Use of the Ketogenic Diet to Treat Intractable Epilepsy in Mitochondrial Disorders

Paleologou, Eleni; Ismayilova, Naila; Kinali, Maria

doi:10.3390/jcm6060056

Cited by 28 publications

(22 citation statements)

References 68 publications

(149 reference statements)

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“…The clinical relevance of nutritional ketosis to mitochondrial function is further indicated by promotion of ketogenic diets for treatment of mitochondrial disorders [ 19 , 20 , 26 , 30 , 247 , 403 ]. The most prominent example is the study of mitochondrial adaptations as a mechanism for the well-known antiseizure effect of ketogenic diets [ 19 , 29 , 33 , 162 , 247 , 403 – 405 ]. As previously discussed, the dramatic shift in energy metabolism and subsequent increase in circulating ketones induced by a ketogenic diet can enhance mitochondrial function and endogenous antioxidant defense.…”

Section: Discussionmentioning

confidence: 99%

Nutritional Ketosis and Mitohormesis: Potential Implications for Mitochondrial Function and Human Health

Miller

Villamena

Volek

2018

Journal of Nutrition and Metabolism

148

119

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Impaired mitochondrial function often results in excessive production of reactive oxygen species (ROS) and is involved in the etiology of many chronic diseases, including cardiovascular disease, diabetes, neurodegenerative disorders, and cancer. Moderate levels of mitochondrial ROS, however, can protect against chronic disease by inducing upregulation of mitochondrial capacity and endogenous antioxidant defense. This phenomenon, referred to as mitohormesis, is induced through increased reliance on mitochondrial respiration, which can occur through diet or exercise. Nutritional ketosis is a safe and physiological metabolic state induced through a ketogenic diet low in carbohydrate and moderate in protein. Such a diet increases reliance on mitochondrial respiration and may, therefore, induce mitohormesis. Furthermore, the ketone β-hydroxybutyrate (BHB), which is elevated during nutritional ketosis to levels no greater than those resulting from fasting, acts as a signaling molecule in addition to its traditionally known role as an energy substrate. BHB signaling induces adaptations similar to mitohormesis, thereby expanding the potential benefit of nutritional ketosis beyond carbohydrate restriction. This review describes the evidence supporting enhancement of mitochondrial function and endogenous antioxidant defense in response to nutritional ketosis, as well as the potential mechanisms leading to these adaptations.

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Section: Discussionmentioning

confidence: 99%

Nutritional Ketosis and Mitohormesis: Potential Implications for Mitochondrial Function and Human Health

Miller

Villamena

Volek

2018

Journal of Nutrition and Metabolism

148

119

View full text Add to dashboard Cite

show abstract

“…The ketogenic diet is particularly the treatment of choice in patients suffering from seizures due to glucose transporter 1 (GLUT-1) deficiency syndrome and pyruvate dehydrogenase complex deficiency, given that it circumvents the metabolic deficiencies in these syndromes [ 37 ]. However, the ketogenic diet has also been found to be an effective treatment in syndromes which are not directly linked to mutations in the metabolic pathway, such as Dravet syndrome or Doose syndrome [ 37 , 38 ] and has been advocated for the treatment of epilepsies due to mitochonridal diseases [ 39 ]. The exact mechanisms of the seizure suppressive effect of the ketogenic remain elusive.…”

Section: Mitochondria and Epilepsy—adenosine Triphosphate (Atp) Cmentioning

confidence: 99%

Metabolic and Homeostatic Changes in Seizures and Acquired Epilepsy—Mitochondria, Calcium Dynamics and Reactive Oxygen Species

Kovač

Dinkova‐Kostova

Herrmann

et al. 2017

IJMS

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Acquired epilepsies can arise as a consequence of brain injury and result in unprovoked seizures that emerge after a latent period of epileptogenesis. These epilepsies pose a major challenge to clinicians as they are present in the majority of patients seen in a common outpatient epilepsy clinic and are prone to pharmacoresistance, highlighting an unmet need for new treatment strategies. Metabolic and homeostatic changes are closely linked to seizures and epilepsy, although, surprisingly, no potential treatment targets to date have been translated into clinical practice. We summarize here the current knowledge about metabolic and homeostatic changes in seizures and acquired epilepsy, maintaining a particular focus on mitochondria, calcium dynamics, reactive oxygen species and key regulators of cellular metabolism such as the Nrf2 pathway. Finally, we highlight research gaps that will need to be addressed in the future which may help to translate these findings into clinical practice.

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“…Therefore, increasing the clearance of Aβ across the BBB via the induction of P-gp or/and LRP1 expression, and consequently PICALM, may be an effective strategy to protect the brain from the accumulation of Aβ [20] and prevent AD onset. One of the new AD treatments currently under development is the ketogenic diet (KD) [21][22][23][24]. KD is characterized by a nutrient intake that is very poor in carbohydrates and high in fatty acids [25]; hence, it produces much of the same physiological effects of low food intake (i.e., fasting) [26,27] and promotes the production of KBs (in liver mitochondria), β-hydroxybutyrate (βHB) and acetoacetate (AcAc) in particular.…”

Section: Introductionmentioning

confidence: 99%

Ketone Bodies Promote Amyloid-β1–40 Clearance in a Human in Vitro Blood–Brain Barrier Model

Versele

Corsi

Fuso

et al. 2020

IJMS

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Alzheimer’s disease (AD) is characterized by the abnormal accumulation of amyloid-β (Aβ) peptides in the brain. The pathological process has not yet been clarified, although dysfunctional transport of Aβ across the blood–brain barrier (BBB) appears to be integral to disease development. At present, no effective therapeutic treatment against AD exists, and the adoption of a ketogenic diet (KD) or ketone body (KB) supplements have been investigated as potential new therapeutic approaches. Despite experimental evidence supporting the hypothesis that KBs reduce the Aβ load in the AD brain, little information is available about the effect of KBs on BBB and their effect on Aβ transport. Therefore, we used a human in vitro BBB model, brain-like endothelial cells (BLECs), to investigate the effect of KBs on the BBB and on Aβ transport. Our results show that KBs do not modify BBB integrity and do not cause toxicity to BLECs. Furthermore, the presence of KBs in the culture media was combined with higher MCT1 and GLUT1 protein levels in BLECs. In addition, KBs significantly enhanced the protein levels of LRP1, P-gp, and PICALM, described to be involved in Aβ clearance. Finally, the combined use of KBs promotes Aβ efflux across the BBB. Inhibition experiments demonstrated the involvement of LRP1 and P-gp in the efflux. This work provides evidence that KBs promote Aβ clearance from the brain to blood in addition to exciting perspectives for studying the use of KBs in therapeutic approaches.

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Use of the Ketogenic Diet to Treat Intractable Epilepsy in Mitochondrial Disorders

Cited by 28 publications

References 68 publications

Nutritional Ketosis and Mitohormesis: Potential Implications for Mitochondrial Function and Human Health

Nutritional Ketosis and Mitohormesis: Potential Implications for Mitochondrial Function and Human Health

Metabolic and Homeostatic Changes in Seizures and Acquired Epilepsy—Mitochondria, Calcium Dynamics and Reactive Oxygen Species

Ketone Bodies Promote Amyloid-β1–40 Clearance in a Human in Vitro Blood–Brain Barrier Model

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