Cited by 523Diet and metabolism studiesEpilepsy research and treatmentDietary Effects on Health

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Anticonvulsant Mechanisms of the Ketogenic Diet

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Bough, Kristopher J., Rho, Jong M.·2007·Epilepsia

DOI 10.1111/j.1528-1167.2007.00915.x

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Abstract

Summary: The ketogenic diet (KD) is a broadly effective treatment for medically refractory epilepsy. Despite nearly a century of use, the mechanisms underlying its clinical efficacy remain unknown. In this review, we present one intersecting view of how the KD may exert its anticonvulsant activity against the backdrop of several seemingly disparate mechanistic theories. We summarize key insights gleaned from experimental and clinical studies of the KD, and focus particular attention on the role that ketone bodies, fatty acids, and limited glucose may play in seizure control. Chronic ketosis is anticipated to modify the tricarboxcylic acid cycle to increase GABA synthesis in brain, limit reactive oxygen species (ROS) generation, and boost energy production in brain tissue. Among several direct neuro‐inhibitory actions, polyunsaturated fatty acids increased after KD induce the expression of neuronal uncoupling proteins (UCPs), a collective up‐regulation of numerous energy metabolism genes, and mitochondrial biogenesis. These effects further limit ROS generation and increase energy production. As a result of limited glucose and enhanced oxidative phosphorylation, reduced glycolytic flux is hypothesized to activate metabolic K ATP channels and hyperpolarize neurons and/or glia. Although it is unlikely that a single mechanism, however well substantiated, will explain all of the diet's clinical benefits, these diverse, coordinated changes seem poised to stabilize synaptic function and increase the resistance to seizures throughout the brain.

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Authors: Bough, K. J., & Rho, J. M.
Affiliations: United States Food and Drug Administration (US)
Barrow Neurological Institute (US)
Corresponding author: Bough, Kristopher J.
ORCID: Bough, Kristopher J.
Rho, Jong M.
Venue: Epilepsia
Publisher: Wiley
Published: 2007-01
Volume: 48
Issue: 1
Pages: 43-58
ISSN: 0013-9580 (ISSN-L)
1528-1167
DOI: 10.1111/j.1528-1167.2007.00915.x
OpenAlex: W2068432022
Cited by: 523
References: 157
Citations by year: 2026: 22 · 2025: 16 · 2024: 27 · 2023: 24 · 2022: 36 · 2021: 32 · 2020: 38 · 2019: 30 · 2018: 22 · 2017: 23 · 2016: 26 · 2015: 20 · 2014: 30 · 2013: 24 · 2012: 24
FWCI: 3.27
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor, 3 d)
Locations: Epilepsia (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Physiology (medical) › Diet and metabolism studies
Health Sciences › Medicine › Clinical Neurology › Epilepsy research and treatment
Health Sciences › Medicine › Physiology (medical) › Dietary Effects on Health
Keywords: ketogenic diet, anticonvulsant mechanism, drug-resistant epilepsy, ketone bodies, fatty acids, glucose restriction, TCA cycle, GABA synthesis, reactive oxygen species, mitochondrial biogenesis, uncoupling proteins, polyunsaturated fatty acids, glycolytic flux, ATP-sensitive potassium channels, neuronal hyperpolarization, brain energy metabolism, oxidative phosphorylation
MeSH terms: Dietary Carbohydrates, Dietary Fats, Dietary Proteins, Energy Metabolism, Epilepsy, Humans, Ketone Bodies, Ketosis, Treatment Outcome, Reactive Oxygen Species, Diet, Carbohydrate-Restricted

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