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

Abstract

The preterm fetus is capable of surviving prolonged periods of severe hypoxia without neural injury for much longer than at term. To evaluate the hypothesis that regulated suppression of brain metabolism contributes to this remarkable tolerance, we assessed changes in the redox state of cytochrome oxidase (CytOx) relative to cerebral heat production, and cytotoxic edema measured using cerebral impedance, during 25 min of complete umbilical cord occlusion or sham occlusion in fetal sheep at 0.7 gestation. Occlusion was followed by rapid, profound reduction in relative cerebral oxygenation and EEG intensity and an immediate increase in oxidized CytOx, indicating a reduction in electron flow down the mitochondrial electron transfer chain. Confirming rapid suppression of cerebral metabolism there was a loss of the temperature difference between parietal cortex and body at a time when carotid blood flow was maintained at control values. As occlusion continued, severe hypotension/hypoperfusion developed, with a further increase in CytOx levels to a plateau between 8 and 13 min and a progressive rise in cerebral impedance. In conclusion, these data strongly suggest active regulation of cerebral metabolism during the initial response to severe hypoxia, which may help to protect the immature brain from injury. asphyxia; preterm; umbilical cord occlusion FETAL AND NEONATAL ANIMALS are well known to be able to survive much longer periods of hypoxia than adults (9, 22). More recently, it has become clear that preterm animals can withstand even longer periods of profound hypoxia and hypotension/hypoperfusion without neural injury than at term (17,28,35). 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). 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).This regulated suppression of metabolic rate during hypoxia or ischemia, before energy stores are depleted, has been termed adaptive hypometabolism (38). It may be of considerable importance not only before birth but also during birth itself and in other settings involving adaptation to low oxygen levels (34). The near-term fetus of the high-altitude, hypoxia-adapted llama...

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

“…In fetal sheep, the increase in impedance during asphyxia or ischemia peaks approximately 10 min after reperfusion and takes 30 to 60 min to resolve (27,28). By 2 h after release of occlusion in the current paradigm, cytochrome activity and impedance are normal (15,27). Thus, metabolic failure cannot explain continuing EEG suppression.…”

“…In turn, this metabolic failure leads to cell swelling (cytotoxic edema) that may be measured by increased brain impedance (27). In fetal sheep, the increase in impedance during asphyxia or ischemia peaks approximately 10 min after reperfusion and takes 30 to 60 min to resolve (27,28). By 2 h after release of occlusion in the current paradigm, cytochrome activity and impedance are normal (15,27).…”

“…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). In turn, this metabolic failure leads to cell swelling (cytotoxic edema) that may be measured by increased brain impedance (27). In fetal sheep, the increase in impedance during asphyxia or ischemia peaks approximately 10 min after reperfusion and takes 30 to 60 min to resolve (27,28).…”

The vulnerable developing brain

“…Therefore, if the physiology underlying the fetal brain-sparing response to adverse challenges in pregnancy only matures toward the end of gestation, which mechanisms protect the developing brain from adverse challenges in early pregnancy? Although it is known that the immature fetal brain is more tolerant to hypoxia than the mature fetal brain (15), undernutrition in early pregnancy may render the immature fetal brain particularly susceptible to developmental problems.…”

Global Hypoxia-Ischemia Induced Inflammation and Structural Changes in the Preterm Ovine Gut Which Were Not Ameliorated by Mesenchymal Stem Cell Treatment

“…Perinatal asphyxia is one of the most frequent causes of perinatal morbidity, accounting for approximately 23% of neonatal deaths worldwide (3,4 Daan RMG Ophelders, 1,2 Harry WM Steinbusch, 2 Boris W Kramer, 1,2,3 and Tim GAM Wolfs UCO was applied as previously reported (37). In addition, transient clamping of the umbilical cord for 25 min at this GA has been previously reported to result in fetal HI and cerebral and gastrointestinal hypoperfusion in ovine fetuses (37)(38)(39)(40). One hour after the end of UCO (HI group, n = 6) or sham-UCO (control group, n = 8), saline or MSCs (HI + MSC group, n = 7) were given intravenously to the fetuses.…”