Erythropoietin Restores Long-Term Neurocognitive Function Involving Mechanisms of Neuronal Plasticity in a Model of Hyperoxia-Induced Preterm Brain Injury.

Daniela Hoeber,Martin Hadamitzky,Ivo Bendix,Joachim Fandrey,Josephine Herz,Meray Serdar,Stefanie Endesfelder,Yohan Van De Looij,Marco Sifringer,Ursula Felderhoff-Müser,Stéphane V Sizonenko,Joanna Palasz,Karina Kempe

doi:10.1155/2016/9247493

Abstract

Cerebral white and grey matter injury is the leading cause of an adverse neurodevelopmental outcome in prematurely born infants. High oxygen concentrations have been shown to contribute to the pathogenesis of neonatal brain damage. Here, we focused on motor-cognitive outcome up to the adolescent and adult age in an experimental model of preterm brain injury. In search of the putative mechanisms of action we evaluated oligodendrocyte degeneration, myelination, and modulation of synaptic plasticity-related molecules. A single dose of erythropoietin (20,000 IU/kg) at the onset of hyperoxia (24 hours, 80% oxygen) in 6-day-old Wistar rats improved long-lasting neurocognitive development up to the adolescent and adult stage. Analysis of white matter structures revealed a reduction of acute oligodendrocyte degeneration. However, erythropoietin did not influence hypomyelination occurring a few days after injury or long-term microstructural white matter abnormalities detected in adult animals. Erythropoietin administration reverted hyperoxia-induced reduction of neuronal plasticity-related mRNA expression up to four months after injury. Thus, our findings highlight the importance of erythropoietin as a neuroregenerative treatment option in neonatal brain injury, leading to improved memory function in adolescent and adult rats which may be linked to increased neuronal network connectivity.

Highlights

Over the last 20 years considerable progress in the care of high-risk prematurely born infants has led to increased survival, and to a change in the pattern of pathology associated with neurological impairments [1]
Functional deficits and behavioural abnormalities were analysed at adolescent (P30) and adult (P90) developmental stage and the same animals were partially used for postmortem diffusion tensor imaging (DTI) performed at P125 to evaluate long-term microstructural white matter changes and mRNA analysis of neuroplasticity-associated genes. mRNA analysis was conducted at postnatal day 7 (P7) and p11
Since neonatal exposure to hyperoxia is associated with motor-cognitive impairment in rodents [18, 19], we assessed the potential protective effect of Epo treatment on motor activity and cognitive function in adolescent (P30) and adult (P90) rats following neonatal hyperoxia (P6, 24 hours of 80% oxygen)

Summary

Introduction

Over the last 20 years considerable progress in the care of high-risk prematurely born infants has led to increased survival, and to a change in the pattern of pathology associated with neurological impairments [1]. Survivors of preterm birth suffer from altered function ranging from severe motor impairment to cognitive problems, attention deficit disorders, behavioural alterations, and psychiatric disease [6, 7]. The latter have brought the search for neuroprotective and/or regenerative therapies into the focus of preclinical experiments to prepare for clinical trials. Recent studies in rodents further revealed hyperactivity and coordination deficits at adolescent age [18] and cognitive impairment persisting into adulthood [19], which parallel the clinical situation in preterm infants

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