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.

The ATP-sensitive K channel is seizure protective and required for effective dietary therapy in a model of mitochondrial encephalomyopathy

“…The first hypothesis is that K ATP channels are directly modulated by ketone bodies. This phenomenon has been reported at hippocampal synapses (Kim do et al, 2015) and in the substantia nigra pars reticulata, where ketones inhibit neuronal firing by increasing K ATP open probability (Lutas et al, 2014; W. Ma, Berg, & Yellen, 2007).…”

New insights into the mechanisms of the ketogenic diet

“…Genetic manipulation of BAD designed to reduce glucose metabolism produced an increase in the activity of neuronal K ATP channels and resistance to seizures in vivo [34]. In line with those findings, pharmacological inhibition or genetic manipulation of K ATP function abrogated or attenuated ketone-induced neuroprotection and seizure resistance [34,35 •] . In the substantia nigra K ATP channels are activated under conditions that favor decreased mitochondrial respiration [36].…”

Synergistic protection against acute flurothyl‐induced seizures by adjuvant treatment of the ketogenic diet with the type 2 diabetes drug pioglitazone

“…15 Also, ketone bodies generated during a KD have been implicated in the antiseizure effects of the KD via diverse mechanisms including, but not limited to, increased Epilepsia ILAE adenosine triphosphate (ATP) generation, inhibition of the mitochondrial membrane transition pore, opening K ATP channels, inhibiting vesicular glutamate transporters, increasing adenosine, and activating A1 receptors. 3,9,[16][17][18][19][20][21] However, the lack of increase of ketone bodies in mice treated with a 1:1 KD ( Fig. 2A) suggests that the actions of ketone bodies do not contribute to the synergism.…”

“…The saturated and unsaturated fatty acids provided by the KD are most likely the ligands that activate PPARγ, but they may also modulate ion channels and neurotransmitter receptors important for dampening cellular hyperexcitability 37 . Also, ketone bodies generated during a KD have been implicated in the antiseizure effects of the KD via diverse mechanisms including, but not limited to, increased ATP generation, inhibition of the mitochondrial membrane transition pore, opening K ATP channels, inhibiting vesicular glutamate transporters, increasing adenosine and activating A1 receptors 3,9,23-27,36 . However, the lack of increase of ketone bodies in mice treated with a 1:1 KD (Fig.…”