: Recent studies have shown that neuronal disorders closely correlate with prenatal events and one of the major risk factors appears to be fetal hypoxia. Efforts to minimize the incidence of neonatal disorders have been hindered by the fact that little is known about either normal metabolism in the developing fetal brain or the pathophysiology associated with fetal distress. This application will focus on the age-dependent changes in regional brain metabolism, on the effect of reduced supply of nutrients to the developing fetal brain; and, finally, on the time threshold for hypoxia/ischemia to alter normal brain development and/or elicit hypoxic cell damage. The fetal hypoxia model involves occlusion of the uterine artery and the uterine branch of the ovarian artery in pregnant rats. These experiments are designed to answer a number of questions that are fundamental to furthering the understanding of the relationship between fetal brain distress and neonatal dysfunction: 1) Do age-dependent changes in normal developing brain metabolism influence the response to an insult?; 2) Do all regions of the brain respond similarly to a metabolic stress independent of age, or are there windows of susceptibility for different regions?; 3) How critical are the duration of the insult and gestational age to fetal survival and normal development of the brain?; and 4) Are there interventions which can minimize damage following fetal hypoxia? The specific aims are: 1) To characterize cell damage in the perinatal brain following hypoxic insults at various gestational times using histochemical, immunocytochemical and in situ hybridization techniques; 2) To characterize normal metabolism at various gestational ages and its responses to increasing periods of 2-vessel occlusion, and to relate the metabolic changes to regional pattern of damage; 3) To determine the ability of the brain to recover metabolically from the insult upon de-occlusion of the vessels and examine posthypoxic changes in neurotransmitters and second messengers; and 4) To evaluate the potential neuroprotective effect of hyperglycemia at various gestational times. The severity of the insult will be assessed by quantitative histochemical measurement of metabolites in nanogram pieces of brain, nanoliters of CSF and in fetal blood. The resulting biochemical profile of the various fetal brain compartments from E11 to E21 will reflect metabolic changes during fetal development, and will be related to the patterns of damage observed at varying perinatal times. The results will yield a dynamic picture of the critical metabolic and structural events during development, and how hypoxia may alter these relationships, and will provide a basis for developing novel strategies to minimize neonatal brain dysfunction following fetal distress.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurology B Subcommittee 2 (NEUB)
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Spinella, Giovanna M
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Case Western Reserve University
Schools of Medicine
United States
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Pundik, Svetlana; Robinson, Shenandoah; Lust, W David et al. (2006) Regional metabolic status of the E-18 rat fetal brain following transient hypoxia/ischemia. Metab Brain Dis 21:309-17
Zechel, Jennifer L; Gamboa, Jorge L; Peterson, Allyn G et al. (2005) Neuronal migration is transiently delayed by prenatal exposure to intermittent hypoxia. Birth Defects Res B Dev Reprod Toxicol 74:287-99
Lust, W David; Pundik, Svetlana; Zechel, Jennifer et al. (2003) Changing metabolic and energy profiles in fetal, neonatal, and adult rat brain. Metab Brain Dis 18:195-206