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Nature. 2014 Feb 13;506(7487):230-4. doi: 10.1038/nature12880. Epub 2013 Dec 25.

Intranasal epidermal growth factor treatment rescues neonatal brain injury.

Author information

  • 11] Center for Neuroscience Research, Children's National Medical Center, Washington DC 20010, USA [2] Department of Neurology, Children's National Medical Center, Washington DC 20010, USA.
  • 21] Center for Neuroscience Research, Children's National Medical Center, Washington DC 20010, USA [2] Institute for Biomedical Sciences, The George Washington University, Washington DC 20052, USA.
  • 3Department of Anesthesiology & Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
  • 4Center for Neuroscience Research, Children's National Medical Center, Washington DC 20010, USA.
  • 5Department of Neurobiology, Yale University, New Haven, Connecticut 06520, USA.
  • 6MRRC, Department of Diagnostic Radiology, Yale University, New Haven, Connecticut 06520, USA.
  • 7Center for Translational Science, Children's National Medical Center, Washington DC 20010, USA.

Abstract

There are no clinically relevant treatments available that improve function in the growing population of very preterm infants (less than 32 weeks' gestation) with neonatal brain injury. Diffuse white matter injury (DWMI) is a common finding in these children and results in chronic neurodevelopmental impairments. As shown recently, failure in oligodendrocyte progenitor cell maturation contributes to DWMI. We demonstrated previously that the epidermal growth factor receptor (EGFR) has an important role in oligodendrocyte development. Here we examine whether enhanced EGFR signalling stimulates the endogenous response of EGFR-expressing progenitor cells during a critical period after brain injury, and promotes cellular and behavioural recovery in the developing brain. Using an established mouse model of very preterm brain injury, we demonstrate that selective overexpression of human EGFR in oligodendrocyte lineage cells or the administration of intranasal heparin-binding EGF immediately after injury decreases oligodendroglia death, enhances generation of new oligodendrocytes from progenitor cells and promotes functional recovery. Furthermore, these interventions diminish ultrastructural abnormalities and alleviate behavioural deficits on white-matter-specific paradigms. Inhibition of EGFR signalling with a molecularly targeted agent used for cancer therapy demonstrates that EGFR activation is an important contributor to oligodendrocyte regeneration and functional recovery after DWMI. Thus, our study provides direct evidence that targeting EGFR in oligodendrocyte progenitor cells at a specific time after injury is clinically feasible and potentially applicable to the treatment of premature children with white matter injury.

PMID:
24390343
[PubMed - indexed for MEDLINE]
PMCID:
PMC4106485
Free PMC Article

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