Kathleen Ennis1, Hannah Dotterman1, Ariel Stein1, Raghavendra Rao2. 1. Department of Pediatrics, Division of Neonatology, University of Minnesota, Minneapolis, Minnesota. 2. 1] Department of Pediatrics, Division of Neonatology, University of Minnesota, Minneapolis, Minnesota [2] Center for Neurobehavioral Development, University of Minnesota, Minneapolis, Minnesota.
Abstract
BACKGROUND: Prolonged hypoglycemia leads to brain injury, despite treatment with 10% dextrose. Whether induction of hyperglycemia or ketonemia achieves better neuroprotection is unknown. Hyperglycemia is neuroprotective in other brain injuries during development; however, it worsens hypoglycemia-induced injury in the adult brain via poly(ADP-ribose)polymerase-1 (PARP-1) overactivation. METHODS: Three-week-old rats were subjected to insulin-induced hypoglycemia and treated with 10% dextrose or 50% dextrose. Neuronal injury, PARP-1, and brain-derived neurotrophic factor (BDNF) III/TrkB/p75(NTR) expressions were determined. In the second experiment, ketonemia was induced by administering β-hydroxybutyrate during hypoglycemia and its effect on neuronal injury was compared with those conventionally treated using 10% dextrose. RESULTS: Both 10 and 50% dextrose administration led to hyperglycemia (50% dextrose > 10% dextrose). Compared with the 10% dextrose group, neuronal injury was greater in the 50% dextrose group and was accompanied by PARP-1 overactivation. BDNF III and p75(NTR), but not TrkBFL, mRNA expressions were upregulated. Neuronal injury was less severe in the rats subjected to ketonemia, compared with those conventionally treated using 10% dextrose. CONCLUSION: Hyperglycemia accentuated hypoglycemia-induced neuronal injury, likely via PARP-1 overactivation. Although BDNF was upregulated, it was not neuroprotective and potentially exaggerated injury by binding to p75(NTR) receptor. Conversely, ketonemia during hypoglycemia attenuated neuronal injury.
BACKGROUND: Prolonged hypoglycemia leads to brain injury, despite treatment with 10% dextrose. Whether induction of hyperglycemia or ketonemia achieves better neuroprotection is unknown. Hyperglycemia is neuroprotective in other brain injuries during development; however, it worsens hypoglycemia-induced injury in the adult brain via poly(ADP-ribose)polymerase-1 (PARP-1) overactivation. METHODS: Three-week-old rats were subjected to insulin-induced hypoglycemia and treated with 10% dextrose or 50% dextrose. Neuronal injury, PARP-1, and brain-derived neurotrophic factor (BDNF) III/TrkB/p75(NTR) expressions were determined. In the second experiment, ketonemia was induced by administering β-hydroxybutyrate during hypoglycemia and its effect on neuronal injury was compared with those conventionally treated using 10% dextrose. RESULTS: Both 10 and 50% dextrose administration led to hyperglycemia (50% dextrose > 10% dextrose). Compared with the 10% dextrose group, neuronal injury was greater in the 50% dextrose group and was accompanied by PARP-1 overactivation. BDNF III and p75(NTR), but not TrkBFL, mRNA expressions were upregulated. Neuronal injury was less severe in the rats subjected to ketonemia, compared with those conventionally treated using 10% dextrose. CONCLUSION:Hyperglycemia accentuated hypoglycemia-induced neuronal injury, likely via PARP-1 overactivation. Although BDNF was upregulated, it was not neuroprotective and potentially exaggerated injury by binding to p75(NTR) receptor. Conversely, ketonemia during hypoglycemia attenuated neuronal injury.
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