AAHS - The Epidermal Growth Factor Receptor (EGFR) Inhibitor Gefitinib Enhances In Vitro and In Vivo Sensory Neuron Regeneration Following Transection in a Mouse Median Nerve Injury Model

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The Epidermal Growth Factor Receptor (EGFR) Inhibitor Gefitinib Enhances In Vitro and In Vivo Sensory Neuron Regeneration Following Transection in a Mouse Median Nerve Injury Model
Payton Sparks, BS¹; Max Topley, BScH²; Anne-Marie Crotty, BSc²; Michael Kawaja, PhD, MSc²; J. Michael Hendry, MD, MSc, FRCSC²
¹Marian University College of Osteopathic Medicine, Indianapolis, IN; ²Queen's University, Kingston, ON, Canada

Introduction

Currently, nerve injuries lack approved remedies for prolonged reinnervation delays. The epidermal growth factor receptor (EGFR; ErbB1), a membrane-bound receptor tyrosine kinase, remains unexplored in nerve regeneration but is suspected to impede this process. This study investigates the effects of EGFR inhibition on nerve regeneration using gefitinib, a commercially accessible small molecule inhibitor. Focusing on EGFR's role, this research explores its impact on reinnervation, particularly in delayed healing. Utilizing gefitinib, the study assesses its influence on the pace and efficacy of nerve regeneration. Through structural, functional, and molecular evaluations, this investigation seeks to discover gefitinib's potential in enhancing peripheral nerve regeneration. This could pave the way for targeted therapies addressing delayed reinnervation, advancing nerve injury management, and potentially extending its applications to broader clinical contexts.

Materials & Methods

The study used in vitro assays with cultured dorsal root ganglion (DRG) neurons from adult C57Bl/6 wildtype mice, focusing on neurite outgrowth on immobilized chondroitin sulphate proteoglycans (CSPG). Methods included immunofluorescence, retrograde labeling, and histomorphometry to assess EGFR expression, quantify regenerated neurons, and evaluate myelination of motor and sensory neurons. Mice received either gefitinib or a vehicle, and functional recovery was measured using forelimb grip strength. These assays provided insights into EGFR inhibition by gefitinib on nerve regeneration, spanning structural, molecular, and functional aspects, informing potential therapeutic strategies for nerve injuries.

Results

EGFR expression was identified in both dorsal root ganglion (DRG) and spinal motor neurons. Medium-sized (30-50 ?m) DRG neurons exhibited heightened neurite outgrowth upon exposure to gefitinib with CSPG. In animals treated with gefitinib, a marked increase in regenerated sensory neurons was observed, with no significant change in motor neurons. Regenerated axons in gefitinib-treated animals had a larger diameter and an elevated g-ratio compared to the vehicle control. Additionally, animals given gefitinib showcased swifter recovery of grip strength. These findings outline the effects of EGFR inhibition via gefitinib in promoting sensory neuron regeneration, altering axonal properties, and expediting functional recovery, supporting its potential as a therapeutic intervention for peripheral nerve injuries.

Conclusions

Our study shows that EGFR inhibits sensory neuron regeneration but not motor neuron regeneration. It also highlights the potential of repurposing drugs like gefitinib for new therapeutic uses. These findings suggest EGFR's selective role in nerve regeneration and the possibility of targeted interventions, offering promising prospects for nerve injury treatment.

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