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

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology Vol. 321; no. 2; pp. R100 - R111
• Main Authors: Stavitzski, Nicole M, Landon, Carol S, Hinojo, Christopher M, Poff, Angela M, Rogers, Christopher Q, D'Agostino, Dominic P, Dean, Jay B
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.08.2021
• Subjects: Animals; Anticonvulsants - pharmacokinetics; Anticonvulsants - pharmacology; Anticonvulsants - toxicity; Behavior, Animal - drug effects; Brain - drug effects; Brain - physiopathology; Breathing; Central nervous system; Cognition; Cognition & reasoning; Cognition - drug effects; Cognitive ability; Disease Models, Animal; Esters - pharmacokinetics; Esters - pharmacology; Esters - toxicity; Gait; Hyperbaric oxygen; Hyperbaric Oxygenation - adverse effects; Hyperoxia; Ketones; Ketones - pharmacokinetics; Ketones - pharmacology; Ketones - toxicity; Latency; Male; Males; Motor Activity - drug effects; Motor task performance; Object recognition; Oxygen; Pattern recognition; Rats; Rats, Sprague-Dawley; Reaction Time; Respiration; Rodents; Seizures; Seizures - etiology; Seizures - physiopathology; Seizures - prevention & control; Seizures - psychology; Therapy; Toxicity; Undersea; ketone ester; seizure; hyperbaric oxygen; behavior; oxygen toxicity
• ISSN: 0363-6119; 1522-1490
• DOI: 10.1152/ajpregu.00088.2021

Hyperbaric oxygen (HBO ) is breathing >1 atmosphere absolute (ATA; 101.3 kPa) O and is used in HBO therapy and undersea medicine. What limits the use of HBO 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) O (≤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.