Key neuroprotective role for endogenous adenosine A₁ receptor activation during asphyxia in the fetal sheep

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 A ₁ receptor during severe asphyxia mediates the initial suppression of neural activity and is an important mechanism that protects the fetal brain.