Therapeutic ketosis with ketone ester delays central nervous system oxygen toxicity seizures in rats

Am J Physiol Regul Integr Comp Physiol. 2013 May 15;304(10):R829-36. doi: 10.1152/ajpregu.00506.2012. Epub 2013 Apr 3.


Central nervous system oxygen toxicity (CNS-OT) seizures occur with little or no warning, and no effective mitigation strategy has been identified. Ketogenic diets (KD) elevate blood ketones and have successfully treated drug-resistant epilepsy. We hypothesized that a ketone ester given orally as R,S-1,3-butanediol acetoacetate diester (BD-AcAc(2)) would delay CNS-OT seizures in rats breathing hyperbaric oxygen (HBO(2)). Adult male rats (n = 60) were implanted with radiotelemetry units to measure electroencephalogram (EEG). One week postsurgery, rats were administered a single oral dose of BD-AcAc(2), 1,3-butanediol (BD), or water 30 min before being placed into a hyperbaric chamber and pressurized to 5 atmospheres absolute (ATA) O2. Latency to seizure (LS) was measured from the time maximum pressure was reached until the onset of increased EEG activity and tonic-clonic contractions. Blood was drawn at room pressure from an arterial catheter in an additional 18 animals that were administered the same compounds, and levels of glucose, pH, Po(2), Pco(2), β-hydroxybutyrate (BHB), acetoacetate (AcAc), and acetone were analyzed. BD-AcAc(2) caused a rapid (30 min) and sustained (>4 h) elevation of BHB (>3 mM) and AcAc (>3 mM), which exceeded values reported with a KD or starvation. BD-AcAc(2) increased LS by 574 ± 116% compared with control (water) and was due to the effect of AcAc and acetone but not BHB. BD produced ketosis in rats by elevating BHB (>5 mM), but AcAc and acetone remained low or undetectable. BD did not increase LS. In conclusion, acute oral administration of BD-AcAc(2) produced sustained ketosis and significantly delayed CNS-OT seizures by elevating AcAc and acetone.

Keywords: acetoacetate; acetone; epilepsy; hyperbaric oxygen; ketogenic diet.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acetoacetates / pharmacology
  • Acetoacetates / therapeutic use*
  • Animals
  • Blood Glucose
  • Brain / drug effects*
  • Brain / physiopathology
  • Butylene Glycols / pharmacology
  • Butylene Glycols / therapeutic use*
  • Electroencephalography
  • Ketosis / chemically induced*
  • Male
  • Oxygen*
  • Rats
  • Rats, Sprague-Dawley
  • Seizures / drug therapy*
  • Seizures / physiopathology
  • Telemetry


  • 1,3-butanediol diacetoacetate
  • Acetoacetates
  • Blood Glucose
  • Butylene Glycols
  • Oxygen