Key neuroprotective role for endogenous adenosine A1 receptor activation during asphyxia in the fetal sheep.
OBJECTIVE
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.
Hunter
Christian J
CJ
Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, Calif ., USA.
Bennet
Laura
L
Power
Gordon G
GG
Roelfsema
Vincent
V
Blood
Arlin B
AB
Quaedackers
Josine S
JS
George
Sherly
S
Guan
Jian
J
Gunn
Alistair J
AJ
D000818:Animals; D001237:Asphyxia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D001784:Blood Gas Analysis; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000196:embryology / Q000473:pathology / Q000503:physiopathology*; D002151:Calorimetry / Q000379:methods; D002452:Cell Count; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D004333:Drug Administration Routes; D004569:Electroencephalography / Q000187:drug effects; D005315:Fetal Diseases / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D005865:Gestational Age; D006439:Hemodynamics / Q000187:drug effects; D019344:Lactic Acid / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D010101:Oxygen Consumption; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D020127:Recovery of Function; D012756:Sheep; D014470:Umbilical Cord / Q000503:physiopathology; D014655:Vascular Resistance / Q000187:drug effects; D014970:Xanthines / Q000494:pharmacology
D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1; D014970:Xanthines; D019344:Lactic Acid; C051360:1,3-dipropyl-8-cyclopentylxanthine