Effects of d-3-hydroxybutyrate treatment on hypoglycemic coma in rat pups.
d-3-Hydroxybutyrate (3OHB) is an alternative energy substrate for the brain during hypoglycemia, especially in infancy. Knowledge of the capacity and limits of 3OHB to compensate for cerebral glucose depletion during hypoglycemia in developing brain is important for its potential clinical use, but is scarce. We studied the effect of 3OHB treatment during insulin-induced hypoglycemia in 13-day-old rat pups. 3OHB treatment resulted in increased 3OHB plasma levels in hypoglycemic animals (3-4mM vs. 0.5-1mM untreated), and delayed the onset of clinical coma by 70min and of burst-suppression coma by 90min. 3OHB treated animals did not survive after resuscitation with glucose, compared to 80% survival of untreated hypoglycemic pups. Cleaved-caspase-3 immunohistochemistry and double labeling studies demonstrated a 20-fold increase of apoptotic mature oligodendrocytes in white matter of 3OHB treated animals. 3OHB treatment delays the onset of clinical and burst-suppression coma during hypoglycemia, but the prolonged duration of hypoglycemia is associated with increased mortality after resuscitation and cellular white matter injury.
Department of Pediatrics, British Columbia Children's Hospital and University of British Columbia, Vancouver, BC, Canada. schutz@interchange.ubc.ca
Peter W
PW
Schutz
Peter K H
PK
Wong
John
J
O'Kusky
Sheila M
SM
Innis
Sylvia
S
Stockler
D020155:3-Hydroxybutyric Acid / Q000627:therapeutic use*; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D003128:Coma / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D004347:Drug Interactions; D004569:Electroencephalography / Q000379:methods; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007003:Hypoglycemia / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D007004:Hypoglycemic Agents / Q000009:adverse effects; D007328:Insulin / Q000009:adverse effects; D009419:Nerve Tissue Proteins / Q000378:metabolism; D000076104:Oligodendrocyte Transcription Factor 2; D011247:Pregnancy; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012151:Resuscitation / Q000379:methods; D013997:Time Factors
D020155:3-Hydroxybutyric Acid; D051792:Basic Helix-Loop-Helix Proteins; D053148:Caspase 3; D005904:Glial Fibrillary Acidic Protein; D007004:Hypoglycemic Agents; D007328:Insulin; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; C522729:Olig2 protein, rat