• DOI:10.1152/ajpregu.00506.2012
• Corpus ID: 556095

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

@article{DAgostino2013TherapeuticKW,
  title={Therapeutic ketosis with ketone ester delays central nervous system oxygen toxicity seizures in rats.},
  author={Dominic P D'Agostino and Raffaele Pilla and Heather E. Held and Carol S. Landon and Michelle A. Puchowicz and Henri Brunengraber and Csilla Ari and Patrick Arnold and Jay B. Dean},
  journal={American journal of physiology. Regulatory, integrative and comparative physiology},
  year={2013},
  volume={304 10},
  pages={
          R829-36
        }
}

• D. D'Agostino, R. Pilla, +6 authors J. Dean
• Published 15 May 2013
• Biology
• American journal of physiology. Regulatory, integrative and comparative physiology

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.