title: The ErbB2 inhibitor Herceptin (Trastuzumab) promotes axonal outgrowth four weeks after acute nerve transection and repair.
abstract: Accumulating evidence suggests that neuregulin, a potent Schwann cell mitogen, and its receptor, ErbB2, have an important role in regulating peripheral nerve regeneration. We hypothesized that Herceptin (Trastuzumab), a monoclonal antibody that binds ErbB2, would disrupt ErbB2 signaling, allowing us to evaluate ErbB2's importance in peripheral nerve regeneration. In this study, the extent of peripheral motor and sensory nerve regeneration and distal axonal outgrowth was analyzed two and four weeks after common peroneal (CP) nerve injury in rats. Outcomes analyzed included neuron counts after retrograde labeling, histomorphometry, and protein analysis. The data analysis revealed that there was no impact of Herceptin administration on either the numbers of motor or sensory neurons that regenerated their axons but histomorphometry revealed that Herceptin significantly increased the number of regenerated axons in the distal repaired nerve after 4 weeks. Protein analysis with Western blotting revealed no difference in either expression levels of ErbB2 or the amount of activated, phosphorylated ErbB2 in injured nerves. In conclusion, administration of the ErbB2 receptor inhibitor after nerve transection and surgical repair did not alter the number of regenerating neurons but markedly increased the number of regenerated axons per neuron in the distal nerve stump. Enhanced axon outgrowth in the presence of this ErbB2 inhibitor indicates that ErbB2 signaling may limit the numbers of axons that are emitted from each regenerating neuron.
authors.affiliation: Division of Plastic and Reconstructive Surgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria; Division of Plastic and Reconstructive Surgery, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada.
authors.forename: Eva
authors.initials: E
authors.lastname: Placheta
authors.affiliation: Division of Plastic and Reconstructive Surgery, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Department of Surgery, University of Toronto, 149 College Street, 5th Floor, Toronto, ON M5T 1P5, Canada; Institute of Medical Science, University of Toronto, 1 King's College Circle, Room 2374, Toronto, ON M5S 1A8, Canada.
authors.forename: J Michael
authors.initials: JM
authors.lastname: Hendry
authors.affiliation: Division of Plastic and Reconstructive Surgery, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Wood
authors.affiliation: Division of Plastic and Reconstructive Surgery, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada.
authors.forename: Christine W
authors.initials: CW
authors.lastname: Lafontaine
authors.affiliation: Division of Plastic and Reconstructive Surgery, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada.
authors.forename: Edward H
authors.initials: EH
authors.lastname: Liu
authors.affiliation: Division of Plastic and Reconstructive Surgery, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Institute of Biomaterials and Biomedical Engineering, University of Toronto, Rosebrugh Building, RM 407 164 College Street, Toronto, ON M5S 3G9, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Cecilia Alvarez Veronesi
authors.affiliation: Division of Plastic and Reconstructive Surgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.
authors.forename: Manfred
authors.initials: M
authors.lastname: Frey
authors.affiliation: Division of Plastic and Reconstructive Surgery, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada.
authors.forename: Tessa
authors.initials: T
authors.lastname: Gordon
authors.affiliation: Division of Plastic and Reconstructive Surgery, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Department of Surgery, University of Toronto, 149 College Street, 5th Floor, Toronto, ON M5T 1P5, Canada; Institute of Medical Science, University of Toronto, 1 King's College Circle, Room 2374, Toronto, ON M5S 1A8, Canada; Institute of Biomaterials and Biomedical Engineering, University of Toronto, Rosebrugh Building, RM 407 164 College Street, Toronto, ON M5S 3G9, Canada. Electronic address: gregory.borschel@sickkids.ca.
authors.forename: Gregory H
authors.initials: GH
authors.lastname: Borschel
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology* / Q000627:therapeutic use; D001369:Axons / Q000187:drug effects* / Q000502:physiology; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000473:pathology; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology; D009416:Nerve Regeneration / Q000187:drug effects*; D059348:Peripheral Nerve Injuries / Q000188:drug therapy / Q000503:physiopathology*; D010543:Peroneal Nerve / Q000187:drug effects* / Q000293:injuries / Q000503:physiopathology; D017207:Rats, Sprague-Dawley; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human
keywords: Herceptin/Trastuzumab; Nerve injury; Nerve regeneration; Neuregulin; Peripheral nerve; erbB2-Receptor