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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Barrow Neurological Institute, St Joseph's Hospital and Medical Center, Phoenix, AZ.
authors.forename: Do Young
authors.initials: DY
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, Creighton University School of Medicine, Omaha, NE.
authors.forename: Kristina A
authors.initials: KA
authors.lastname: Simeone
authors.affiliation: Department of Pharmacology, Creighton University School of Medicine, Omaha, NE.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Simeone
authors.affiliation: Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY.
authors.forename: Jignesh D
authors.initials: JD
authors.lastname: Pandya
authors.affiliation: Barrow Neurological Institute, St Joseph's Hospital and Medical Center, Phoenix, AZ.
authors.forename: Julianne C
authors.initials: JC
authors.lastname: Wilke
authors.affiliation: Departments of Pediatrics and Clinical Neurosciences, Alberta Children's Hospital Research Institute for Child and Maternal Health, University of Calgary Faculty of Medicine, Calgary, Alberta, Canada.
authors.forename: Younghee
authors.initials: Y
authors.lastname: Ahn
authors.affiliation: Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY.
authors.forename: James W
authors.initials: JW
authors.lastname: Geddes
authors.affiliation: Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY.
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Sullivan
authors.affiliation: Departments of Pediatrics and Clinical Neurosciences, Alberta Children's Hospital Research Institute for Child and Maternal Health, University of Calgary Faculty of Medicine, Calgary, Alberta, Canada.
authors.forename: Jong M
authors.initials: JM
authors.lastname: Rho
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D055423:Diet, Ketogenic; D004195:Disease Models, Animal; D004569:Electroencephalography; D004833:Epilepsy, Temporal Lobe; D007657:Ketone Bodies / Q000494:pharmacology; D051662:Kv1.1 Potassium Channel / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects* / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D018408:Patch-Clamp Techniques
chemical_list: D000927:Anticonvulsants; C496947:Kcna1 protein, mouse; D007657:Ketone Bodies; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D051662:Kv1.1 Potassium Channel; D020155:3-Hydroxybutyric Acid