Children who are born very preterm are prone to cerebral palsy, epilepsy, cognitive delay and behavioral problems, but current interventions have failed to reduce the neurologic morbidity. Typically, systemic hypoxia- ischemia (HI), infection, or more commonly a combination of both, cause prenatal central nervous system (CNS) injury prior to birth with prolonged postnatal loss of neurons and oligodendrocytes, culminating in impaired circuit formation. Neural cell loss occurs primarily by apoptosis with failure of new waves of progenitors to survive. Erythropoietin (EPO) and its cognate receptor EPOR are required for prenatal brain development, especially in the second half of gestation, where EPO signaling locally regulates neural cell survival to prune neural cell overproduction. Unbound EPOR drives neural cells to apoptosis, while ligand- bound EPOR activates survival signaling pathways. EPO also has neuroprotective properties and crosses the blood-brain barrier. We used an established model of prenatal transient systemic HI from uterine artery occlusion, and transient systemic HI plus intracervical lipopolysaccharide (LPS) to mimic human systemic prenatal HI insults and combined ischemic/inflammatory insults. We found neonatal EPO treatment reverses the histological and functional deficits of adult rats after prenatal HI injury. Our pilot data reveal a novel molecular mechanism of EPO signaling that helps to explain the excess apoptosis that occurs after prenatal insults, and suggests a novel drug intervention using exogenous EPO in the neonatal period. We found that systemic prenatal HI appears to upregulate neural cell EPOR on the most vulnerable neural cells, neurons and oligodendrocytes, and that exogenous neonatal EPO appears to enhance survival and process formation by neural cells after prenatal HI. We hypothesize that prenatal insults upregulate EPOR on neural cells and that without adequate EPO present these cells undergo apoptosis. We propose that after prenatal insults neonatal exogenous EPO rescues neural cells, enhances their survival and differentiation, ultimately improving circuit formation, and leading to functional recovery. We will use our model of prenatal HI with and without intracervical lipopolysaccharide (LPS) to produce prenatal insults to test our hypothesis.
In Aim 1 we will define the expression pattern of EPO, EPOR and identify the up and downstream signaling molecules active in damaged developing neural cells after prenatal HI, and LPS plus HI.
In Aim 2 we will test the whether EPO signaling regulates neural cell survival and differentiation in vitro using dose-response curves and specific molecular inhibitors. Lastly, in Aim 3 we will manipulate the expression of EPOR in damaged developing neural cells to clarify whether over-expression or silencing of EPOR supports our predictions. Together, these studies will clarify the mechanism of EPO-induced neural cell recovery after prenatal injury. They will provide the much needed preclinical foundation for potentially translating this promising therapeutic option using neonatal EPO to infants born prematurely, and optimize the chance these children develop without deficits. Children who are born very preterm suffer from cerebral palsy, epilepsy, cognitive delay and behavioral problems, placing a tremendous burden on these children, their families, and society. Current interventions have failed to improve their outcome. To treat infants born preterm, we propose a novel drug intervention with erythropoietin, a drug currently used to treat anemia, as EPO both provides neuroprotection and enhances development of the neural cells most vulnerable to damage from preterm insults. ? ? ?

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Developmental Brain Disorders Study Section (DBD)
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Hicks, Ramona R
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Case Western Reserve University
Schools of Medicine
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Robinson, Shenandoah; Corbett, Christopher J; Winer, Jesse L et al. (2018) Neonatal erythropoietin mitigates impaired gait, social interaction and diffusion tensor imaging abnormalities in a rat model of prenatal brain injury. Exp Neurol 302:1-13
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Jantzie, Lauren L; Robinson, Shenandoah (2015) Preclinical Models of Encephalopathy of Prematurity. Dev Neurosci 37:277-88
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Jantzie, Lauren L; Miller, Robert H; Robinson, Shenandoah (2013) Erythropoietin signaling promotes oligodendrocyte development following prenatal systemic hypoxic-ischemic brain injury. Pediatr Res 74:658-67
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