title: ErbB2 blockade with Herceptin (trastuzumab) enhances peripheral nerve regeneration after repair of acute or chronic peripheral nerve injury.
abstract: Attenuation of the growth supportive environment within the distal nerve stump after delayed peripheral nerve repair profoundly limits nerve regeneration. Levels of the potent Schwann cell mitogen neuregulin and its receptor ErbB2 decline during this period, but the regenerative impact of this change is not completely understood. Herein, the ErbB2 receptor pathway is inhibited with the selective monoclonal antibody Herceptin (trastuzumab) to determine its significance in regulating acute and chronic regeneration in a rat hindlimb.
  
  
  
  The common peroneal nerve of Sprague-Dawley rats was transected and repaired immediately or after 4 months of chronic denervation, followed by administration of Herceptin or saline solution. Regenerated motor and sensory neurons were counted using a retrograde tracer 1, 2, or 4, weeks after repair. Distal myelinated axon outgrowth after 4 weeks was quantified using histomorphometry. Immunofluorescent imaging was used to evaluate Schwann cell proliferation and epidermal growth factor receptor (EGFR) activation in the regenerating nerves.
  
  
  
  Herceptin administration increased the rate of motor and sensory neuron regeneration and the number of proliferating Schwann cells in the distal stump after the first week. Herceptin also increased the number of myelinated axons that regenerated 4 weeks after immediate and delayed repair. Reduced EGFR activation was observed using immunofluorescent imaging.
  
  
  
  Inhibition of the ErbB2 receptor with Herceptin unexpectedly enhances nerve regeneration after acute and delayed nerve repair. This finding raises the possibility of using targeted molecular therapies to improve outcomes of peripheral nerve injuries. The mechanism may involve a novel inhibitory association between ErbB2 and EGFR. Ann Neurol 2016;80:112-126.
authors.affiliation: Division of Plastic and Reconstructive Surgery, Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Surgery, University of Toronto, Toronto, Ontario, Canada.|Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
authors.forename: J Michael
authors.initials: JM
authors.lastname: Hendry
authors.affiliation: Division of Plastic and Reconstructive Surgery, Hospital for Sick Children, Toronto, Ontario, Canada.|Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.
authors.forename: M Cecilia
authors.initials: MC
authors.lastname: Alvarez-Veronesi
authors.affiliation: Division of Plastic and Reconstructive Surgery, Medical University of Vienna, Vienna, Austria.
authors.forename: Eva
authors.initials: E
authors.lastname: Placheta
authors.affiliation: Division of Plastic and Reconstructive Surgery, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Zhang
authors.affiliation: Division of Plastic and Reconstructive Surgery, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Tessa
authors.initials: T
authors.lastname: Gordon
authors.affiliation: Division of Plastic and Reconstructive Surgery, Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Surgery, University of Toronto, Toronto, Ontario, Canada.|Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.|Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Gregory H
authors.initials: GH
authors.lastname: Borschel
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D008297:Male; D009413:Nerve Fibers, Myelinated / Q000378:metabolism; D009416:Nerve Regeneration / Q000187:drug effects*; D059348:Peripheral Nerve Injuries / Q000601:surgery*; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012583:Schwann Cells / Q000187:drug effects; D000068878:Trastuzumab / Q000494:pharmacology*
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C483804:Erbb2 protein, rat