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(Stroke. 2003;34:2240.)
© 2003 American Heart Association, Inc.

Original Contributions

Key Neuroprotective Role for Endogenous Adenosine A₁ Receptor Activation During Asphyxia in the Fetal Sheep

Christian J. Hunter, PhD; Laura Bennet, PhD; Gordon G. Power, PhD; Vincent Roelfsema, BS; Arlin B. Blood, PhD; Josine S. Quaedackers, BS; Sherly George, PhD; Jian Guan, PhD Alistair J. Gunn, MBChB, PhD

From the Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, Calif (C.J.H., G.G.P., A.B.B.), Liggins Institute, Auckland University, Auckland, New Zealand (L.B., V.R., J.S.Q., S.G., J.G., A.J.G.).

Correspondence to Dr Alistair Jan Gunn, Liggins Institute, University of Auckland, Private Bag 92019, Auckland, New Zealand. E-mail aj.gunn{at}auckland.ac.nz

Background and Purpose— The fetus is well known to be able to survive prolonged exposure to asphyxia with minimal injury compared with older animals. We and others have observed a rapid suppression of EEG intensity with the onset of asphyxia, suggesting active inhibition that may be a major neuroprotective adaptation to asphyxia. Adenosine is a key regulator of cerebral metabolism in the fetus.

Methods— We therefore tested the hypothesis that infusion of the specific adenosine A₁ receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), given before 10 minutes of profound asphyxia in near-term fetal sheep, would prevent neural inhibition and lead to increased brain damage.

Results— DPCPX treatment was associated with a transient rise and delayed fall in EEG activity in response to cord occlusion (n=8) in contrast with a rapid and sustained suppression of EEG activity in controls (n=8). DPCPX was also associated with an earlier and greater increase in cortical impedance, reflecting earlier onset of primary cytotoxic edema, and a significantly smaller reduction in calculated cortical heat production after the start of cord occlusion. After reperfusion, DPCPX-treated fetuses but not controls developed delayed onset of seizures, which continued for 24 hours, and sustained greater selective hippocampal, striatal, and parasagittal neuronal loss after 72-hour recovery.

Conclusions— These data support the hypothesis that endogenous activation of the adenosine A₁ receptor during severe asphyxia mediates the initial suppression of neural activity and is an important mechanism that protects the fetal brain.

Key Words: adenosine • antagonists and inhibitors • asphyxia • fetus • ischemia • seizures • sheep

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