Journal Article

Multi-Modal Assessment of Long-Term Erythropoietin Treatment after Neonatal Hypoxic-Ischemic Injury in Rat Brain

Hüppi, Petra S., van de Looij, Yohan, Sizonenko, Stéphane V., Chatagner, Alexandra, Quairiaux, Charles, Gruetter, Rolf

2014

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Animal models / Animals / Animals, Newborn / Astrocytes - pathology / Brain / Brain damage / Brain injury / Brain research / Cerebral Cortex - metabolism / Cerebral Cortex - pathology / Child development / Cicatrix - pathology / Cortex / Cortex (somatosensory) / Damage assessment / Diffusion Tensor Imaging / Disease Models, Animal / Diseases / Erythropoietin / Erythropoietin - administration & dosage / Erythropoietin - pharmacology / Evoked Potentials, Somatosensory / Female / Head injuries / Histopathology / Hypoxia / Hypoxia-Ischemia, Brain - drug therapy / Hypoxia-Ischemia, Brain - metabolism / Hypoxia-Ischemia, Brain - pathology / Infants (Newborn) / Injuries / Injury prevention / Intermediate Filaments - metabolism / Ischemia / Laboratories / Magnetic resonance / Magnetic resonance imaging / Male / Medicine / Medicine and Health Sciences / Metabolism / Metabolites / Metabolome / Metabolomics / Microstructure / Myelin Sheath - metabolism / Neonates / Neural networks / Neurogenesis / Neuroimaging / Neurons - pathology / Neuroprotection / Neuroprotective Agents - administration & dosage / Neuroprotective Agents - pharmacology / Neurosciences / Newborn babies / NMR / Nuclear magnetic resonance / Organ Size / Proton Magnetic Resonance Spectroscopy / Rats / Recovery / Recovery of function / Research and Analysis Methods / Rodents / Somatosensory cortex / Somatosensory evoked potentials / Spectroscopy / Spectrum analysis / Stroke / Structural damage / Structure-function relationships / Substantia alba / Time Factors / Traumatic brain injury / Vibrissae