Epidermal growth factor receptor inhibitors promote CNS axon growth through off-target effects on glia

Research output: Contribution to journalArticle

Colleges, School and Institutes

Abstract

Administration of epidermal growth factor receptor (EGFR) inhibitors (e. g. AG1478/PD168393) promotes central nervous system (CNS) axon regeneration in vivo by an unknown mechanism. Here, we show that EGFR activation is not required for AG1478-/PD168393-induced neurite outgrowth in cultures of dorsal root ganglion neurons (DRGN) with added inhibitory CNS myelin extract (CME), but is mediated by the paracrine and autocrine actions of the glia-/neuron-derived neurotrophins (NT) NGF, BDNF and NT-3 through Trk signalling in DRGN potentiated by elevated cAMP levels. The DRGN neurite growth seen in CME-inhibited cultures treated with AG1478 is eradicated by blocking Trk signalling but undiminished after siRNA knockdown of >90% EGFR. Moreover, addition of the combined triplet of NT restores neurite outgrowth in CME-inhibited cultures, when cAMP levels are raised. Accordingly, we suggest that chemical EGFR inhibitors act independently of EGFR, inducing glia and neurons to secrete NT and raising cAMP levels in DRG cultures, leading to Trk-dependent disinhibited DRGN neurite outgrowth. (C) 2009 Elsevier Inc. All rights reserved.

Details

Original languageEnglish
Pages (from-to)142-150
Number of pages9
JournalNeurobiology of Disease
Volume36
Issue number1
Early online date24 Jul 2009
Publication statusPublished - 1 Sep 2009

Keywords

  • aggressive behaviour, EGFR, haloperidol, Neurotrophins, AG1478/PD168393, Neurite outgrowth, DRGN, Inhibitory CNS myelin, Glia, risperidone, intellectual disability