Adenosine A 2A Receptor Contributes to Ischemic Brain Damage in Newborn Piglet

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.