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

Abstract

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.

• Authors: Dominic P D'Agostino, Raffaele Pilla, Heather E Held, Carol S Landon, Michelle Puchowicz, Henri Brunengraber, Csilla Ari, Patrick Arnold, Jay B Dean
• Journal: American journal of physiology. Regulatory, integrative and comparative physiology (Am J Physiol Regul Integr Comp Physiol) Vol. 304 Issue 10 Pg. R829-36 (May 15 2013) ISSN: 1522-1490 [Electronic] United States
• PMID: 23552496 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

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

Topics

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