Cerebral palsy continues to be a devastating personal, social, medical, and medicolegal problem. Despite advances in perinatal care and electronic intrapartum monitoring, cerebral palsy still occurs in 2-3 per 1,000 live births. The long-term goal of this proposal is to explore the link between lack of fetal oxygen and specific mechanisms of fetal neuronal damage. This will be examined in an animal model that mimics the neuropathologic findings of cerebral palsy. Our proposed studies will take place in unanesthetized, chronically instrumented fetal sheep at both midgestation and near-term. The fetal sheep model was chosen because it is physically large enough to allow the necessary biochemical and physiological measurements in utero. This model has been used extensively to study the physiology of pregnancy. It has also been used by many investigators (including the PI) to study the pathophysiology of in utero asphyxia. The excitatory neurotransmitter glutamate can, in conditions of hypoxia- ischemia, lead to neuronal injury in adult brain. It is thought that glutamate may play the same role in fetal brain injury. We will measure glutamate release, in selected regions of the fetal brain, in response to a variety of clinically relevant situations. We will measure glutamate efflux from the fetal brain using the unique application of chronic in utero intracerebral microdialysis. We will study the efflux of glutamate, and other neurotransmitters, in response to acute, chronic, and acute-superimposed-on-chronic fetal hypoxemia. In a similar group of animals, we will examine the fetal brain for histopathologic evidence of brain injury. These studies will also be carried out in two gestational age groups of fetuses; midgestation and near-term. We are particularly interested in tow unique comparisons: 1) We will study control versus acute hypoxemia in midgestation fetuses. A clinical correlate of these studies is the human fetus in premature labor; and 2) we will study chronic versus acute-superimposed-on-chronic hypoxemia in the near-term fetus. A clinical correlate of this comparison is the small for gestational age term fetus about the undergo labor and delivery. The link between hypoxic brain injury and hypoxic release of excitatory amino acid neurotransmitters will be tested in the final year of the proposed project. The excitatory amino acid antagonist MK-801 will be administered to similar fetuses as in the pathology studies, to see if it attenuates any histopathological changes that would otherwise be expected. The long-term benefit of these studies is a greater understanding of the pathologic process responsible for cerebral palsy. We hope to identify and test clinically useful interventions that may lead to a reduction in the incidence and severity of cerebral palsy.
| Henderson, J L; Reynolds, J D; Dexter, F et al. (1998) Chronic hypoxemia causes extracellular glutamate concentration to increase in the cerebral cortex of the near-term fetal sheep. Brain Res Dev Brain Res 105:287-93 |
