title: Intranasal epidermal growth factor treatment rescues neonatal brain injury.
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.
authors.affiliation: 1] 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.
authors.forename: Joseph
authors.initials: J
authors.lastname: Scafidi
authors.affiliation: 1] 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.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Hammond
authors.affiliation: Department of Anesthesiology & Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Susanna
authors.initials: S
authors.lastname: Scafidi
authors.affiliation: Center for Neuroscience Research, Children's National Medical Center, Washington DC 20010, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Ritter
authors.affiliation: Center for Neuroscience Research, Children's National Medical Center, Washington DC 20010, USA.
authors.forename: Beata
authors.initials: B
authors.lastname: Jablonska
authors.affiliation: Center for Neuroscience Research, Children's National Medical Center, Washington DC 20010, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Roncal
authors.affiliation: Department of Neurobiology, Yale University, New Haven, Connecticut 06520, USA.
authors.forename: Klara
authors.initials: K
authors.lastname: Szigeti-Buck
authors.affiliation: MRRC, Department of Diagnostic Radiology, Yale University, New Haven, Connecticut 06520, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Coman
authors.affiliation: MRRC, Department of Diagnostic Radiology, Yale University, New Haven, Connecticut 06520, USA.
authors.forename: Yuegao
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Center for Translational Science, Children's National Medical Center, Washington DC 20010, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: McCarter
authors.affiliation: MRRC, Department of Diagnostic Radiology, Yale University, New Haven, Connecticut 06520, USA.
authors.forename: Fahmeed
authors.initials: F
authors.lastname: Hyder
authors.affiliation: Department of Neurobiology, Yale University, New Haven, Connecticut 06520, USA.
authors.forename: Tamas L
authors.initials: TL
authors.lastname: Horvath
authors.affiliation: Center for Neuroscience Research, Children's National Medical Center, Washington DC 20010, USA.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Gallo
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D000831:Animals, Newborn; D001930:Brain Injuries / Q000151:congenital* / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003711:Demyelinating Diseases / Q000151:congenital / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D004195:Disease Models, Animal; D004815:Epidermal Growth Factor / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007235:Infant, Premature, Diseases / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D058990:Molecular Targeted Therapy; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D012038:Regeneration / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
chemical_list: D004815:Epidermal Growth Factor; D066246:ErbB Receptors