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 (3-4 mM vs. 0.5-1 mM untreated), and delayed the onset of clinical coma by 70 min and of burst-suppression coma by 90 min. 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.

Research Highlights►Ketone treatment during hypoglycemia delays the onset of clinical coma and EEG suppression in infant rats. ►Hypoglycemic coma and EEG suppression in ketone treated animals is associated with increased mortality and white matter injury after glucose resuscitation. ►The neuroprotective effect of ketones during hypoglycemia in infancy has limitations, which may be related to metabolic differences between ketones and glucose.