title: Nonadditive neuroprotection with early glutamate receptor blockade and delayed hypothermia after asphyxia in preterm fetal sheep.
abstract: OBJECTIVE
  Hypothermia induced after perinatal hypoxia-ischemia is partially protective. This study examined whether early treatment with the noncompetitive N-methyl-d-aspartate receptor antagonist, dizocilpine, can augment neuroprotection with delayed hypothermia after severe asphyxia in preterm fetal sheep at 0.7 weeks gestation (equivalent to 28-32 weeks in humans).
  
  
  METHODS
  Fifty minutes after umbilical cord occlusion for 25 minutes, fetuses were randomized to either dizocilpine (2 mg/kg estimated fetal weight intravenously, then 0.07 mg/kg/h for 4 hours) and then after 5.5 hours to whole-body cooling to 3°C below baseline, or sham cooling, until 72 hours, and euthanized 7 days after umbilical cord occlusion.
  
  
  RESULTS
  Delayed hypothermia was associated with improved neuronal survival (P<0.02) and reduced microglia (P=0.004) and caspase-3-positive cells (P<0.01) compared with umbilical cord occlusion. Dizocilpine was associated with reduced microglia (P<0.05) but no effect on caspase-3 induction and improved survival only in CA1/2 (P<0.05) with no apparent additive effect with delayed hypothermia.
  
  
  CONCLUSIONS
  Early N-methyl-d-aspartate blockade and a clinical regime of delayed whole-body hypothermia provide nonadditive neuroprotection in the preterm brain.
authors.affiliation: Department of Physiology, The University of Auckland, Private Bag 92019, Auckland 1023, New Zealand.
authors.forename: Sherly A
authors.initials: SA
authors.lastname: George
authors.forename: Robert D
authors.initials: RD
authors.lastname: Barrett
authors.forename: Laura
authors.initials: L
authors.lastname: Bennet
authors.forename: Sam
authors.initials: S
authors.lastname: Mathai
authors.forename: Ellen C
authors.initials: EC
authors.lastname: Jensen
authors.forename: Alistair J
authors.initials: AJ
authors.lastname: Gunn
mesh_terms: D000818:Animals; D001237:Asphyxia / Q000150:complications; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005333:Fetus; D007036:Hypothermia, Induced; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D012756:Sheep
chemical_list: D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D016291:Dizocilpine Maleate