Adenosine A2A receptor contributes to ischemic brain damage in newborn piglet

Zeng Jin Yang, Bing Wang, Herman Kwansa, Kerry D. Heitmiller, Gina Hong, Erin L. Carter, Jessica L. Jamrogowicz, Abby C. Larson, Lee J Martin, Raymond C Koehler

Research output: Contribution to journalArticle

Abstract

Pharmacologic inactivation or genetic deletion of adenosine A 2A receptors protects ischemic neurons in adult animals, but studies in neonatal hypoxia-ischemia (H-I) are inconclusive. The present study in neonatal piglets examined the hypothesis that A 2A receptor signaling after reoxygenation from global H-I contributes to injury in highly vulnerable striatal neurons where A 2A receptors are enriched. A 2A receptor immunoreactivity was detected in striatopallidal neurons. In nonischemic piglets, direct infusion of the selective A 2A receptor agonist CGS 21680 through microdialysis probes into putamen increased phosphorylation of N-methyl-D-aspartic acid (NMDA) receptor NR1 subunit and Na +,K +-ATPase selectively at protein kinase A (PKA)-sensitive sites. In ischemic piglets, posttreatment with SCH 58261, a selective A 2A receptor antagonist, improved early neurologic recovery and preferentially protected striatopallidal neurons. SCH 58261 selectively inhibited the ischemia-induced phosphorylation of NR1, Na +,K +-ATPase, and cAMP-regulated phosphoprotein 32 KDa (DARPP32) at PKA-sensitive sites at 3 hours of recovery and improved Na +,K +-ATPase activity. SCH 58261 also suppressed ischemia-induced protein nitration and oxidation. Thus, A 2A receptor activation during reoxygenation contributes to the loss of a subpopulation of neonatal putamen neurons after H-I. Its toxic signaling may be related to DARPP32-dependent phosphorylation of PKA-sensitive sites on NR1 and Na +,K +-ATPase, thereby augmenting excitotoxicity-induced oxidative stress after reoxygenation.

Original languageEnglish (US)
Pages (from-to)1612-1620
Number of pages9
JournalJournal of Cerebral Blood Flow and Metabolism
Volume33
Issue number10
DOIs
StatePublished - Oct 2013

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Keywords

  • adenosine
  • dopamine
  • global ischemia
  • neonatal ischemia
  • receptors

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Clinical Neurology
  • Neurology

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