title: Hyperglycemia accentuates and ketonemia attenuates hypoglycemia-induced neuronal injury in the developing rat brain.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pediatrics, Division of Neonatology, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Ennis
authors.affiliation: Department of Pediatrics, Division of Neonatology, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Hannah
authors.initials: H
authors.lastname: Dotterman
authors.affiliation: Department of Pediatrics, Division of Neonatology, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Ariel
authors.initials: A
authors.lastname: Stein
authors.affiliation: 1] Department of Pediatrics, Division of Neonatology, University of Minnesota, Minneapolis, Minnesota [2] Center for Neurobehavioral Development, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Raghavendra
authors.initials: R
authors.lastname: Rao
mesh_terms: D000818:Animals; D001921:Brain / Q000196:embryology*; D001930:Brain Injuries / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000150:complications*; D007003:Hypoglycemia / Q000150:complications*; D007328:Insulin / Q000737:chemistry / Q000378:metabolism; D007662:Ketosis / Q000150:complications*; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D015854:Up-Regulation
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D007328:Insulin; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases