Delaying latency to hyperbaric oxygen‐induced<scp>CNS</scp>oxygen toxicity seizures by combinations of exogenous ketone supplements

Ari, Csilla; Koutnik, Andrew P.; DeBlasi, Janine M.; Landon, Carol S.; Rogers, Christopher Q.; Vallas, John; Bharwani, Sahil; Puchowicz, Michelle A.; Bederman, Ilya; Diamond, David M.; Kindy, Mark S.; Dean, J. Michael; D’Agostino, Dominic P.

doi:10.14814/phy2.13961

Cited by 21 publications

(13 citation statements)

References 44 publications

(68 reference statements)

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“…Several discussions on how to evaluate oxygen toxicity in humans are ongoing, and a matter of debate; newly developed approaches have been very recently analyzed, implying new calculations, markers, and also dietetic approaches [54][55][56][57]. In our setting, it is very complicated to set direct links between pulmonary and neurological oxygen toxicity from a clinical point-of-view.…”

Section: Oxygen Toxicitymentioning

confidence: 99%

Hyperoxia Alters Ultrastructure and Induces Apoptosis in Leukemia Cell Lines

et al. 2020

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Oxygenation conditions are crucial for growth and tumor progression. Recent data suggests a decrease in cancer cell proliferation occurring after exposure to normobaric hyperoxia. Those changes are associated with fractal dimension. The purpose of this research was to study the impact of hyperoxia on apoptosis and morphology of leukemia cell lines. Two hematopoietic lymphoid cancer cell lines (a T-lymphoblastoid line, JURKAT and a B lymphoid line, CCRF-SB) were tested under conditions of normobaric hyperoxia (FiO2 > 60%, ± 18h) and compared to a standard group (FiO2 = 21%). We tested for apoptosis using a caspase-3 assay. Cell morphology was evaluated by cytospin, microphotography after coloration, and analysis by a fractal dimension calculation software. Our results showed that exposure of cell cultures to transient normobaric hyperoxia induced apoptosis (elevated caspase-3) as well as significant and precocious modifications in cell complexity, as highlighted by increased fractal dimensions in both cell lines. These features are associated with changes in structure (pycnotic nucleus and apoptosis) recorded by microscopic analysis. Such morphological alterations could be due to several molecular mechanisms and rearrangements in the cancer cell, leading to cell cycle inhibition and apoptosis as shown by caspase-3 activity. T cells seem less resistant to hyperoxia than B cells.

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Section: Oxygen Toxicitymentioning

confidence: 99%

Hyperoxia Alters Ultrastructure and Induces Apoptosis in Leukemia Cell Lines

et al. 2020

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“…Subjects report difficulty maintaining ketosis as excess consumption of carbohydrates or protein can rapidly shift the body back towards glycolysis and inhibit ketogenesis [ 13 ]. Alternative solutions to achieving nutritional ketosis are needed, and exogenous ketone supplementation has been reported to be an effective alternative to KD in the context of various disease states [ 11 , 14 , 15 , 16 , 17 , 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

“…Ketone supplementation that contains either KE, ketone salt (KS), medium chain triglycerides (MCTs), or their combinations (e.g., KEKS, KEMCT, and KSMCT) has been studied in both animal models and humans. It has been demonstrated that exogenous ketone supplementation is a safe and effective option to induce nutritional ketosis [ 16 , 29 , 30 , 31 , 32 ], and, consequently, evoke alleviating effects of ketosis on motor performance similar to KD [ 2 , 4 , 6 , 33 ]. Indeed, it was suggested that administration of KE and MCTs may evoke beneficial effects on motor dysfunction [ 34 , 35 ].…”

Section: Introductionmentioning

confidence: 99%

Exogenous Ketone Supplements Improved Motor Performance in Preclinical Rodent Models

et al. 2020

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Nutritional ketosis has been proven effective for neurometabolic conditions and disorders linked to metabolic dysregulation. While inducing nutritional ketosis, ketogenic diet (KD) can improve motor performance in the context of certain disease states, but it is unknown whether exogenous ketone supplements—alternatives to KDs—may have similar effects. Therefore, we investigated the effect of ketone supplements on motor performance, using accelerating rotarod test and on postexercise blood glucose and R-beta-hydroxybutyrate (R-βHB) levels in rodent models with and without pathology. The effect of KD, butanediol (BD), ketone-ester (KE), ketone-salt (KS), and their combination (KE + KS: KEKS) or mixtures with medium chain triglyceride (MCT) (KE + MCT: KEMCT; KS + MCT: KSMCT) was tested in Sprague-Dawley (SPD) and WAG/Rij (WR) rats and in GLUT-1 Deficiency Syndrome (G1D) mice. Motor performance was enhanced by KEMCT acutely, KE and KS subchronically in SPD rats, by KEKS and KEMCT groups in WR rats, and by KE chronically in G1D mice. We demonstrated that exogenous ketone supplementation improved motor performance to various degrees in rodent models, while effectively elevated R-βHB and in some cases offsets postexercise blood glucose elevations. Our results suggest that improvement of motor performance varies depending on the strain of rodents, specific ketone formulation, age, and exposure frequency.

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“…The addition of MCTs to ketone esters or ketone salts may offer a novel way to improve or further augment their anti-seizure/neuroprotective potential (Ari et al, 2018). A combination of BHB salts and MCT oil has been administered in ratios of 1:1 to 1:2 mixtures.…”

Section: Medium Chain Triglyceridesmentioning

confidence: 99%

“…Exogenous ketone supplements have typically been studied as a single stand-alone supplement, but the unique combination MCT added to ketone salts or ketone esters appears to have pharmacokinetic advantages and favorable behavior effects (Ari et al, 2016; Kesl et al, 2016). Formulating specific supplements will likely enhance the tolerability, absorption, peak and sustained levels of ketones in the blood, which may also translate to greater therapeutic potency and anti-seizure efficacy (Kovacs et al, 2017; Ari et al, 2018).…”

Section: Medium Chain Triglyceridesmentioning

confidence: 99%

Ketone Administration for Seizure Disorders: History and Rationale for Ketone Esters and Metabolic Alternatives

2019

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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.

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Delaying latency to hyperbaric oxygen‐inducedCNSoxygen toxicity seizures by combinations of exogenous ketone supplements

Cited by 21 publications

References 44 publications

Hyperoxia Alters Ultrastructure and Induces Apoptosis in Leukemia Cell Lines

Hyperoxia Alters Ultrastructure and Induces Apoptosis in Leukemia Cell Lines

Exogenous Ketone Supplements Improved Motor Performance in Preclinical Rodent Models

Ketone Administration for Seizure Disorders: History and Rationale for Ketone Esters and Metabolic Alternatives

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