Plastic Surgery Research Council
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PSRC 60th Annual Meeting
Program and Abstracts

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Monoclonal Antibody (Herceptin) Mediated Enhancement of Peripheral Motor and Sensory Neuron Regeneration Operates through a Potential New Pathway Involving ErbB2 and the Epidermal Growth Factor Receptor (ErbB1)
Mike Hendry, MD, MSc.1, Eva Placheta, MD2, Cecilia Alvarez-Veronesi, MASc.1, Tessa Gordon, PhD.1, Gregory Borschel, MD1.
1University of Toronto, Toronto, ON, Canada, 2Medical University of Vienna, Vienna, Austria, Austria.

Purpose: Chronic denervation profoundly limits peripheral nerve regeneration through several mechanisms, including the attenuation of neurotrophic factor signaling such as neuregulin acting through its endogenous receptor, ErbB2. The neuregulin/ErbB2-signaling axis has been implicated in Schwann cell proliferation and remyelination of neurons following peripheral nerve injury. We recently reported the paradoxical increase in axon outgrowth on histomorphometry following nerve injury with administration of the high affinity monoclonal antibody Herceptin. In this more extensive study, we selectively inhibited the neuregulin receptor, ErbB2, with Herceptin to further characterize its impact on peripheral nerve regeneration in a rat model.
Methods: Herceptin or placebo was administered to female Sprague-Dawley rats recovering after common peroneal nerve transection and repair. Nerve repair was performed immediately or after 4-months of chronic denervation. Axons from regenerating motor or sensory neurons were labeled with retrograde dye 1, 2 or 4 weeks following injury and counted in the ventral horn of the spinal cord or dorsal root ganglia, respectively. Histomorphometry was also performed 10 mm distal to the repair site after 4 weeks. Protein analysis and immunohistochemistry evaluated levels of ErbB2, Akt, BrdU and activated EGFR within the regenerating nerve.
Results: Herceptin administration increased the rate of motoneuron regeneration by 3x and sensory neuron regeneration by 3.7x compared to saline treated animals after the first week. However, the extent of motor and sensory regeneration was nearly complete in both groups by the end of the second week. In addition, the total number of myelinated fibers growing distally beyond the repair site was significantly increased in rats receiving Herceptin (2488 ± 154) compared to rats that received saline (1896 ± 251) (p < 0.05) four weeks after repair. When delayed repair was performed after a 3-month period of chronic denervation, Herceptin increased the number of acutely, but not chronically, axotomized motoneurons after two weeks. Interestingly, Western blot analysis revealed no change in ErbB2 activation with Herceptin administration. However, immunofluorescent imaging revealed decreased levels of activated EGFR on regenerating neurons, a factor known to be inhibitory to axon regeneration.
Conclusions: ErbB2 receptor blockade with Herceptin enhances nerve regeneration following acute and delayed nerve repair independent of neuregulin signaling. The mechanism proposed to explain these effects involves Herceptin’s prevention of an inhibitory association between ErbB2 and EGFR, a potential new pathway that regulates nerve regeneration. These findings also raise the exciting possibility of
using therapeutic monoclonal antibody therapy to improve outcomes following surgical repair of nerve injuries.


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