Multi-modal assessment of long-term erythropoietin treatment after neonatal hypoxic-ischemic injury in rat brain

PLoS One. 2014 Apr 22;9(4):e95643. doi: 10.1371/journal.pone.0095643. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Astrocytes / pathology
  • Cerebral Cortex / metabolism
  • Cerebral Cortex / pathology
  • Cicatrix / pathology
  • Diffusion Tensor Imaging
  • Disease Models, Animal
  • Erythropoietin / administration & dosage
  • Erythropoietin / pharmacology*
  • Evoked Potentials, Somatosensory
  • Female
  • Hypoxia-Ischemia, Brain / drug therapy*
  • Hypoxia-Ischemia, Brain / metabolism
  • Hypoxia-Ischemia, Brain / pathology*
  • Intermediate Filaments / metabolism
  • Male
  • Metabolome
  • Metabolomics
  • Myelin Sheath / metabolism
  • Neurons / pathology
  • Neuroprotective Agents / administration & dosage
  • Neuroprotective Agents / pharmacology
  • Organ Size
  • Proton Magnetic Resonance Spectroscopy
  • Rats
  • Time Factors

Substances

  • Neuroprotective Agents
  • Erythropoietin

Grant support

This work was funded by the Swiss National Fund (N°31003A-112233 and N°33CM30-124101) and by the ELA Foundation-France (N°ELA 2006-049I5). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.