TY - JOUR
T1 - Do ketone bodies mediate the anti-seizure effects of the ketogenic diet?
AU - Simeone, Timothy A.
AU - Simeone, Kristina A.
AU - Stafstrom, Carl E.
AU - Rho, Jong M.
N1 - Funding Information:
This work was supported by Citizens United for Research in Epilepsy Foundation (KAS), NIH NS072179 (KAS), NIH NS085389 (TAS), and the Canadian Institutes of Health Research MOP-119594 , PJT-148871 (JMR). Please note, the second author has published under the names K Dorenbos, KA Fenoglio, KA Fenoglio-Simeone and KA Simeone.
Publisher Copyright:
© 2018 Elsevier Ltd
PY - 2018/5/1
Y1 - 2018/5/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85041589409&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85041589409&partnerID=8YFLogxK
U2 - 10.1016/j.neuropharm.2018.01.011
DO - 10.1016/j.neuropharm.2018.01.011
M3 - Review article
C2 - 29325899
AN - SCOPUS:85041589409
VL - 133
SP - 233
EP - 241
JO - Neuropharmacology
JF - Neuropharmacology
SN - 0028-3908
ER -