The Monoclonal Antibody Herceptin Enhances Peripheral Nerve Regeneration through a Potential New Pathway involving Erbb2 and the Epidermal Growth Factor Receptor (ErB1)
J. Mike Hendry, MD1; Eva Placheta, MD2; M. Cecilia Alvarez Veronesi, MASc1; Tessa Gordon, PhD1; Gregory H. Borschel, PhD1
1Division of Plastic and Reconstructive Surgery, The Hospital for Sick Children, Toronto, ON, Canada; 2Division of Plastic and Reconstructive Surgery, Medical University of Vienna, Vienna, Austria
Introduction: Peripheral nerve regeneration is profoundly limited by aspects of chronic denervation that are known to involve attenuation of neurotrophic factors such as neuregulin and its endogenous receptor ErbB2. The neuregulin/ErbB2 signaling axis has been implicated in Schwann cell proliferation and remyelination of neurons following peripheral nerve injury. However, the specific impact of attenuated neuregulin/ErbB2 expression over the period of chronic denervation is unknown. In this study we selectively inhibited the receptor for neuregulin, ErbB2, with the high affinity monoclonal antibody Herceptin to examine its effect on nerve regeneration in a rat model.
Materials & 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 motoneurons were labeled with retrograde dye 1, 2 or 4 weeks following injury and counted in the ventral horn of the spinal cord. 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 compared to saline treated animals after the first week, whereas the extent of 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 4-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. 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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