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The ketone body D-3-hydroxybutyrate (3OHB) is an alternative energy substrate for the brain during hypoglycemia. The capacity and limitations of 3OHB to compensate for cerebral glucose depletion in developing brain is insufficiently understood. We studied the effect of 3OHB treatment in a newly developed infant rat model of insulin induced, sustained, and EEG-controlled hypoglycemia. Continuous treatment with 3OHB during hypoglycemia resulted in increased 3OHB plasma levels in hypoglycemic animals and delayed the onset of clinical coma and of EEG burst-suppression (burst-suppression coma). 3OHB treated animals did not survive after resuscitation with glucose, compared to 80% survival of untreated hypoglycemic pups. Cleaved-caspase-3 immunohistochemistry and double labelling studies demonstrated a 20-fold increase of apoptotic mature oligodendrocytes in white matter of 3OHB treated animals, indicating a limited protective effect of 3OHB treatment.In contrast to glucose, D-3-hydroxybutyrate is not an anaplerotic substrate. Anaplerosis plays in important role in cerebral glutamate glutamine metabolism. Combination of D-3-hydroxybutyrate with the anaplerotic substrate propionate could enhance its protective effect during hypoglycemia. We compared the effectiveness of treatment with a single dose D-3-hydroxybutyrate alone or combined with propionate at the time of EEG burst-suppression coma. Both treatments resulted in a reversion of EEG activity from burst suppression to continuity, but only combined treatment resulted in clincal improvement of the comatose state. 3OHB alone largely corrected pathometabolic changes of glutamate metabolism but not of glycolytic and pentose phosphate pathway intermediates or of long chain acylcarnitines. Combined treatment was not associated with biochemical corrections over and above those achieved by 3OHB alone for the metabolites measured. 3OHB treatment has a limited effectiveness on clinical and neuropathology outcome after hypoglycemia in infant rats. The limited effectiveness of 3OHB treatment may be related to its inability to support glycolysis with associated pentose phosphate pathway and anaplerotic activity. Combined treatment with propionate enhances 3OHB’s protective effect during hypoglycemic coma. Future protective treatment should be based on complementary metabolic substrates.