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The Monoclonal Antibody Herceptin Improves Nerve Regeneration in a Rat Nerve Transection and Repair Model
J. Mike Hendry, MD
Division of Plastic and Reconstructive Surgery, University of Toronto, Toronto, ON, Eva Placheta, Division of Plastic and Reconstructive Surgery, Medical University of Vienna, Vienna, Austria, Tessa Gordon, Division of Plastic and Reconstructive Surgery, The Hospital for Sick Children, Toronto, ON, Canada and Gregory Borschel, Plastic Surgery, The Hospital for Sick Children, Toronto, ON, Canada
Background: Chronic denervation resulting from long regeneration times and distances is a major contributor to suboptimal regenerative outcomes following nerve injuries. The molecular mechanisms regulating these harmful effects are poorly understood. The regulatory role of ErbB2, the receptor for the potent Schwann cell mitogen Neuregulin-1 (NRG-1), remains controversial. In this study we selectively inhibit ErbB2 with the high affinity monoclonal antibody, Herceptin, which is used clinically to treat breast cancer, to examine its effect on nerve regeneration in a rat model. Methods: The common peroneal nerves of Sprague-Dawley rats were surgically transected and repaired. Repaired nerves were allowed to regenerate for 1, 2 or 4 weeks. Common peroneal motoneurons were retrogradely labeled 1 cm distal to the site of repair with fluorescent dye and counted in the ventral horn of the spinal cord. Histomorphometry was used to quantify total myelinated fiber number, fiber diameter and myelin thickness within the regenerating nerve. Protein analysis (Western blot) of whole nerve lysate was performed to examine the impact of Herceptin on ErbB2 signaling after acute transection and repair. Results: Significantly greater numbers of motoneurons regenerated in rats treated with Herceptin (169 ± 31) compared with rats receiving saline (62 ± 15) when assessed 1 week post repair (p < 0.05). No difference was observed at 2 or 4 weeks post-repair in rats treated with Herceptin compared to saline controls. Total myelinated fiber counts were significantly increased in rats that received Herceptin (2488 ± 154) compared to rats that received saline (1896 ± 251) (p < 0.05). Mean regenerated fiber diameter (FD) and myelin thickness (MT) did not differ between rats treated with Herceptin (FD = 2.06 ± 0.05 µm; MT = 0.50 ± 0.03 µm) and those treated with saline (FD = 2.01 ± 0.05 µm; MT = 0.49 ± 0.02 µm) at 4 weeks post-repair. Interestingly, Western blots revealed increased phosphorylation of ErbB2, but also indicated suppression of the downstream ErbB2 signaling pathway. Conclusions: Disrupting ErbB2 signaling with systemic, targeted molecular therapy using a commercial monoclonal antibody leads to improved nerve regeneration in the early regenerative period. This raises the exciting possibility of using this and similar pharmacologic therapies to improve outcomes following surgical repair of nerve injuries.
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