Development, testing and therapeutic applications of ketone esters (KE) for CNS oxygen toxicity (CNS‐OT); i.e., hyperbaric oxygen (HBO2)‐induced seizures

Abstract

We previously described the effect of KEs, non‐ionized precursors of ketone bodies, in delaying seizures in rats breathing HBO2 at 5 ATA. We hypothesize that oral administration of specific KEs (esters of acetoacetate) will cause a rapid and sustained ketosis that confers neuroprotection against CNS‐OT in rats. Male rats (n = 53) were implanted with radio‐transmitters to measure diaphragmatic electromyogram (dEMG), ECG and EEG. ≥ 7 days post‐surgery, rats were fasted for 12h and administered intragastrically with 1 of 2 KEs (10g/kg), including R,S‐1,3‐butanediol acetoacetate monoester (mKE) or R,S‐1,3‐butanediol acetoacetate di‐ester (dKE) and placed into a hyperbaric chamber and pressurized to 5 ATA O2. Latency to seizure (LS) was measured from the beginning of maximum level of HBO2 until the onset of increased EEG activity and/or tonic‐clonic twitches. Blood was drawn from 18 animals and levels of glucose, pH, pO2, pCO2, β‐hydroxybutyrate, acetoacetate and acetone were analyzed. KEs caused a rapid and sustained ketosis and delayed LS by ~227% (mKE) and ~574% (dKE) compared to control (water). In conclusion, KEs mimic the mild therapeutic ketosis produced by ketogenic diets and confer a significant neuroprotective effect by delaying CNS‐OT (ONR).