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To evaluate the neuroprotection exerted by ketosis against acute damage of the mammalian central nervous system (CNS). Search engines were interrogated to identify experimental studies comparing the mitigating effect of ketosis (intervention) versus non-ketosis (control) on acute CNS damage. Primary endpoint was a reduction in mortality. Secondary endpoints were a reduction in neuronal damage and dysfunction, and an 'aggregated advantage' (composite of all primary and secondary endpoints). Hedges' g was the effect measure. Subgroup analyses evaluated the modulatory effect of age, insult type, and injury site. Meta-regression evaluated timing, type, and magnitude of intervention as predictors of neuroprotection. The selected publications were 49 experimental murine studies (period 1979-2020). The intervention reduced mortality (g 2.45, SE 0.48, p < .01), neuronal damage (g 1.96, SE 0.23, p < .01) and dysfunction (g 0.99, SE 0.10, p < .01). Reduction of mortality was particularly pronounced in the adult subgroup (g 2.71, SE 0.57, p < .01). The aggregated advantage of ketosis was stronger in the pediatric (g 3.98, SE 0.71, p < .01), brain (g 1.96, SE 0.18, p < .01), and ischemic insult (g 2.20, SE 0.23, p < .01) subgroups. Only the magnitude of intervention was a predictor of neuroprotection (g 0.07, SE 0.03, p 0.01 per every mmol/L increase in ketone levels). Ketosis exerts a potent neuroprotection against acute damage to the mammalian CNS in terms of reduction of mortality, of neuronal damage and dysfunction. Hematic levels of ketones are directly proportional to the effect size of neuroprotection., (© 2021 International Society for Neurochemistry.)

The ability to switch between glycolysis and ketosis promotes survival by enabling metabolism through fat oxidation during periods of fasting. Carbohydrate restriction or stress can also elicit metabolic switching. Keto-adapting from glycolysis is delayed in aged rats, but factors mediating this age-related impairment have not been identified. We measured metabolic switching between glycolysis and ketosis, as well as glycogen dynamics, in young and aged rats undergoing time-restricted feeding (TRF) with a standard diet or a low carbohydrate ketogenic diet (KD). TRF alone reversed markers of insulin-related metabolic deficits and accelerated metabolic switching in aged animals. A KD+TRF, however, provided additive benefits on these variables. Remarkably, the ability to keto-adapt was not related to glycogen levels and KD-fed rats showed an enhanced elevation in glucose following epinephrine administration. This study provides new insights into the mechanisms of keto-adaptation demonstrating the utility of dietary interventions to treat metabolic impairments across the lifespan.

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.

The ketone bodies acetoacetate (AcAc) and β-hydroxybutyrate (βHB) are the subject of renewed interest given recently established pleiotropic effects regulating inflammation, oxidative stress, and gene expression. Anticatabolic effects of β-hydroxybutyrate have recently been demonstrated in human skeletal muscle under inflammatory insult, thereby expanding upon the wide-ranging therapeutic applications of nutritional ketosis., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Ketogenic diet (KD) and exogenous ketone supplements can evoke sustained ketosis, which may modulate sleep and sleep-like effects. However, no studies have been published examining the effect of ketosis on the onset of general isoflurane induced anesthesia. Therefore, we investigated the effect of the KD and different exogenous ketogenic supplements on the onset of akinesia induced by inhalation of isoflurane., Methods: We used a high fat, medium protein and low carbohydrate diet (KD) chronically (10 weeks) in the glucose transporter 1 (GLUT1) deficiency (G1D) syndrome mice model and sub-chronically (7 days) in Sprague-Dawley (SPD) rats. To investigate the effect of exogenous ketone supplements on anesthetic induction we also provided either 1) a standard rodent chow diet (SD) mixed with 20% ketone salt supplement (KS), or 2) SD mixed with 20% ketone ester supplement (KE; 1,3 butanediol-acetoacetate diester) to G1D mice for 10 weeks. Additionally, SPD rats and Wistar Albino Glaxo Rijswijk (WAG/Rij) rats were fed the SD, which was supplemented by oral gavage of KS or KE for 7 days (SPD rats: 5 g/kg body weight/day; WAG/Rij rats: 2.5 g/kg body weight/day). After these treatments (10 weeks for the mice, and 7 days for the rats) isoflurane (3%) was administered in an anesthesia chamber, and the time until anesthetic induction (time to immobility) was measured. Blood ketone levels were measured after anesthetic induction and correlation was calculated for blood beta-hydroxybutyrate (βHB) and anesthesia latency., Results: Both KD and exogenous ketone supplementation increased blood ketone levels and delayed the onset of isoflurane-induced immobility in all investigated rodent models, showing positive correlation between the two measurements. These results demonstrate that elevated blood ketone levels by either KD or exogenous ketones delayed the onset of isoflurane-induced anesthesia in these animal models., Conclusions: These findings suggest that ketone levels might affect surgical anesthetic needs, or could potentially decrease or delay effects of other narcotic gases.

Central nervous system oxygen toxicity (CNS-OT) seizures occur with little or no warning, and no effective mitigation strategy has been identified. Ketogenic diets (KD) elevate blood ketones and have successfully treated drug-resistant epilepsy. We hypothesized that a ketone ester given orally as R,S-1,3-butanediol acetoacetate diester (BD-AcAc(2)) would delay CNS-OT seizures in rats breathing hyperbaric oxygen (HBO(2)). Adult male rats (n = 60) were implanted with radiotelemetry units to measure electroencephalogram (EEG). One week postsurgery, rats were administered a single oral dose of BD-AcAc(2), 1,3-butanediol (BD), or water 30 min before being placed into a hyperbaric chamber and pressurized to 5 atmospheres absolute (ATA) O2. Latency to seizure (LS) was measured from the time maximum pressure was reached until the onset of increased EEG activity and tonic-clonic contractions. Blood was drawn at room pressure from an arterial catheter in an additional 18 animals that were administered the same compounds, and levels of glucose, pH, Po(2), Pco(2), β-hydroxybutyrate (BHB), acetoacetate (AcAc), and acetone were analyzed. BD-AcAc(2) caused a rapid (30 min) and sustained (>4 h) elevation of BHB (>3 mM) and AcAc (>3 mM), which exceeded values reported with a KD or starvation. BD-AcAc(2) increased LS by 574 ± 116% compared with control (water) and was due to the effect of AcAc and acetone but not BHB. BD produced ketosis in rats by elevating BHB (>5 mM), but AcAc and acetone remained low or undetectable. BD did not increase LS. In conclusion, acute oral administration of BD-AcAc(2) produced sustained ketosis and significantly delayed CNS-OT seizures by elevating AcAc and acetone.

The ketogenic diet (KD) is a high-fat, low-carbohydrate treatment for medically intractable epilepsy. One of the hallmark features of the KD is the production of ketone bodies which have long been believed, but not yet proven, to exert direct anti-seizure effects. The prevailing view has been that ketosis is an epiphenomenon during KD treatment, mostly due to clinical observations that blood ketone levels do not correlate well with seizure control. Nevertheless, there is increasing experimental evidence that ketone bodies alone can exert anti-seizure properties through a multiplicity of mechanisms, including but not limited to: (1) activation of inhibitory adenosine and ATP-sensitive potassium channels; (2) enhancement of mitochondrial function and reduction in oxidative stress; (3) attenuation of excitatory neurotransmission; and (4) enhancement of central γ-aminobutyric acid (GABA) synthesis. Other novel actions more recently reported include inhibition of inflammasome assembly and activation of peripheral immune cells, and epigenetic effects by decreasing the activity of histone deacetylases (HDACs). Collectively, the preclinical evidence to date suggests that ketone administration alone might afford anti-seizure benefits for patients with epilepsy. There are, however, pragmatic challenges in administering ketone bodies in humans, but prior concerns may largely be mitigated through the use of ketone esters or balanced ketone electrolyte formulations that can be given orally and induce elevated and sustained hyperketonemia to achieve therapeutic effects.

Numerous oral ketone supplements are marketed with the claim that they will rapidly induce ketosis and improve exercise performance. The purpose of this study was to assess exercise performance time and related physiological, metabolic and perceptual responses of recreational endurance runners after ingestion of a commercially available oral ketone supplement. Recreational endurance runners (n = 10; age: 20.8 ± 1.0 years; body mass: 68.9 ± 5.6 kg; height: 175.6 ± 4.9 cm) participated in a double-blind, crossover, repeated-measures study where they were randomized to 300 mg.kg-1 body weight of an oral β-hydroxybutyrate-salt + Medium Chain Triglyceride (βHB-salt+MCT) ketone supplement or a flavor matched placebo (PLA) 60 min prior to performing a 5-km running time trial (5KTT) on a treadmill. Time, HR, RPE, affect, RER, VO2, VCO2, and VE were measured during the 5-km run. The Session RPE and affect (Feeling Scale) were obtained post-5KTT. Plasma glucose, lactate and ketones were measured at baseline, 60-min post-supplement, and immediately post-5KTT. Plasma R-βHB (endogenous isomer) was elevated from baseline and throughout the entire protocol under the βHB-salt+MCT condition (p < 0.05). No significant difference (58.3 ± 100.40 s; 95% CI: -130.12 – 13.52; p = 0.100) was observed between the βHB-salt+MCT supplement (1430.0 ± 187.7 s) and the PLA (1488.3 ± 243.8 s) in time to complete the 5KTT. No other differences (p > 0.05) were noted in any of the other physiological, metabolic or perceptual measures. [ABSTRACT FROM AUTHOR]

The ketogenic diet (KD) is a high-fat, low-carbohydrate treatment for medically intractable epilepsy. One of the hallmark features of the KD is the production of ketone bodies which have long been believed, but not yet proven, to exert direct anti-seizure effects. The prevailing view has been that ketosis is an epiphenomenon during KD treatment, mostly due to clinical observations that blood ketone levels do not correlate well with seizure control. Nevertheless, there is increasing experimental evidence that ketone bodies alone can exert anti-seizure properties through a multiplicity of mechanisms, including but not limited to: (1) activation of inhibitory adenosine and ATP-sensitive potassium channels; (2) enhancement of mitochondrial function and reduction in oxidative stress; (3) attenuation of excitatory neurotransmission; and (4) enhancement of central γ-aminobutyric acid (GABA) synthesis. Other novel actions more recently reported include inhibition of inflammasome assembly and activation of peripheral immune cells, and epigenetic effects by decreasing the activity of histone deacetylases (HDACs). Collectively, the preclinical evidence to date suggests that ketone administration alone might afford anti-seizure benefits for patients with epilepsy. There are, however, pragmatic challenges in administering ketone bodies in humans, but prior concerns may largely be mitigated through the use of ketone esters or balanced ketone electrolyte formulations that can be given orally and induce elevated and sustained hyperketonemia to achieve therapeutic effects. [ABSTRACT FROM AUTHOR]

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-β-hydroxybutyrate (βHB), 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. [ABSTRACT FROM AUTHOR]

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 (βHB) 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 βHB 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. [ABSTRACT FROM AUTHOR]

Anxiety disorders are one of the most common mental health problems worldwide, but the exact pathophysiology remains largely unknown. It has been demonstrated previously that administration of exogenous ketone supplement KSMCT (ketone salt/KS + medium chain triglyceride/MCT oil) by intragastric gavage for 7 days decreased the anxiety level in genetically absence epileptic Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. To investigate the potential role of the adenosinergic system in the pathomechanism of anxiety we tested whether the inhibition of adenosine A1 receptors (A1Rs) influence the anxiolytic effect of the exogenous ketone supplement. As A1Rs may mediate such an effect, in the present study we used a specific A1R antagonist, DPCPX (1,3-dipropyl-8-cyclopentylxanthine) to test whether it modulates the anxiolytic effect of sub-chronically (7 days) applied KSMCT in the previously tested animal model by using elevated plus maze (EPM) test. We administered KSMCT (2.5 g/kg/day) alone by intragastric gavage and in combination with intraperitoneally (i.p.) injected of DPCPX in two doses (lower: 0.15 mg/kg, higher: 0.25 mg/kg). Control groups represented i.p saline and water gavage with or without i.p. DPCPX administration (2.5 g/kg/day). After treatments, the level of blood glucose and beta-hydroxybutyrate (βHB), as well as body weight were recorded. KSMCT alone significantly increased the time spent in the open arms and decreased the time spent in the closed arms, supporting our previous results. Injection of lower dose of DPCPX decreased, while higher dose of DPCPX abolished the effect of KSMCT administration on EPM. Blood bHB levels were significantly increased after administration of KSMCT, while DPCPX did not change the KSMCT induced increase in blood βHB levels. These results demonstrate that A1R inhibition modified (decreased) the anti-anxiety effect of KSMCT administration implying that the adenosinergic system, likely via A1Rs, may modulate the exogenous ketone supplement induced anxiolytic influence. [ABSTRACT FROM AUTHOR]

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 C 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 (bHB) levels were significantly increased alike after KE and KSMCT gavage, compared to control levels. The SWD number and bHB 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Gliomas are a highly heterogeneous tumor, refractory to treatment and the most frequently diagnosed primary brain tumor. Although the current WHO grading system (2016) demonstrates promise towards identifying novel treatment modalities and better prediction of prognosis over time, to date, existing targeted and mono therapy approaches have failed to elicit a robust impact on disease progression and patient survival. It is possible that tumor heterogeneity as well as specifically targeted agents fail because redundant molecular pathways in the tumor make it refractory to such approaches. Additionally, the underlying metabolic pathology, which is significantly altered during neoplastic transformation and tumor progression, is unaccounted for. With several molecular and metabolic pathways implicated in the carcinogenesis of CNS tumors, including glioma, we postulate that a systemic, broad spectrum approach to produce robust targeting of relevant and multiple molecular and metabolic regulation of growth and survival pathways, critical to the modulation of hallmarks of carcinogenesis, without clinically limiting toxicity, may provide a more sustained impact on clinical outcomes compared to the modalities of treatment evaluated to date. The objective of this review is to examine the emerging hallmark of reprogramming energy metabolism of the tumor cells and the tumor microenvironment during carcinogenesis, and to provide a rationale for exploiting this hallmark and its biological capabilities as a target for secondary chemoprevention and treatment of glioma. This review will primarily focus on interventions to induce ketosis to target the glycolytic phenotype of many cancers, with specific application to secondary chemoprevention of low grade glioma- to halt the progression of lower grade tumors to more aggressive subtypes, as evidenced by reduction in validated intermediate endpoints of disease progression including clinical symptoms. [ABSTRACT FROM AUTHOR]