American Society for Peripheral Nerve
ASPN Home ASPN Home Past & Future Meetings Past & Future Meetings

Back to 2023 Abstracts


Selective Inhibition of Epidermal Growth Factor Receptor (EGFR) Enhances Nerve Regeneration following Mouse Median Nerve Transection and Repair
Max Topley, BScH; Anne-Marie Crotty, BSc; Michael Kawaja, PhD, MSc; J. Michael Hendry, MD, MSc, FRCSC
Queen's University, Kingston, ON, Canada

Introduction Outcomes following peripheral nerve injury are limited by several antagonistic factors, including cues from inhibitory molecules within the regenerative milieu such as chondroitin sulphate proteoglycans (CSPG). Currently, no FDA approved pharmacological methods exist to augment the rate of axonal elongation. Increasing the rate at which axons elongate towards their targets could limit the degree to which chronic denervation, chronic axotomy and denervation atrophy impact on functional outcomes. Recent work has implicated the epidermal growth factor receptor (EGFR), a member of the ErbB family of receptor tyrosine kinases, as an inhibitor of peripheral nerve regeneration. This study investigates the impact of EGFR blockade using the small molecular inhibitor ‘gefitinib’, an FDA approved cancer drug, on nerve regeneration in vitro and in vivo using a mouse forelimb median nerve injury model.
Materials and Methods In vitro assays of neurite outgrowth were used to assess the impact of EGFR blockade in the presence of inhibitory CSPG substrate. Adult dorsal root ganglia (DRG) neurons were harvested from adult C57Bl/6 mice and cultured in the presence of CSPG (200nM), with or without gefinitib (10mM). In vivo experimentation involved ten C57BL/6 mice that underwent right median nerve transection and immediate microsurgical repair. Animals were orally administered gefitinib or vehicle daily for five days from the time of surgery. On day 5, regenerated neurons were labeled using Fluorogold neurotracer 5 mm distal to the repair site, followed by tissue collection 1 week later. Western blot analysis was performed to assess the levels of total and activated (phosphorylated) EGFR.
Results After 5 days, significantly greater numbers of DRG neurons (738±174 vs. 280±107) but not motoneurons (60±31 vs 18±4; p=0.15) were observed in mice that received gefitinib compared with vehicle, respectively. DRG neurons cultured in the presence of CSPG alone showed profoundly diminished neurite extension. Culturing DRG neurons in the presence of gefitinib restored neurite length to control levels and demonstrated significantly increased mean neurite length compared to CSPG alone.
Conclusions Selective inhibition of EGFR using the FDA approved, commercially available drug gefitinib rescued in vitro neurite outgrowth back to control levels in the presence of inhibitory CSPG. Furthermore, greater numbers of DRG neurons reached the 5mm retrograde labeling site in the gefitinib group suggesting an increased rate of sensory neuron regeneration. One interpretation could be that EGFR inhibition diminishes the response of elongating axons to inhibitory cues in the regenerative milieu such as those from CSPG


Back to 2023 Abstracts