripheral metabolism, behavioral performance and biochemical changes in the hippocampus. Endogenous ketosis improved behavioral and metabolic parameters associated with energy metabolism and cognition while ketone supplementation replicated the biochemical effects within the hippocampus but only showed modest effects on behavioral improvements.

Adenosine A1 Receptor Antagonism Abolished the Anti-seizure Effects of Exogenous Ketone Supplementation in Wistar Albino Glaxo Rijswijk Rats.

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 (ßHB) levels were significantly increased alike after KE and KSMCT gavage, compared to control levels. The SWD number and ßHB 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.

Corrigendum: Exogenous Ketone Supplements Reduce Anxiety-Related Behavior in Sprague-Dawley and Wistar Albino Glaxo/Rijswijk Rats.

[This corrects the article on p. 137 in vol. 9, PMID: 27999529.].

Exogenous Ketone Supplements Reduce Anxiety-Related Behavior in Sprague-Dawley and Wistar Albino Glaxo/Rijswijk Rats.

Nutritional ketosis has been proven effective for seizure disorders and other neurological disorders. The focus of this study was to determine the effects of ketone supplementation on anxiety-related behavior in Sprague-Dawley (SPD) and Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. We tested exogenous ketone supplements added to food and fed chronically for 83 days in SPD rats and administered sub-chronically for 7 days in both rat models by daily intragastric gavage bolus followed by assessment of anxiety measures on elevated plus maze (EPM). The groups included standard diet (SD) or SD + ketone supplementation. Low-dose ketone ester (LKE; 1,3-butanediol-acetoacetate diester, ~10 g/kg/day, LKE), high dose ketone ester (HKE; ~25 g/kg/day, HKE), beta-hydroxybutyrate-mineral salt (ßHB-S; ~25 g/kg/day, KS) and ßHB-S + medium chain triglyceride (MCT; ~25 g/kg/day, KSMCT) were used as ketone supplementation for chronic administration. To extend our results, exogenous ketone supplements were also tested sub-chronically on SPD rats (KE, KS and KSMCT; 5 g/kg/day) and on WAG/Rij rats (KE, KS and KSMCT; 2.5 g/kg/day). At the end of treatments behavioral data collection was conducted manually by a blinded observer and with a video-tracking system, after which blood ßHB and glucose levels were measured. Ketone supplementation reduced anxiety on EPM as measured by less entries to closed arms (sub-chronic KE and KS: SPD rats and KSMCT: WAG/Rij rats), more time spent in open arms (sub-chronic KE: SPD and KSMCT: WAG/Rij rats; chronic KSMCT: SPD rats), more distance traveled in open arms (chronic KS and KSMCT: SPD rats) and by delayed latency to entrance to closed arms (chronic KSMCT: SPD rats), when compared to control. Our data indicates that chronic and sub-chronic ketone supplementation not only elevated blood ßHB levels in both animal models, but reduced anxiety-related behavior. We conclude that ketone supplementation may represent a promising anxiolytic strategy through a novel means of inducing nutritional ketosis.