Nonadditive Neuroprotection With Early Glutamate Receptor Blockade and Delayed Hypothermia After Asphyxia in Preterm Fetal Sheep
Background and Purpose—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.
- Received July 25, 2012.
- Accepted July 30, 2012.
- © 2012 American Heart Association, Inc.