title: Erythropoietin Restores Long-Term Neurocognitive Function Involving Mechanisms of Neuronal Plasticity in a Model of Hyperoxia-Induced Preterm Brain Injury.
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.
authors: Department of Paediatrics I, Neonatology, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany; Institute of Physiology, University of Duisburg-Essen, 45147 Essen, Germany.
authors: Daniela
authors: 0000-0003-4106-3545
authors: D
authors: Hoeber
authors: Department of Anaesthesiology and Intensive Care Medicine, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, 13353 Berlin, Germany.
authors: Marco
authors: M
authors: Sifringer
authors: Division of Child Growth and Development, Department of Paediatrics, University of Geneva, 1205 Geneva, Switzerland; Laboratory of Functional and Metabolic Imaging, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors: Yohan
authors: Y
authors: van de Looij
authors: Department of Paediatrics I, Neonatology, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany.
authors: Josephine
authors: J
authors: Herz
authors: Division of Child Growth and Development, Department of Paediatrics, University of Geneva, 1205 Geneva, Switzerland.
authors: Stéphane V
authors: SV
authors: Sizonenko
authors: Department of Paediatrics I, Neonatology, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany.
authors: Karina
authors: K
authors: Kempe
authors: Department of Paediatrics I, Neonatology, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany.
authors: Meray
authors: 0000-0001-7838-9413
authors: M
authors: Serdar
authors: Department of Paediatrics I, Neonatology, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany.
authors: Joanna
authors: J
authors: Palasz
authors: Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany.
authors: Martin
authors: M
authors: Hadamitzky
authors: Department of Neonatology, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany.
authors: Stefanie
authors: 0000-0002-4030-7969
authors: S
authors: Endesfelder
authors: Institute of Physiology, University of Duisburg-Essen, 45147 Essen, Germany.
authors: Joachim
authors: J
authors: Fandrey
authors: Department of Paediatrics I, Neonatology, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany.
authors: Ursula
authors: 0000-0002-7765-8893
authors: U
authors: Felderhoff-Müser
authors: Department of Paediatrics I, Neonatology, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany.
authors: Ivo
authors: 0000-0002-9751-3640
authors: I
authors: Bendix
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects; D001930:Brain Injuries / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D003071:Cognition / Q000187:drug effects; D056324:Diffusion Tensor Imaging; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D004921:Erythropoietin / Q000494:pharmacology*; D018496:Hyperoxia; D007150:Immunohistochemistry; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000378:metabolism; D004676:Myelin Basic Protein / Q000378:metabolism; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects*; D039942:Neuropilin-1 / Q000235:genetics / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016708:Synaptophysin / Q000235:genetics / Q000378:metabolism; D066127:White Matter / Q000187:drug effects / Q000378:metabolism
chemical_list: D004676:Myelin Basic Protein; D020890:Neuregulin-1; D018696:Neuroprotective Agents; D016708:Synaptophysin; D004921:Erythropoietin; D039942:Neuropilin-1