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
Notice bibliographique
Résumé
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.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».