Ketone bodies mediate antiseizure effects through mitochondrial permeability transition

Do Young Kim, Kristina A. Simeone, Timothy Simeone, Jignesh D. Pandya, Julianne C. Wilke, Younghee Ahn, James W. Geddes, Patrick G. Sullivan, Jong M. Rho

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

Objective Ketone bodies (KB) are products of fatty acid oxidation and serve as essential fuels during fasting or treatment with the high-fat antiseizure ketogenic diet (KD). Despite growing evidence that KB exert broad neuroprotective effects, their role in seizure control has not been firmly demonstrated. The major goal of this study was to demonstrate the direct antiseizure effects of KB and to identify an underlying target mechanism. Methods We studied the effects of both the KD and KB in spontaneously epileptic Kcna1-null mice using a combination of behavioral, planar multielectrode, and standard cellular electrophysiological techniques. Thresholds for mitochondrial permeability transition (mPT) were determined in acutely isolated brain mitochondria. Results KB alone were sufficient to: (1) exert antiseizure effects in Kcna1-null mice, (2) restore intrinsic impairment of hippocampal long-term potentiation and spatial learning-memory defects in Kcna1-null mutants, and (3) raise the threshold for calcium-induced mPT in acutely prepared mitochondria from hippocampi of Kcna1-null animals. Targeted deletion of the cyclophilin D subunit of the mPT complex abrogated the effects of KB on mPT, and in vivo pharmacological inhibition and activation of mPT were found to mirror and reverse, respectively, the antiseizure effects of the KD in Kcna1-null mice. Interpretation The present data reveal the first direct link between mPT and seizure control, and provide a potential mechanistic explanation for the KD. Given that mPT is increasingly being implicated in diverse neurological disorders, our results suggest that metabolism-based treatments and/or metabolic substrates might represent a worthy paradigm for therapeutic development.

Original languageEnglish
Pages (from-to)77-87
Number of pages11
JournalAnnals of Neurology
Volume78
Issue number1
DOIs
StatePublished - Jul 1 2015

Fingerprint

Ketone Bodies
Permeability
Ketogenic Diet
Mitochondria
Seizures
Long-Term Potentiation
Neuroprotective Agents
Nervous System Diseases
Fasting
Hippocampus
Fatty Acids
Therapeutics
Fats
Pharmacology
Calcium
Brain

All Science Journal Classification (ASJC) codes

  • Neurology
  • Clinical Neurology

Cite this

Ketone bodies mediate antiseizure effects through mitochondrial permeability transition. / Kim, Do Young; Simeone, Kristina A.; Simeone, Timothy; Pandya, Jignesh D.; Wilke, Julianne C.; Ahn, Younghee; Geddes, James W.; Sullivan, Patrick G.; Rho, Jong M.

In: Annals of Neurology, Vol. 78, No. 1, 01.07.2015, p. 77-87.

Research output: Contribution to journalArticle

Kim, DY, Simeone, KA, Simeone, T, Pandya, JD, Wilke, JC, Ahn, Y, Geddes, JW, Sullivan, PG & Rho, JM 2015, 'Ketone bodies mediate antiseizure effects through mitochondrial permeability transition', Annals of Neurology, vol. 78, no. 1, pp. 77-87. https://doi.org/10.1002/ana.24424
Kim, Do Young ; Simeone, Kristina A. ; Simeone, Timothy ; Pandya, Jignesh D. ; Wilke, Julianne C. ; Ahn, Younghee ; Geddes, James W. ; Sullivan, Patrick G. ; Rho, Jong M. / Ketone bodies mediate antiseizure effects through mitochondrial permeability transition. In: Annals of Neurology. 2015 ; Vol. 78, No. 1. pp. 77-87.
@article{a5e35c2e8e724a538c7b43e73ac56725,
title = "Ketone bodies mediate antiseizure effects through mitochondrial permeability transition",
abstract = "Objective Ketone bodies (KB) are products of fatty acid oxidation and serve as essential fuels during fasting or treatment with the high-fat antiseizure ketogenic diet (KD). Despite growing evidence that KB exert broad neuroprotective effects, their role in seizure control has not been firmly demonstrated. The major goal of this study was to demonstrate the direct antiseizure effects of KB and to identify an underlying target mechanism. Methods We studied the effects of both the KD and KB in spontaneously epileptic Kcna1-null mice using a combination of behavioral, planar multielectrode, and standard cellular electrophysiological techniques. Thresholds for mitochondrial permeability transition (mPT) were determined in acutely isolated brain mitochondria. Results KB alone were sufficient to: (1) exert antiseizure effects in Kcna1-null mice, (2) restore intrinsic impairment of hippocampal long-term potentiation and spatial learning-memory defects in Kcna1-null mutants, and (3) raise the threshold for calcium-induced mPT in acutely prepared mitochondria from hippocampi of Kcna1-null animals. Targeted deletion of the cyclophilin D subunit of the mPT complex abrogated the effects of KB on mPT, and in vivo pharmacological inhibition and activation of mPT were found to mirror and reverse, respectively, the antiseizure effects of the KD in Kcna1-null mice. Interpretation The present data reveal the first direct link between mPT and seizure control, and provide a potential mechanistic explanation for the KD. Given that mPT is increasingly being implicated in diverse neurological disorders, our results suggest that metabolism-based treatments and/or metabolic substrates might represent a worthy paradigm for therapeutic development.",
author = "Kim, {Do Young} and Simeone, {Kristina A.} and Timothy Simeone and Pandya, {Jignesh D.} and Wilke, {Julianne C.} and Younghee Ahn and Geddes, {James W.} and Sullivan, {Patrick G.} and Rho, {Jong M.}",
year = "2015",
month = "7",
day = "1",
doi = "10.1002/ana.24424",
language = "English",
volume = "78",
pages = "77--87",
journal = "Annals of Neurology",
issn = "0364-5134",
publisher = "John Wiley and Sons Inc.",
number = "1",

}

TY - JOUR

T1 - Ketone bodies mediate antiseizure effects through mitochondrial permeability transition

AU - Kim, Do Young

AU - Simeone, Kristina A.

AU - Simeone, Timothy

AU - Pandya, Jignesh D.

AU - Wilke, Julianne C.

AU - Ahn, Younghee

AU - Geddes, James W.

AU - Sullivan, Patrick G.

AU - Rho, Jong M.

PY - 2015/7/1

Y1 - 2015/7/1

N2 - Objective Ketone bodies (KB) are products of fatty acid oxidation and serve as essential fuels during fasting or treatment with the high-fat antiseizure ketogenic diet (KD). Despite growing evidence that KB exert broad neuroprotective effects, their role in seizure control has not been firmly demonstrated. The major goal of this study was to demonstrate the direct antiseizure effects of KB and to identify an underlying target mechanism. Methods We studied the effects of both the KD and KB in spontaneously epileptic Kcna1-null mice using a combination of behavioral, planar multielectrode, and standard cellular electrophysiological techniques. Thresholds for mitochondrial permeability transition (mPT) were determined in acutely isolated brain mitochondria. Results KB alone were sufficient to: (1) exert antiseizure effects in Kcna1-null mice, (2) restore intrinsic impairment of hippocampal long-term potentiation and spatial learning-memory defects in Kcna1-null mutants, and (3) raise the threshold for calcium-induced mPT in acutely prepared mitochondria from hippocampi of Kcna1-null animals. Targeted deletion of the cyclophilin D subunit of the mPT complex abrogated the effects of KB on mPT, and in vivo pharmacological inhibition and activation of mPT were found to mirror and reverse, respectively, the antiseizure effects of the KD in Kcna1-null mice. Interpretation The present data reveal the first direct link between mPT and seizure control, and provide a potential mechanistic explanation for the KD. Given that mPT is increasingly being implicated in diverse neurological disorders, our results suggest that metabolism-based treatments and/or metabolic substrates might represent a worthy paradigm for therapeutic development.

AB - Objective Ketone bodies (KB) are products of fatty acid oxidation and serve as essential fuels during fasting or treatment with the high-fat antiseizure ketogenic diet (KD). Despite growing evidence that KB exert broad neuroprotective effects, their role in seizure control has not been firmly demonstrated. The major goal of this study was to demonstrate the direct antiseizure effects of KB and to identify an underlying target mechanism. Methods We studied the effects of both the KD and KB in spontaneously epileptic Kcna1-null mice using a combination of behavioral, planar multielectrode, and standard cellular electrophysiological techniques. Thresholds for mitochondrial permeability transition (mPT) were determined in acutely isolated brain mitochondria. Results KB alone were sufficient to: (1) exert antiseizure effects in Kcna1-null mice, (2) restore intrinsic impairment of hippocampal long-term potentiation and spatial learning-memory defects in Kcna1-null mutants, and (3) raise the threshold for calcium-induced mPT in acutely prepared mitochondria from hippocampi of Kcna1-null animals. Targeted deletion of the cyclophilin D subunit of the mPT complex abrogated the effects of KB on mPT, and in vivo pharmacological inhibition and activation of mPT were found to mirror and reverse, respectively, the antiseizure effects of the KD in Kcna1-null mice. Interpretation The present data reveal the first direct link between mPT and seizure control, and provide a potential mechanistic explanation for the KD. Given that mPT is increasingly being implicated in diverse neurological disorders, our results suggest that metabolism-based treatments and/or metabolic substrates might represent a worthy paradigm for therapeutic development.

UR - http://www.scopus.com/inward/record.url?scp=84933181448&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84933181448&partnerID=8YFLogxK

U2 - 10.1002/ana.24424

DO - 10.1002/ana.24424

M3 - Article

C2 - 25899847

AN - SCOPUS:84933181448

VL - 78

SP - 77

EP - 87

JO - Annals of Neurology

JF - Annals of Neurology

SN - 0364-5134

IS - 1

ER -