title: 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.affiliation: Department of Molecular Pharmacology and Physiology, Hyperbaric Biomedical Research Laboratory, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA. ddagosti@health.usf.edu
authors.forename: Dominic P
authors.initials: DP
authors.lastname: D'Agostino
authors.forename: Raffaele
authors.initials: R
authors.lastname: Pilla
authors.forename: Heather E
authors.initials: HE
authors.lastname: Held
authors.forename: Carol S
authors.initials: CS
authors.lastname: Landon
authors.forename: Michelle
authors.initials: M
authors.lastname: Puchowicz
authors.forename: Henri
authors.initials: H
authors.lastname: Brunengraber
authors.forename: Csilla
authors.initials: C
authors.lastname: Ari
authors.forename: Patrick
authors.initials: P
authors.lastname: Arnold
authors.forename: Jay B
authors.initials: JB
authors.lastname: Dean
mesh_terms: D000090:Acetoacetates / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001786:Blood Glucose; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology; D002072:Butylene Glycols / Q000494:pharmacology / Q000627:therapeutic use*; D004569:Electroencephalography; D007662:Ketosis / Q000139:chemically induced*; D008297:Male; D010100:Oxygen; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000188:drug therapy* / Q000503:physiopathology; D013686:Telemetry
chemical_list: C094875:1,3-butanediol diacetoacetate; D000090:Acetoacetates; D001786:Blood Glucose; D002072:Butylene Glycols; D010100:Oxygen
keywords: acetoacetate; acetone; epilepsy; hyperbaric oxygen; ketogenic diet