title: Ketones prevent oxidative impairment of hippocampal synaptic integrity through KATP channels.
abstract: Dietary and metabolic therapies are increasingly being considered for a variety of neurological disorders, based in part on growing evidence for the neuroprotective properties of the ketogenic diet (KD) and ketones. Earlier, we demonstrated that ketones afford hippocampal synaptic protection against exogenous oxidative stress, but the mechanisms underlying these actions remain unclear. Recent studies have shown that ketones may modulate neuronal firing through interactions with ATP-sensitive potassium (KATP) channels. Here, we used a combination of electrophysiological, pharmacological, and biochemical assays to determine whether hippocampal synaptic protection by ketones is a consequence of KATP channel activation. Ketones dose-dependently reversed oxidative impairment of hippocampal synaptic integrity, neuronal viability, and bioenergetic capacity, and this action was mirrored by the KATP channel activator diazoxide. Inhibition of KATP channels reversed ketone-evoked hippocampal protection, and genetic ablation of the inwardly rectifying K+ channel subunit Kir6.2, a critical component of KATP channels, partially negated the synaptic protection afforded by ketones. This partial protection was completely reversed by co-application of the KATP blocker, 5-hydoxydecanoate (5HD). We conclude that, under conditions of oxidative injury, ketones induce synaptic protection in part through activation of KATP channels.
authors.affiliation: Departments of Neurology and Neurobiology, Barrow Neurological Institute, St. Joseph's Hospital & Medical Center, Phoenix, Arizona, United States of America.
authors.forename: Do Young
authors.initials: DY
authors.lastname: Kim
authors.affiliation: Departments of Neurology and Neurobiology, Barrow Neurological Institute, St. Joseph's Hospital & Medical Center, Phoenix, Arizona, United States of America.
authors.forename: Mohammed G
authors.initials: MG
authors.lastname: Abdelwahab
authors.affiliation: Departments of Neurology and Neurobiology, Barrow Neurological Institute, St. Joseph's Hospital & Medical Center, Phoenix, Arizona, United States of America.
authors.forename: Soo Han
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Departments of Neurology and Neurobiology, Barrow Neurological Institute, St. Joseph's Hospital & Medical Center, Phoenix, Arizona, United States of America.
authors.forename: Derek
authors.initials: D
authors.lastname: O'Neill
authors.affiliation: Departments of Cell Biology and Anatomy, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Thompson
authors.affiliation: Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Duff
authors.affiliation: Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Sullivan
authors.affiliation: Departments of Pediatrics and Clinical Neurosciences, Alberta Children's Hospital, Calgary, Alberta, Canada.
authors.forename: Jong M
authors.initials: JM
authors.lastname: Rho
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000633:toxicity; D015640:Ion Channel Gating / Q000187:drug effects*; D054086:KATP Channels / Q000378:metabolism*; D007659:Ketones / Q000494:pharmacology*; D017774:Long-Term Potentiation / Q000187:drug effects*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology; D016877:Oxidants / Q000633:toxicity; D018408:Patch-Clamp Techniques; D024661:Potassium Channels, Inwardly Rectifying / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D064233:Sulfonylurea Receptors / Q000378:metabolism; D000099161:Kcnj11 Channel
chemical_list: D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D054086:KATP Channels; D007659:Ketones; D018696:Neuroprotective Agents; D016877:Oxidants; D024661:Potassium Channels, Inwardly Rectifying; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel
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