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The Monoclonal Antibody Herceptin Improves Regeneration After Injured Nerves are Repaired Immediately or After a Period of Chronic Denervation
Mike Hendry, MD1, Eva Placheta, MD2, Tessa Gordon, PhD1, Gregory Borchel, MD, MSc.1.
1University of Toronto, Toronto, ON, Canada, 2University of Vienna, Vienna, Austria, Austria.
Purpose: 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. Nerves were repaired either immediately at the time of injury or repair was delayed by 3 months to allow for chronic denervation. Nerves were allowed to regenerate for 1, 2 or 4 weeks following injury. 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. Western blot analysis of whole nerve lysate was performed to examine the impact of Herceptin on ErbB2 signaling after injury.
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 following immediate 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 and myelin thickness did not differ between groups following immediate repair. Similarly, after a period of chronic denervation, significantly more motoneurons regenerated in rats that received Herceptin (282 ± 31) compared to saline controls (210 ± 24) at 2 weeks post-repair. There was no difference at 4 weeks. Interestingly, Western blot analysis revealed suppression of the downstream ErbB2 signaling pathway with Herceptin administration despite immunofluorescent imaging that suggests increased Schwann cell proliferation.
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 enhanced regeneration applies to the repair of either freshly repaired or chronically denervated nerves. 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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