PMID- 25279990 OWN - NLM STAT- MEDLINE DCOM- 20151231 LR - 20161125 IS - 1530-0447 (Electronic) IS - 0031-3998 (Linking) VI - 77 IP - 1-1 DP - 2015 Jan TI - Hyperglycemia accentuates and ketonemia attenuates hypoglycemia-induced neuronal injury in the developing rat brain. PG - 84-90 LID - 10.1038/pr.2014.146 [doi] AB - 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 beta-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. FAU - Ennis, Kathleen AU - Ennis K AD - Department of Pediatrics, Division of Neonatology, University of Minnesota, Minneapolis, Minnesota. FAU - Dotterman, Hannah AU - Dotterman H AD - Department of Pediatrics, Division of Neonatology, University of Minnesota, Minneapolis, Minnesota. FAU - Stein, Ariel AU - Stein A AD - Department of Pediatrics, Division of Neonatology, University of Minnesota, Minneapolis, Minnesota. FAU - Rao, Raghavendra AU - Rao R AD - 1] Department of Pediatrics, Division of Neonatology, University of Minnesota, Minneapolis, Minnesota [2] Center for Neurobehavioral Development, University of Minnesota, Minneapolis, Minnesota. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20141003 PL - United States TA - Pediatr Res JT - Pediatric research JID - 0100714 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Insulin) RN - EC 2.4.2.30 (Parp1 protein, rat) RN - EC 2.4.2.30 (Poly (ADP-Ribose) Polymerase-1) RN - EC 2.4.2.30 (Poly(ADP-ribose) Polymerases) SB - IM MH - Animals MH - Brain/*embryology MH - Brain Injuries/pathology MH - Brain-Derived Neurotrophic Factor/metabolism MH - Humans MH - Hyperglycemia/*complications MH - Hypoglycemia/*complications MH - Insulin/chemistry/metabolism MH - Ketosis/*complications MH - Neurons/metabolism/*pathology MH - Poly (ADP-Ribose) Polymerase-1 MH - Poly(ADP-ribose) Polymerases/metabolism MH - Rats MH - Up-Regulation EDAT- 2014/10/04 06:00 MHDA- 2016/01/01 06:00 CRDT- 2014/10/04 06:00 PHST- 2014/02/04 00:00 [received] PHST- 2014/08/04 00:00 [accepted] PHST- 2014/10/04 06:00 [entrez] PHST- 2014/10/04 06:00 [pubmed] PHST- 2016/01/01 06:00 [medline] AID - pr2014146 [pii] AID - 10.1038/pr.2014.146 [doi] PST - ppublish SO - Pediatr Res. 2015 Jan;77(1-1):84-90. doi: 10.1038/pr.2014.146. Epub 2014 Oct 3.