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Development, testing and therapeutic applications of ketone esters (KE) for CNS oxygen toxicity (CNS‐OT); i.e., hyperbaric oxygen (HBO2)‐induced seizures
Author(s) -
D'Agostino Dominic,
Pilla Raffaele,
Held Heather,
Landon Carol,
Ari Csilla,
Arnold Patrick,
Dean Jay B
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.711.10
Subject(s) - ketosis , ketone bodies , neuroprotection , anesthesia , chemistry , medicine , electroencephalography , pharmacology , endocrinology , metabolism , psychiatry , diabetes mellitus
We previously described the effect of KEs, non‐ionized precursors of ketone bodies, in delaying seizures in rats breathing HBO 2 at 5 ATA. We hypothesize that oral administration of specific KEs (esters of acetoacetate) will cause a rapid and sustained ketosis that confers neuroprotection against CNS‐OT in rats. Male rats (n = 53) were implanted with radio‐transmitters to measure diaphragmatic electromyogram (dEMG), ECG and EEG. ≥ 7 days post‐surgery, rats were fasted for 12h and administered intragastrically with 1 of 2 KEs (10g/kg), including R,S‐1,3‐butanediol acetoacetate monoester (mKE) or R,S‐1,3‐butanediol acetoacetate di‐ester (dKE) and placed into a hyperbaric chamber and pressurized to 5 ATA O 2 . Latency to seizure (LS) was measured from the beginning of maximum level of HBO 2 until the onset of increased EEG activity and/or tonic‐clonic twitches. Blood was drawn from 18 animals and levels of glucose, pH, pO 2 , pCO 2 , β‐hydroxybutyrate, acetoacetate and acetone were analyzed. KEs caused a rapid and sustained ketosis and delayed LS by ~227% (mKE) and ~574% (dKE) compared to control (water). In conclusion, KEs mimic the mild therapeutic ketosis produced by ketogenic diets and confer a significant neuroprotective effect by delaying CNS‐OT (ONR).