title: Multi-modal assessment of long-term erythropoietin treatment after neonatal hypoxic-ischemic injury in rat brain.
abstract: Erythropoietin (EPO) has been recognized as a neuroprotective agent. In animal models of neonatal brain injury, exogenous EPO has been shown to reduce lesion size, improve structure and function. Experimental studies have focused on short course treatment after injury. Timing, dose and length of treatment in preterm brain damage remain to be defined. We have evaluated the effects of high dose and long-term EPO treatment in hypoxic-ischemic (HI) injury in 3 days old (P3) rat pups using histopathology, magnetic resonance imaging (MRI) and spectroscopy (MRS) as well as functional assessment with somatosensory-evoked potentials (SEP). After HI, rat pups were assessed by MRI for initial damage and were randomized to receive EPO or vehicle. At the end of treatment period (P25) the size of resulting cortical damage and white matter (WM) microstructure integrity were assessed by MRI and cortical metabolism by MRS. Whisker elicited SEP were recorded to evaluate somatosensory function. Brains were collected for neuropathological assessment. The EPO treated animals did not show significant decrease of the HI induced cortical loss at P25. WM microstructure measured by diffusion tensor imaging was improved and SEP response in the injured cortex was recovered in the EPO treated animals compared to vehicle treated animals. In addition, the metabolic profile was less altered in the EPO group. Long-term treatment with high dose EPO after HI injury in the very immature rat brain induced recovery of WM microstructure and connectivity as well as somatosensory cortical function despite no effects on volume of cortical damage. This indicates that long-term high-dose EPO induces recovery of structural and functional connectivity despite persisting gross anatomical cortical alteration resulting from HI.
authors.affiliation: Division of Child Development and Growth, Department of Paediatrics, School of Medicine, University of Geneva and Geneva University Hospital, Geneva, Switzerland; Laboratory for Functional and Metabolic Imaging (LIFMET), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Yohan
authors.initials: Y
authors.lastname: van de Looij
authors.affiliation: Division of Child Development and Growth, Department of Paediatrics, School of Medicine, University of Geneva and Geneva University Hospital, Geneva, Switzerland.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Chatagner
authors.affiliation: Department of Fundamental Neurosciences, School of Medicine, University of Geneva, Geneva, Switzerland.
authors.forename: Charles
authors.initials: C
authors.lastname: Quairiaux
authors.affiliation: Laboratory for Functional and Metabolic Imaging (LIFMET), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland; Department of Radiology, University of Lausanne, Lausanne, Switzerland; Department of Radiology, University of Geneva, Geneva, Switzerland.
authors.forename: Rolf
authors.initials: R
authors.lastname: Gruetter
authors.affiliation: Division of Child Development and Growth, Department of Paediatrics, School of Medicine, University of Geneva and Geneva University Hospital, Geneva, Switzerland.
authors.forename: Petra S
authors.initials: PS
authors.lastname: Hüppi
authors.affiliation: Division of Child Development and Growth, Department of Paediatrics, School of Medicine, University of Geneva and Geneva University Hospital, Geneva, Switzerland.
authors.forename: Stéphane V
authors.initials: SV
authors.lastname: Sizonenko
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000473:pathology; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D002921:Cicatrix / Q000473:pathology; D056324:Diffusion Tensor Imaging; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000008:administration & dosage / Q000494:pharmacology*; D005073:Evoked Potentials, Somatosensory; D005260:Female; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D007382:Intermediate Filaments / Q000378:metabolism; D008297:Male; D055442:Metabolome; D055432:Metabolomics; D009186:Myelin Sheath / Q000378:metabolism; D009474:Neurons / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology; D009929:Organ Size; D066244:Proton Magnetic Resonance Spectroscopy; D051381:Rats; D013997:Time Factors
chemical_list: D018696:Neuroprotective Agents; D004921:Erythropoietin
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