58. The Epidermal Growth Factor Receptor (EGFR) Inhibitor Gefitinib Enhances In Vitro and In Vivo Peripheral Nerve Regeneration in a Mouse Median Nerve Injury Model
Bibliographic record
Abstract
PURPOSE: Peripheral nerve injuries have the capacity for spontaneous recovery, but clinical outcomes are limited by many factors that antagonize the biology of nerve regeneration. These antagonistic factors include repulsive cues, such as chondroitin sulphate proteoglycan (CSPG), within regenerative milieu that are encountered by axons that are elongating towards their targets. Currently, no FDA approved pharmacological methods exist to augment the rate or extent of peripheral nerve regeneration. 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 known to be expressed by peripheral motor and sensory neurons. 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. METHODS:In vitro cell culture assays of neurite outgrowth on inhibitory CSPG substrate were carried out assess the response of adult dorsal root ganglia (DRG) neurons of EGFR inhibition with gefitinib. DRG neurons were harvested from adult C57Bl/6 mice and cultured in the presence of CSPG (200nM), with or without gefinitib (10μM). 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. In a separate cohort of mice, Western blot analysis and grip strength assessment were carried out to assess the signalling and functional impact of gefitinib administration. RESULTS: Neurite extension assays revealed that culturing adult DRG neurons in the presence of CSPG effectively arrested neurite outgrowth. Administration of gefitinib to cultured DRGs in the presence of CSPG restored neurite length to control levels and demonstrated significantly increased mean neurite length compared to CSPG alone. Retrograde labeling 5 days after median nerve injury revealed significantly greater numbers of sensory DRG neurons (738±174 vs. 280±107) but not motoneurons (60±31 vs 18±4; p=0.15) in mice that received gefitinib compared with vehicle, respectively. CONCLUSION: The EGFR receptor is a regulator of peripheral nerve regeneration that has several FDA approved, commercially available inhibitors at market. In this study, selective inhibition of EGFR using the drug gefitinib rescued in vitro neurite outgrowth back to control levels in the presence of inhibitory CSPG. Furthermore, gefitinib increased the number of DRG neurons extending 5 mm beyond the repair site after 5 days compared with vehicle, suggesting an increased rate of sensory neuron regeneration. A focus of future work will be examining what role EGFR may have in mediating the inhibitory cues in the regenerative milieu, such as those from CSPG.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".