Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology
General PapersFetal Brain Injury Following Prolonged Hypoxemia and Placental Insufficiency: A Review
Introduction
In this article we review our recent studies on the effects of prolonged hypoxemia and placental insufficiency on brain development in fetal sheep; we also briefly review the literature relating to pharmacological protection of neurons during exposure to hypoxic conditions. Our studies on the effects of prenatal compromise have been conducted in sheep because this species allows the monitoring of fetal blood gas, endocrine, and metabolic status. We have exposed fetal sheep in utero to “hypoxemic” challenges of differing severity and duration, which have been delivered at different stages of gestation. We use the terms hypoxemia and hypoxia-ischemia throughout this article to describe the compromises to which the fetuses were exposed, although we recognise that these compromises caused more than hypoxemia and/or cerebral ischemia, and include metabolic, cardiovascular, and endocrine perturbations.
We have investigated the effects of three types of “hypoxemic” challenge that mimic different types of placental insufficiency; one was caused by restriction of placental size throughout pregnancy, sufficient to induce the restriction of fetal growth, another by short-term mechanical restriction of uteroplacental blood flow in the ewe, and the third by prolonged, partial embolisation, and hence restriction, of the umbilicoplacental circulation during late gestation.
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Intrauterine Growth Restriction
Restriction of placental size sufficient to induce a reduction of fetal growth, was achieved by the surgical removal of a large proportion of placentation sites (carunclectomy) prior to mating 39, 44. The growth-restricted fetuses resulting from carunclectomy, at least during the last third of gestation when blood samples have been taken, are typically hypoxemic, acidemic, and hypoglycemic [44], as are human growth-restricted fetuses [51]. Although we did not catheterise our fetuses, previous
Effects on fetal brain structure
Our main aim in analysing the tissue was to determine which of the specific events in brain development had been affected by the different regimes of fetal hypoxemia and placental insufficiency. In particular, we were interested in the effects on neurogenesis, neural migration, the growth of axons and dendrites and myelination. Furthermore, we examined the brains for degenerative alterations, such as white matter lesions and neuronal death.
Pharmacological intervention in fetal hypoxic-ischemic brain injury
Processes that contribute to brain injury involve complex and interactive mechanisms that result from the initial cellular energy failure during hypoxemic or hypoxemic-ischemic insults. Levels of excitatory amino-acid neurotransmitters, such as glutamate and aspartate, rise during and following fetal hypoxia-ischemia [53]. Both increased release of presynaptic glutamate and impaired neuronal and glial uptake mechanisms lead to increased extracellular concentrations of glutamate. Although
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