Exogenous ketone ester delays CNS oxygen toxicity without impairing cognitive and motor performance in male Sprague-Dawley rats

Am J Physiol Regul Integr Comp Physiol. 2021 Aug 1;321(2):R100-R111. doi: 10.1152/ajpregu.00088.2021. Epub 2021 Jun 16.


Hyperbaric oxygen (HBO2) is breathing >1 atmosphere absolute (ATA; 101.3 kPa) O2 and is used in HBO2 therapy and undersea medicine. What limits the use of HBO2 is the risk of developing central nervous system (CNS) oxygen toxicity (CNS-OT). A promising therapy for delaying CNS-OT is ketone metabolic therapy either through diet or exogenous ketone ester (KE) supplement. Previous studies indicate that KE induces ketosis and delays the onset of CNS-OT; however, the effects of exogeneous KE on cognition and performance are understudied. Accordingly, we tested the hypothesis that oral gavage with 7.5 g/kg induces ketosis and increases the latency time to seizure (LSz) without impairing cognition and performance. A single oral dose of 7.5 g/kg KE increases systemic β-hydroxybutyrate (BHB) levels within 0.5 h and remains elevated for 4 h. Male rats were separated into three groups: control (no gavage), water-gavage, or KE-gavage, and were subjected to behavioral testing while breathing 1 ATA (101.3 kPa) of air. Testing included the following: DigiGait (DG), light/dark (LD), open field (OF), and novel object recognition (NOR). There were no adverse effects of KE on gait or motor performance (DG), cognition (NOR), and anxiety (LD, OF). In fact, KE had an anxiolytic effect (OF, LD). The LSz during exposure to 5 ATA (506.6 kPa) O2 (≤90 min) increased 307% in KE-treated rats compared with control rats. In addition, KE prevented seizures in some animals. We conclude that 7.5 g/kg is an optimal dose of KE in the male Sprague-Dawley rat model of CNS-OT.

Keywords: behavior; hyperbaric oxygen; ketone ester; oxygen toxicity; seizure.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Anticonvulsants / pharmacokinetics
  • Anticonvulsants / pharmacology*
  • Anticonvulsants / toxicity
  • Behavior, Animal / drug effects*
  • Brain / drug effects*
  • Brain / physiopathology
  • Cognition / drug effects*
  • Disease Models, Animal
  • Esters / pharmacokinetics
  • Esters / pharmacology*
  • Esters / toxicity
  • Hyperbaric Oxygenation / adverse effects
  • Ketones / pharmacokinetics
  • Ketones / pharmacology*
  • Ketones / toxicity
  • Male
  • Motor Activity / drug effects*
  • Rats
  • Rats, Sprague-Dawley
  • Reaction Time
  • Seizures / etiology
  • Seizures / physiopathology
  • Seizures / prevention & control*
  • Seizures / psychology


  • Anticonvulsants
  • Esters
  • Ketones

Associated data

  • figshare/10.6084/m9.figshare.14680509.v2