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. (Stroke. 2012; 43: 3114-3117.)