scholarly journals The Ketogenic Diet Increases In Vivo Glutathione Levels in Patients with Epilepsy

Metabolites ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 504
Author(s):  
Antonio Napolitano ◽  
Daniela Longo ◽  
Martina Lucignani ◽  
Luca Pasquini ◽  
Maria Camilla Rossi-Espagnet ◽  
...  
Keyword(s):  
Blood Serum ◽  
Ketogenic Diet ◽  
Animal Studies ◽  
Ketone Bodies ◽  
Neuroprotective Effect ◽  
Intractable Epilepsy ◽  
Epileptic Seizures ◽  
Resonance Spectroscopy ◽  
Low Carbohydrate Diet

The Ketogenic Diet (KD) is a high-fat, low-carbohydrate diet that has been utilized as the first line treatment for contrasting intractable epilepsy. It is responsible for the presence of ketone bodies in blood, whose neuroprotective effect has been widely shown in recent years but remains unclear. Since glutathione (GSH) is implicated in oxidation-reduction reactions, our aim was to monitor the effects of KD on GSH brain levels by means of magnetic resonance spectroscopy (MRS). MRS was acquired from 16 KD patients and seven age-matched Healthy Controls (HC). We estimated metabolite concentrations with linear combination model (LCModel), assessing differences between KD and HC with t-test. Pearson was used to investigate GHS correlations with blood serum 3-B-Hydroxybutyrate (3HB) concentrations and with number of weekly epileptic seizures. The results have shown higher levels of brain GSH for KD patients (2.5 ± 0.5 mM) compared to HC (2.0 ± 0.5 mM). Both blood serum 3HB and number of seizures did not correlate with GSH concentration. The present study showed a significant increase in GSH in the brain of epileptic children treated with KD, reproducing for the first time in humans what was previously observed in animal studies. Our results may suggest a pivotal role of GSH in the antioxidant neuroprotective effect of KD in the human brain.

scholarly journals An effective medical replacement therapy: ketogenic diet for intractable childhood epilepsy

2021 ◽  
Vol 9 (4) ◽  
pp. 1234
Author(s):  
Ansh Chaudhary ◽  
Bhupendra Chaudhary
Keyword(s):  
Ketogenic Diet ◽  
Ketone Bodies ◽  
Intractable Epilepsy ◽  
Coconut Oil ◽  
Epileptic Seizures ◽  
High Fat ◽  
Low Carbohydrate ◽  
History Of ◽  
Restrictive Diet ◽  
Long Chain Triglycerides

Ketogenic diet (KD) a high fat, adequate protein and low carbohydrate restrictive diet has a long history of its use in intractable epilepsy of childhood. The diet produces biochemical changes mimicking that of starvation. The high levels of ketone bodies produced by KD act as a major source of energy for brain replacing the usual glucose.1 Comprising the ratio of 4:1 (fat:carbohydrate and protein) by weight, the diet produces state of ketonemia or ketosis that leads to reduction in frequency of epileptic seizures by is unique mode of action. To increase the palatability medium chain triglycerides (as coconut oil) in ratio of 3:1 is used which is more efficiently absorbed and have lesser gastro intestinal side effects as compared to traditional 4:1 ratio diet with long chain triglycerides like PUFA

scholarly journals Ketogenic diet for human diseases: the underlying mechanisms and potential for clinical implementations

2022 ◽  
Vol 7 (1) ◽  
Author(s):  
Huiyuan Zhu ◽  
Dexi Bi ◽  
Youhua Zhang ◽  
Cheng Kong ◽  
Jiahao Du ◽  
...  
Keyword(s):  
Ketogenic Diet ◽  
Therapeutic Potential ◽  
Ketone Bodies ◽  
Intractable Epilepsy ◽  
Mechanisms Of Action ◽  
Therapeutic Effects ◽  
Clinical Implementation ◽  
Research Attention ◽  
Low Carbohydrate Diet ◽  
Underlying Mechanisms

AbstractThe ketogenic diet (KD) is a high-fat, adequate-protein, and very-low-carbohydrate diet regimen that mimics the metabolism of the fasting state to induce the production of ketone bodies. The KD has long been established as a remarkably successful dietary approach for the treatment of intractable epilepsy and has increasingly garnered research attention rapidly in the past decade, subject to emerging evidence of the promising therapeutic potential of the KD for various diseases, besides epilepsy, from obesity to malignancies. In this review, we summarize the experimental and/or clinical evidence of the efficacy and safety of the KD in different diseases, and discuss the possible mechanisms of action based on recent advances in understanding the influence of the KD at the cellular and molecular levels. We emphasize that the KD may function through multiple mechanisms, which remain to be further elucidated. The challenges and future directions for the clinical implementation of the KD in the treatment of a spectrum of diseases have been discussed. We suggest that, with encouraging evidence of therapeutic effects and increasing insights into the mechanisms of action, randomized controlled trials should be conducted to elucidate a foundation for the clinical use of the KD.

Ketone Ester Effects on Biomarkers of Brain Metabolism and Cognitive Performance in Cognitively Intact Adults ≥ 55 Years Old. A Study Protocol for a Double-Blinded Randomized Controlled Clinical Trial

2022 ◽  
pp. 1-12
Author(s):  
K.I. Avgerinos ◽  
R.J. Mullins ◽  
J.M. Egan ◽  
D. Kapogiannis
Keyword(s):  
Metabolic Syndrome ◽  
Clinical Trial ◽  
Cognitive Performance ◽  
Animal Studies ◽  
Brain Metabolism ◽  
Ketone Bodies ◽  
Controlled Clinical Trial ◽  
Resonance Spectroscopy ◽  
Double Blinded ◽  
Cognitively Intact

BACKGROUND: Ketone bodies have been proposed as an “energy rescue” for the Alzheimer’s disease (AD) brain, which underutilizes glucose. Prior research has shown that oral ketone monoester (KME) safely induces robust ketosis in humans and has demonstrated cognitive-enhancing and pathology-reducing properties in animal models of AD. However, human evidence that KME may enhance brain ketone metabolism, improve cognitive performance and engage AD pathogenic cascades is scarce. Objectives: To investigate the effects of ketone monoester (KME) on brain metabolism, cognitive performance and AD pathogenic cascades in cognitively normal older adults with metabolic syndrome and therefore at higher risk for AD. Design: Double-blinded randomized placebo-controlled clinical trial. Setting: Clinical Unit of the National Institute on Aging, Baltimore, US. Participants: Fifty cognitively intact adults ≥ 55 years old, with metabolic syndrome. Intervention: Drinks containing 25 g of KME or isocaloric placebo consumed three times daily for 28 days. Outcomes: Primary: concentration of beta-hydroxybutyrate (BHB) in precuneus measured with Magnetic Resonance Spectroscopy (MRS). Exploratory: plasma and urine BHB, multiple brain and muscle metabolites detected with MRS, cognition assessed with the PACC and NIH toolbox, biomarkers of AD and metabolic mediators in plasma extracellular vesicles, and stool microbiome. Discussion: This is the first study to investigate the AD-biomarker and cognitive effects of KME in humans. Ketone monoester is safe, tolerable, induces robust ketosis, and animal studies indicate that it can modify AD pathology. By conducting a study of KME in a population at risk for AD, we hope to bridge the existing gap between pre-clinical evidence and the potential for brain-metabolic, pro-cognitive, and anti-Alzheimer’s effects in humans.

scholarly journals Cortical Substrate Oxidation during Hyperketonemia in the Fasted Anesthetized Rat in Vivo

2011 ◽  
Vol 31 (12) ◽  
pp. 2313-2323 ◽  
Author(s):  
Lihong Jiang ◽  
Graeme F Mason ◽  
Douglas L Rothman ◽  
Robin A de Graaf ◽  
Kevin L Behar
Keyword(s):  
Time Course ◽  
Ketone Bodies ◽  
Tricarboxylic Acid Cycle ◽  
Metabolic Model ◽  
Substrate Oxidation ◽  
Resonance Spectroscopy ◽  
Neural Function ◽  
Anesthetized Rats ◽  
Time Courses

Ketone bodies are important alternate brain fuels, but their capacity to replace glucose and support neural function is unclear. In this study, the contributions of ketone bodies and glucose to cerebral cortical metabolism were measured in vivo in halothane-anesthetized rats fasted for 36 hours ( n=6) and receiving intravenous [2,4-13C2]-d- β-hydroxybutyrate (BHB). Time courses of 13C-enriched brain amino acids (glutamate-C4, glutamine-C4, and glutamate and glutamine-C3) were measured at 9.4 Tesla using spatially localized 1H-[13C]-nuclear magnetic resonance spectroscopy. Metabolic rates were estimated by fitting a constrained, two-compartment (neuron–astrocyte) metabolic model to the 13C time-course data. We found that ketone body oxidation was substantial, accounting for 40% of total substrate oxidation (glucose plus ketone bodies) by neurons and astrocytes. d- β-Hydroxybutyrate was oxidized to a greater extent in neurons than in astrocytes (∼70:30), and followed a pattern closely similar to the metabolism of [1-13C]glucose reported in previous studies. Total neuronal tricarboxylic acid cycle (TCA) flux in hyperketonemic rats was similar to values reported for normal (nonketotic) anesthetized rats infused with [1-13C]glucose, but neuronal glucose oxidation was 40% to 50% lower, indicating that ketone bodies had compensated for the reduction in glucose use.

Exploiting metabolic susceptibilities in glioblastoma via glycolytic inhibition and ketogenic therapy.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e13558-e13558
Author(s):  
Frederic Anthony Vallejo ◽  
Sumedh Shah ◽  
Winston Walters ◽  
Katrina Kostenko ◽  
Ingrid Torrens ◽  
...  
Keyword(s):  
Stem Cell ◽  
Western Blot ◽  
Ketogenic Diet ◽  
Ketone Bodies ◽  
Combined Treatment ◽  
Glycolytic Enzymes ◽  
Parp Cleavage ◽  
Low Carbohydrate Diet ◽  
Dose Dependent Decrease ◽  
Dose Dependent

e13558 Background: Glioblastoma (GBM) remains one of the most lethal primary brain tumors in children and adults. Despite enormous efforts to elucidate the genetic and epigenetic drivers of this disease, the prognosis for patients diagnosed with GBM remains dismal. Because tumor cell metabolism differs greatly from that of normal non-cancerous cells, it is possible to develop therapies which more effectively target the cancer cell while sparing normal cells. Growing in popularity is the ketogenic diet, which is a high fat, very low carbohydrate diet resulting in the production of ketone bodies, acetoacetate (AA) and β-hydroxybutyrate (βHB) to generate ATP. Methods: Analysis conducted by open-access GBM patient database, mts assay, Western blot, neurosphere assay, and TEM. Results: Enzymes required for ketone metabolism (BDH1 and OXCT1) were significantly downregulated in GBM while glycolytic enzymes were significantly upregulated (HK2, HK1, SLC2A3, NAMPT, G6PD). GBM stem cell (GSC) markers (CD44, STAT3) positively correlated with glycolytic enzymes. Ultrastructural analysis of GSCs indicated that about half of the mitochondria were missing cristae, highly suggestive of an increased glycolytic dependency. Treatment of patient-derived GSC lines as well as non-stem cell lines SJGBM2 (pediatric) and U87 (adult) resulted in a dose-dependent decrease in viability in response to the glycolytic inhibitor 2-deoxy-D-glucose (2-DG). When cells were exposed to ketone bodies, AA but not βHB induced a dose-dependent decrease in cell viability with 10 mM reducing viability ranging from 20-80% of non-treated controls. Western blot analysis demonstrated robust caspase activation and PARP cleavage in response to AA. Furthermore, AA significantly reduced GSC neurosphere formation at 2.5 mM suggesting inhibition of GSC self-renewal pathways. Combined treatment of low dose 2-DG (50 μM) with increasing concentrations of AA resulted in more cell death than either treatment. The effect was more than additive at the low concentrations of AA (1- 5 mM) suggesting synergy. Conclusions: Glycolytic inhibition in conjunction with the ketogenic diet may be a promising therapeutic route for this difficult-to-treat cancer.

scholarly journals Ketogenic Diet in Alzheimer’s Disease

2019 ◽  
Vol 20 (16) ◽  
pp. 3892 ◽  
Author(s):  
Marta Rusek ◽  
Ryszard Pluta ◽  
Marzena Ułamek-Kozioł ◽  
Stanisław J. Czuczwar
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Ketogenic Diet ◽  
Neurodegenerative Disorder ◽  
Ketone Bodies ◽  
Amyloid Β ◽  
The Body ◽  
Aging Brain ◽  
Effective Prevention ◽  
Low Carbohydrate Diet

At present, the prevalence of Alzheimer’s disease, a devastating neurodegenerative disorder, is increasing. Although the mechanism of the underlying pathology is not fully uncovered, in the last years, there has been significant progress in its understanding. This includes: Progressive deposition of amyloid β-peptides in amyloid plaques and hyperphosphorylated tau protein in intracellular as neurofibrillary tangles; neuronal loss; and impaired glucose metabolism. Due to a lack of effective prevention and treatment strategy, emerging evidence suggests that dietary and metabolic interventions could potentially target these issues. The ketogenic diet is a very high-fat, low-carbohydrate diet, which has a fasting-like effect bringing the body into a state of ketosis. The presence of ketone bodies has a neuroprotective impact on aging brain cells. Moreover, their production may enhance mitochondrial function, reduce the expression of inflammatory and apoptotic mediators. Thus, it has gained interest as a potential therapy for neurodegenerative disorders like Alzheimer’s disease. This review aims to examine the role of the ketogenic diet in Alzheimer’s disease progression and to outline specific aspects of the nutritional profile providing a rationale for the implementation of dietary interventions as a therapeutic strategy for Alzheimer’s disease.

Case Report

2017 ◽  
Vol 32 (4) ◽  
pp. 403-407 ◽  
Author(s):  
Anita Datta ◽  
Alex Ferguson ◽  
Chris Simonson ◽  
Francesca Zannotto ◽  
Aspasia Michoulas ◽  
...  
Keyword(s):  
Ketogenic Diet ◽  
Neurodegenerative Disorder ◽  
Treatment Options ◽  
Intractable Epilepsy ◽  
Trna Synthetase ◽  
Treatment Resistant ◽  
Synthetase Deficiency ◽  
Low Carbohydrate Diet ◽  
Low Carbohydrate ◽  
And Behavior

Glutaminyl-tRNA synthetase (QARS) deficiency has been described to be a cause of a neurodegenerative disorder associated with severe developmental delay, microcephaly, delayed myelination, and intractable epilepsy. The epilepsy is thought to be more severe than other tRNA synthetase disorders. Only a few cases have been reported in the literature and there is little information about response to different treatment options. The ketogenic diet is a high-fat, low-carbohydrate diet that is used in treatment resistant epilepsy of various etiologies. There are reports that the diet can also improve neuro-cognitive parameters. The authors report a case of a patient with glutaminyl-tRNA synthetase deficiency and treatment resistant seizures where there was a marked and early favorable response in terms of seizures, alertness and behavior to the ketogenic diet.

Ketogenic Diet in a Hippocampal Slice

2016 ◽  
Author(s):  
Masahito Kawamura
Keyword(s):  
Ketogenic Diet ◽  
Hippocampal Slice ◽  
Ketone Bodies ◽  
Hippocampal Slices ◽  
Patch Clamp Technique ◽  
Ketogenic Diets ◽  
Whole Cell Patch Clamp ◽  
Electrophysiological Recordings

The hippocampus is thought to be a good experimental model for investigating epileptogenesis in and/or antiepileptic therapy for temporal lobe epilepsy. The hippocampus is also a useful target for researching the ketogenic diet. This chapter focuses on electrophysiological recordings using hippocampal slices and introduces their use for studying the anticonvulsant effects underlying ketogenic diets. The major difficulty in using hippocampal slices is the inability to precisely reproduce the in vivo condition of ketogenic diet feeding in this in vitro preparation. Three different approaches are reported to reproduce diet effects in the hippocampal slices: (1) direct application of ketone bodies, (2) mimicking the ketogenic diet condition with whole-cell patch-clamp technique, and (3) hippocampal slices from ketogenic diet–fed animals. Significant results have been found with each of these methods. These three approaches are useful tools to elucidate the underlying anticonvulsant mechanisms of the ketogenic diet.

scholarly journals Assessing Cerebral Metabolism in the Immature Rodent: From Extracts to Real-Time Assessments

2018 ◽  
Vol 40 (5-6) ◽  
pp. 463-474
Author(s):  
Alkisti Mikrogeorgiou ◽  
Duan Xu ◽  
Donna M. Ferriero ◽  
Susan J. Vannucci
Keyword(s):  
Ketone Bodies ◽  
Current Knowledge ◽  
Cerebral Metabolism ◽  
High Energy ◽  
Resonance Spectroscopy ◽  
Neurodevelopmental Outcomes ◽  
1H Mrs ◽  
13C Mrs ◽  
The Brain

Brain development is an energy-expensive process. Although glucose is irreplaceable, the developing brain utilizes a variety of substrates such as lactate and the ketone bodies, β-hydroxybutyrate and acetoacetate, to produce energy and synthesize the structural components necessary for cerebral maturation. When oxygen and nutrient supplies to the brain are restricted, as in neonatal hypoxia-ischemia (HI), cerebral energy metabolism undergoes alterations in substrate use to preserve the production of adenosine triphosphate. These changes have been studied by in situ biochemical methods that yielded valuable quantitative information about high-energy and glycolytic metabolites and established a temporal profile of the cerebral metabolic response to hypoxia and HI. However, these analyses relied on terminal experiments and averaging values from several animals at each time point as well as challenging requirements for accurate tissue processing.More recent methodologies have focused on in vivo longitudinal analyses in individual animals. The emerging field of metabolomics provides a new investigative tool for studying cerebral metabolism. Magnetic resonance spectroscopy (MRS) has enabled the acquisition of a snapshot of the metabolic status of the brain as quantifiable spectra of various intracellular metabolites. Proton (1H) MRS has been used extensively as an experimental and diagnostic tool of HI in the pursuit of markers of long-term neurodevelopmental outcomes. Still, the interpretation of the metabolite spectra acquired with 1H MRS has proven challenging, due to discrepancies among studies, regarding calculations and timing of measurements. As a result, the predictive utility of such studies is not clear. 13C MRS is methodologically more challenging, but it provides a unique window on living tissue metabolism via measurements of the incorporation of 13C label from substrates into brain metabolites and the localized determination of various metabolic fluxes. The newly developed hyperpolarized 13C MRS is an exciting method for assessing cerebral metabolism in vivo, that bears the advantages of conventional 13C MRS but with a huge gain in signal intensity and much shorter acquisition times. The first part of this review article provides a brief description of the findings of biochemical and imaging methods over the years as well as a discussion of their associated strengths and pitfalls. The second part summarizes the current knowledge on cerebral metabolism during development and HI brain injury.

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