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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS060765-02
Application #
7643181
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Hicks, Ramona R
Project Start
2008-07-01
Project End
2012-06-30
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
2
Fiscal Year
2009
Total Cost
$309,094
Indirect Cost
Name
Case Western Reserve University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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
Jantzie, Lauren L; Winer, Jesse L; Corbett, Christopher J et al. (2016) Erythropoietin Modulates Cerebral and Serum Degradation Products from Excess Calpain Activation following Prenatal Hypoxia-Ischemia. Dev Neurosci 38:15-26
Jantzie, Lauren L; Robinson, Shenandoah (2015) Preclinical Models of Encephalopathy of Prematurity. Dev Neurosci 37:277-88
Jantzie, Lauren L; Winer, Jesse L; Maxwell, Jessie R et al. (2015) Modeling Encephalopathy of Prematurity Using Prenatal Hypoxia-ischemia with Intra-amniotic Lipopolysaccharide in Rats. J Vis Exp :
Jantzie, L L; Getsy, P M; Firl, D J et al. (2014) Erythropoietin attenuates loss of potassium chloride co-transporters following prenatal brain injury. Mol Cell Neurosci 61:152-62
Jantzie, Lauren L; Corbett, Christopher J; Berglass, Jacqueline et al. (2014) Complex pattern of interaction between in utero hypoxia-ischemia and intra-amniotic inflammation disrupts brain development and motor function. J Neuroinflammation 11:131
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
Robinson, Shenandoah (2012) Neonatal posthemorrhagic hydrocephalus from prematurity: pathophysiology and current treatment concepts. J Neurosurg Pediatr 9:242-58
Robinson, Shenandoah; Mikolaenko, Irina; Thompson, Ian et al. (2010) Loss of cation-chloride cotransporter expression in preterm infants with white matter lesions: implications for the pathogenesis of epilepsy. J Neuropathol Exp Neurol 69:565-72
Mazur, Marcus; Miller, Robert H; Robinson, Shenandoah (2010) Postnatal erythropoietin treatment mitigates neural cell loss after systemic prenatal hypoxic-ischemic injury. J Neurosurg Pediatr 6:206-21