Understanding Mechanisms of Fetal Hypoxic Brain Injury Resulting in Cerebral Pals

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DESCRIPTION (provided by applicant): Despite improvements in perinatal practice during the past several decades, the incidence of cerebral palsy (CP), most of them of antenatal origin, has remained essentially unchanged. Currently there is no way to diagnose human fetal brain injury directly and our understanding of cellular mechanisms causing CP is very limited. To study mechanisms of brain injury resulting in cerebral palsy, a clinically relevant rabbit model of fetal hypoxia-ischemia (H-I) has been developed in our laboratory that produces motor deficits in newborn kits. Given our recent ability to prognosticate fetal injury resulting in postnatal motor deficits using in vivo neuroimaging, this proposal investigates cellular and molecular mechanisms of injury resulting in postnatal motor deficits. Immediate brain response to H-I in this model has been found to be determine postnatal motor deficits thus implying a critical role of oxidative mechanism of injury, predominant at this phase of H-I injury. Free radicals have been implicated as a key mechanism of brain injury after H-I, causing "reperfusion injury" from a cascade of subsequent reactions. Our central hypothesis is that the interaction of free radicals and antioxidants in the developing brain determines the degree of brain injury. The individual fetus brain response can now be assessed non-invasively using diffusion weighted imaging (DWI) and derived apparent diffusion coefficient (ADC) and associated with postnatal outcome. The proposal investigates whether immediate brain response, assessed by the ADC and predictive of postnatal outcome, is associated with concomitant excess free radical production, mitochondrial dysfunction, and consequent cell death and apoptosis. The concept of maturation dependent interaction of free radicals and antioxidants will be tested by assessing ADC response and markers of oxidative stress on two gestational ages of rabbit - preterm (79% gestation) and near term (90% gestation) and in brain regions with less vulnerable to H-I cortex and more vulnerable basal ganglia, thalamus and brainstem. In Specific Aim 1 we will determine whether the severity of brain injury, as assessed by ADC immediately after hypoxia-ischemia, can predict the extent of motor deficits postnatally. In Specific Aim 2 we will determine whether oxidative stress and mitochondrial dysfunction are responsible for brain injury after hypoxia-ischemia as assessed by ADC. The third Specific Aim will address feasibility and utility of the human fetal DWI to diagnose and prognosticate H-I brain injury and ensuing postnatal neurological deficits on patients with high risk of fetal H-I injury. The long term goal of this project is to develop DWI-based surrogate marker to diagnose and treat human fetal brain at the time of injury. PUBLIC HEALTH RELEVANCE: This study is designed to use magnetic resonance imaging to improve our understanding of the fetal brain injury resulting in cerebral palsy and other motor deficits. Based on animal model data, this understanding has the potential to identify human fetuses-at-risk, early diagnose fetal brain injury and implement preventive or therapeutic strategies, ultimately reducing incidents and disabilities of cerebral palsy.