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

Dominic P. D'Agostino, Raffaele Pilla, Heather E. Held, Carol S. Landon, Michelle Puchowicz, Henri Brunengraber, Csilla Ari, Patrick Arnold, Jay B. Dean

Research output: Contribution to journalArticle

53 Citations (Scopus)

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-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) 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, PO2, PCO2, β-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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume304
Issue number10
DOIs
StatePublished - Jun 11 2013
Externally publishedYes

Fingerprint

Butylene Glycols
Ketosis
Ketones
Esters
Seizures
Central Nervous System
Oxygen
Acetone
Ketogenic Diet
Therapeutics
Electroencephalography
Hydroxybutyrates
Water
Starvation
Atmosphere
Oral Administration
acetoacetic acid
Arterial Pressure
Respiration
Catheters

All Science Journal Classification (ASJC) codes

  • Physiology
  • Physiology (medical)

Cite this

Therapeutic ketosis with ketone ester delays central nervous system oxygen toxicity seizures in rats. / D'Agostino, Dominic P.; Pilla, Raffaele; Held, Heather E.; Landon, Carol S.; Puchowicz, Michelle; Brunengraber, Henri; Ari, Csilla; Arnold, Patrick; Dean, Jay B.

In: American Journal of Physiology - Regulatory Integrative and Comparative Physiology, Vol. 304, No. 10, 11.06.2013.

Research output: Contribution to journalArticle

D'Agostino, Dominic P. ; Pilla, Raffaele ; Held, Heather E. ; Landon, Carol S. ; Puchowicz, Michelle ; Brunengraber, Henri ; Ari, Csilla ; Arnold, Patrick ; Dean, Jay B. / Therapeutic ketosis with ketone ester delays central nervous system oxygen toxicity seizures in rats. In: American Journal of Physiology - Regulatory Integrative and Comparative Physiology. 2013 ; Vol. 304, No. 10.
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