Journal
AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY
Volume 304, Issue 10, Pages R829-R836Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpregu.00506.2012
Keywords
epilepsy; acetoacetate; acetone; ketogenic diet; hyperbaric oxygen
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Funding
- Office of Naval Research (ONR) [N000140710890, N000140910244]
- ONR-DOD/DURIP Equipment [N000140210643]
- Case Western MMPC [UK DK76174]
- USF [ONR N000140910244]
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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-AcAc2) would delay CNS-OT seizures in rats breathing hyperbaric oxygen (HBO2). 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-AcAc2, 1,3-butanediol (BD), or water 30 min before being placed into a hyperbaric chamber and pressurized to 5 atmospheres absolute (ATA) O-2. 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, PO2, PCO2, beta-hydroxybutyrate (BHB), acetoacetate (AcAc), and acetone were analyzed. BD-AcAc2 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-AcAc2 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-AcAc2 produced sustained ketosis and significantly delayed CNS-OT seizures by elevating AcAc and acetone.
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