Ketones Prevent Oxidative Impairment of Hippocampal Synaptic Integrity through K_ATP Channels

Authors

Do Young Kim, St. Joseph’s Hospital & Medical Center
Mohammed G. Abdelwahab, St. Joseph’s Hospital & Medical Center
Soo Han Lee, St. Joseph’s Hospital & Medical Center
Derek O'Neill, St. Joseph’s Hospital & Medical Center
Roger J. Thompson, University of Calgary, Canada
Henry J. Duff, University of Calgary, Canada
Patrick G. Sullivan, University of KentuckyFollow
Jong M. Rho, Alberta Children’s Hospital, Canada

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 (K_ATP) channels. Here, we used a combination of electrophysiological, pharmacological, and biochemical assays to determine whether hippocampal synaptic protection by ketones is a consequence of K_ATP channel activation. Ketones dose-dependently reversed oxidative impairment of hippocampal synaptic integrity, neuronal viability, and bioenergetic capacity, and this action was mirrored by the K_ATP channel activator diazoxide. Inhibition of K_ATP 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 K_ATP blocker, 5-hydoxydecanoate (5HD). We conclude that, under conditions of oxidative injury, ketones induce synaptic protection in part through activation of K_ATP channels.

Document Type

Article

Publication Date

1-29-2015

Notes/Citation Information

Published in PLOS One, v. 10, no. 4, article e0119316, p. 1-14.

© 2015 Kim et al.

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Digital Object Identifier (DOI)

http://dx.doi.org/10.1371/journal.pone.0119316

Funding Information

This work was supported by NIH grant NS 070261 (DYK/JMR), the Canadian Institutes of Health Research (JMR), the Barrow Neurological Foundation and the Arizona Biomedical Research Commission (DYK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Repository Citation

Kim, Do Young; Abdelwahab, Mohammed G.; Lee, Soo Han; O'Neill, Derek; Thompson, Roger J.; Duff, Henry J.; Sullivan, Patrick G.; and Rho, Jong M., "Ketones Prevent Oxidative Impairment of Hippocampal Synaptic Integrity through K_ATP Channels" (2015). Spinal Cord and Brain Injury Research Center Faculty Publications. 11.
https://uknowledge.uky.edu/scobirc_facpub/11