Key Neuroprotective Role for Endogenous Adenosine A ₁ Receptor Activation During Asphyxia in the Fetal Sheep

Abstract

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 A 1 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 (nϭ8) in contrast with a rapid and sustained suppression of EEG activity in controls (nϭ8). 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.

Regulation of cytochrome oxidase redox state during umbilical cord occlusion in preterm fetal sheep

“…Following a maternal midline abdominal incision and exteriorization of the uterus and either the top or bottom half of the fetus, catheters were placed in the left fetal femoral artery and vein, right axillary artery, and the amniotic sac. An ultrasonic blood flow probe (size 3S; Transonic Systems, Ithaca, NY) was placed around the left carotid artery to measure carotid blood flow as an index of global cerebral blood flow (19,23,52). Two small, flexible fiber optic probes for NIRS recordings were placed biparietally on the skull 3.0 cm apart, 1.5 cm anterior to bregma.…”

“…In part, this remarkable tolerance to hypoxia may be related to greater anaerobic capacity in the immature brain (48), but an important additional factor is likely to be actively regulated suppression of cerebral activity. This mechanism, which is mediated by release of endogenous inhibitory neuromodulators such as ␥-aminobutyric acid (GABA) and adenosine during hypoxia, recently has been shown to be active in near-term (0.8 to 0.9 gestation) fetal sheep (6,23,33,49). For example, hypoxemia or adenosine infusion in near-term fetal sheep increased oxidation of cerebral cytochrome oxidase (CytOx) on near-infrared measurements, indicating a rapid reduction in electron flow down the mitochondrial electron transfer chain and, thus, a fall in metabolic activity (40,41).…”

“…For example, hypoxemia or adenosine infusion in near-term fetal sheep increased oxidation of cerebral cytochrome oxidase (CytOx) on near-infrared measurements, indicating a rapid reduction in electron flow down the mitochondrial electron transfer chain and, thus, a fall in metabolic activity (40,41). Conversely, blockade of adenosine A 1 receptor activity during umbilical cord occlusion in near-term fetal sheep accelerated the onset and increased the magnitude of cerebral anoxic cytotoxic edema, with subsequently increased neuronal loss (23).…”

Limited predictive value of early changes in EEG spectral power for neural injury after asphyxia in preterm fetal sheep

“…The rapid EEG suppression at the onset of asphyxia is actively mediated through adenosine and other inhibitory neuromodulators in near-term fetal sheep (25). However, the continuing suppression after approximately the first 3 min is mediated by profound depletion of high-energy phosphates as measured by magnetic resonance spectroscopy in the piglet (26), and inhibition of mitochondrial cytochrome oxidase activity in preterm fetal sheep (27).…”

“…Electrocardiograph electrodes were sewn across the chest to record fetal heart rate. An ultrasonic blood flow probe (size 3S; Transonic Systems, Ithaca, NY) was placed around the left carotid artery to measure carotid blood flow as an index of global cerebral blood flow (25,37). Two pairs of EEG electrodes (AS633-7SSF, Cooner Wire, Chatsworth, CA) were placed on the dura bilaterally over the parasagittal parietal cortex (5 mm and 10 mm anterior to bregma and 5 mm lateral).…”