• Dawn Mueller-Burke, Raymond C Koehler, and Lee J Martin.
• School of Nursing, University of Maryland at Baltimore, Baltimore, MD 21201, USA.
• Int. J. Dev. Neurosci. 2008 Feb 1;26(1):67-76.

AbstractThe basal ganglia of newborns are extremely vulnerable to hypoxic ischemia (HI). Striatal neurons undergo prominent necrosis after HI. The mechanisms for this degeneration are not well understood. Postasphyxic hypothermia ameliorates the striatal necrosis, but the mechanisms of hypothermia-induced neuroprotection are not known. We used a newborn piglet model of hypoxic-asphyxic cardiac arrest to test the hypotheses that N-methyl-d-aspartate receptor activation and free radical damage coexist, prior to neurodegeneration, early after resuscitation, and that these changes are attenuated with hypothermia. Piglets were subjected to 30min of hypoxia followed by 7min of airway occlusion, causing asphyxic cardiac arrest, and then were resuscitated and survived normothermically for 5min, 3h, or 6h, or hypothermically for 3h. By 6h of normothermic recovery, 50% of neurons in putamen showed ischemic cytopathology. Striatal tissue was fractionated into membrane or soluble proteins and was assayed by immunoblotting for carbonyl modification, phosphorylation of the N-methyl-d-aspartate receptor subunit NR1, and neuronal nitric oxide synthase. Significant accumulation of soluble protein carbonyls was present at 3h (196% of control) and 6h (142% of control). Phosphorylation of serine-897 of NR1 was increased significantly at 5min (161% of control) and 3h (226% of control) after HI. Phosphorylation of serine-890 of NR1 was also increased after HI. Membrane-associated neuronal nitric oxide synthase was increased by 35% at 5min. Hypothermia attenuated the oxidative damage and the NR1 phosphorylation in striatum. We conclude that neuronal death signaling in newborn striatum after HI is engaged rapidly through N-methyl-d-aspartate receptor activation, neuronal nitric oxide synthase recruitment, and oxidative stress. Postasphyxic, mild whole body hypothermia provides neuroprotection by suppressing N-methyl-d-aspartate receptor phosphorylation and protein oxidation.

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