The ErbB2 inhibitor Herceptin (Trastuzumab) promotes axonal outgrowth four weeks after acute nerve transection and repair

• Published in: Neuroscience letters 2014-10, Vol.582, p.81-86
• Main Authors: Placheta, Eva, Hendry, J. Michael, Wood, Matthew D., Lafontaine, Christine W., Liu, Edward H., Cecilia Alvarez Veronesi, M., Frey, Manfred, Gordon, Tessa, Borschel, Gregory H.
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal, Humanized - pharmacology; Antibodies, Monoclonal, Humanized - therapeutic use; Axons - drug effects; Axons - physiology; erbB2-Receptor; Female; Ganglia, Spinal - drug effects; Ganglia, Spinal - pathology; Herceptin/Trastuzumab; Motor Neurons - drug effects; Motor Neurons - physiology; Nerve injury; Nerve regeneration; Nerve Regeneration - drug effects; Neuregulin; Peripheral nerve; Peripheral Nerve Injuries - drug therapy; Peripheral Nerve Injuries - physiopathology; Peroneal Nerve - drug effects; Peroneal Nerve - injuries; Peroneal Nerve - physiopathology; Rats, Sprague-Dawley; Receptor, ErbB-2 - antagonists & inhibitors; Sensory Receptor Cells - drug effects; Sensory Receptor Cells - physiology; Time Factors; Trastuzumab
• ISSN: 0304-3940; 1872-7972
• DOI: 10.1016/j.neulet.2014.09.006

•Herceptin administration after nerve repair increases axonal outgrowth.•Neuregulin mediated ErbB2 activation does not change with Herceptin treatment.•Motor and sensory neuron regeneration is not altered by Herceptin treatment. 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.