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Neuropharmacology. 2018 May 1;133:233-241. doi: 10.1016/j.neuropharm.2018.01.011. Epub 2018 Jan 8.

Do ketone bodies mediate the anti-seizure effects of the ketogenic diet?

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Department of Pharmacology, Creighton University School of Medicine, Omaha, NE, USA.
Department of Neurology, and Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Department of Pediatrics, Department of Clinical Neurosciences, and Department of Physiology and Pharmacology, Alberta Children's Hospital Research Institute, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada. Electronic address:


Although the mechanisms underlying the anti-seizure effects of the high-fat ketogenic diet (KD) remain unclear, a long-standing question has been whether ketone bodies (i.e., β-hydroxybutyrate, acetoacetate and acetone), either alone or in combination, contribute mechanistically. The traditional belief has been that while ketone bodies reflect enhanced fatty acid oxidation and a general shift toward intermediary metabolism, they are not likely to be the key mediators of the KD's clinical effects, as blood levels of β-hydroxybutyrate do not correlate consistently with improved seizure control. Against this unresolved backdrop, new data support ketone bodies as having anti-seizure actions. Specifically, β-hydroxybutyrate has been shown to interact with multiple novel molecular targets such as histone deacetylases, hydroxycarboxylic acid receptors on immune cells, and the NLRP3 inflammasome. Clearly, as a diet-based therapy is expected to render a broad array of biochemical, molecular, and cellular changes, no single mechanism can explain how the KD works. Specific metabolic substrates or enzymes are only a few of many important factors influenced by the KD that can collectively influence brain hyperexcitability and hypersynchrony. This review summarizes recent novel experimental findings supporting the anti-seizure and neuroprotective properties of ketone bodies.


Acetoacetate; Beta-hydroxybutyrate; Epilepsy; Ketogenic diet; Ketone bodies; Neuroprotection

[Available on 2019-05-01]
[Indexed for MEDLINE]

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