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 language | English (US) |
|---|---|
| Pages (from-to) | 1612-1620 |
| Number of pages | 9 |
| Journal | Journal of Cerebral Blood Flow and Metabolism |
| Volume | 33 |
| Issue number | 10 |
| DOIs | |
| State | Published - 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
Cite this
Adenosine A2A receptor contributes to ischemic brain damage in newborn piglet. / Yang, Zeng Jin; Wang, Bing; Kwansa, Herman; Heitmiller, Kerry D.; Hong, Gina; Carter, Erin L.; Jamrogowicz, Jessica L.; Larson, Abby C.; Martin, Lee J; Koehler, Raymond C.
In: Journal of Cerebral Blood Flow and Metabolism, Vol. 33, No. 10, 10.2013, p. 1612-1620.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Adenosine A2A receptor contributes to ischemic brain damage in newborn piglet
AU - Yang, Zeng Jin
AU - Wang, Bing
AU - Kwansa, Herman
AU - Heitmiller, Kerry D.
AU - Hong, Gina
AU - Carter, Erin L.
AU - Jamrogowicz, Jessica L.
AU - Larson, Abby C.
AU - Martin, Lee J
AU - Koehler, Raymond C
PY - 2013/10
Y1 - 2013/10
N2 - 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.
AB - 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.
KW - adenosine
KW - dopamine
KW - global ischemia
KW - neonatal ischemia
KW - receptors
UR - http://www.scopus.com/inward/record.url?scp=84885019248&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84885019248&partnerID=8YFLogxK
U2 - 10.1038/jcbfm.2013.117
DO - 10.1038/jcbfm.2013.117
M3 - Article
C2 - 23860373
AN - SCOPUS:84885019248
VL - 33
SP - 1612
EP - 1620
JO - Journal of Cerebral Blood Flow and Metabolism
JF - Journal of Cerebral Blood Flow and Metabolism
SN - 0271-678X
IS - 10
ER -