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ErbB2-Receptor Inhibition with Herceptin (Trastuzumab) Reduces Nerve Regeneration after Peroneal Nerve Cut and Repair in the Rat Model
Eva Placheta; Matthew D. Wood; Christine Lafontaine; Edward H. Liu; Cecilia Alvarez Veronesi; Manfred Frey; Tessa Gordon; Gregory H. Borschel
Division of Plastic Surgery, The Hospital for Sick Children, Toronto, Canada
Introduction: After nerve injury, Neuregulin is produced by regenerating axons, encouraging proliferation of Schwann cells. Neuregulin binds to erbB2/3 receptors that are upregulated in denervated Schwann cells up to day 30 after nerve injury. We used Herceptin (Trastuzumab), a monoclonal antibody targeting the erbB2 receptor in erbB2-receptor-expressing cells in order to reduce Neuregulin signalling. Herceptin is FDA-approved and widely used in the treatment of erbB2-overexpressing breast cancer. Thereby we aim to determine whether Neuregulin signalling is essential for peripheral nerve regeneration.
Methods: In female Sprague Dawley rats (n=8) the common peroneal (fibular) nerve was cut and immediately repaired. The treatment groups received Herceptin intraperitoneally (i.p.) three times per week for 2 or 4 weeks. The control groups were treated with i.p. saline injections. The sham groups underwent a sham operation and postoperatively received either Herceptin or saline injections. After 2 and 4 weeks of regeneration, the neurons were retrogradely labeled distal to the repair site. Nerve samples were harvested for histomorphometry and immunohistochemical analysis. Treatment and control groups were compared using an unpaired t-test (p<0.05).
Results: Inhibition of the erbB2 receptor with Herceptin resulted in significantly decreased numbers of regenerating motoneurons 2 weeks after nerve cut and repair. Motoneuron counts were the same in both groups 4 weeks postoperatively. Histomorphometric analysis of the nerve distal to the suture site revealed significantly increased axon counts 4 weeks after repair under Herceptin treatment (axonal sprouting). In the sham-operated animals, Herceptin treatment did not alter the motoneuron numbers or the axon counts compared to the control. Immunohistochemical staining of the erbB2 and phosphorylated-erbB2 receptors demonstrated increased phosphorylation of the erbB2 receptor after nerve injury, which was reduced by Herceptin.
Conclusion: After peripheral nerve cut and repair and administration of the erbB receptor inhibitor, Herceptin, the numbers of neurons that regenerate their axons declines. At the same time, Herceptin increases sprouting of axons. Therefore, we conclude that Neuregulin hastens axon outgrowth across the suture line whilst minimizing excess axonal sprouting. Neuregulin appears to be necessary for efficient axonal regeneration.
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