Rapid NMDA receptor phosphorylation and oxidative stress precede striatal neurodegeneration after hypoxic ischemia in newborn piglets and are attenuated with hypothermia

Dawn Mueller-Burke, Raymond C. Koehler, Lee J. Martin

Research output: Contribution to journalArticlepeer-review

Abstract

The 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 30 min of hypoxia followed by 7 min of airway occlusion, causing asphyxic cardiac arrest, and then were resuscitated and survived normothermically for 5 min, 3 h, or 6 h, or hypothermically for 3 h. By 6 h 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 3 h (196% of control) and 6 h (142% of control). Phosphorylation of serine-897 of NR1 was increased significantly at 5 min (161% of control) and 3 h (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 5 min. 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.

Original languageEnglish (US)
Pages (from-to)67-76
Number of pages10
JournalInternational Journal of Developmental Neuroscience
Volume26
Issue number1
DOIs
StatePublished - Feb 2008

Keywords

  • Asphyxia
  • Cardiac arrest
  • Neonatal brain ischemia
  • Nitric oxide
  • Pediatric brain damage
  • Protein carbonyl

ASJC Scopus subject areas

  • Developmental Neuroscience
  • Developmental Biology

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