title: Epidermal growth factor receptor inhibitors promote CNS axon growth through off-target effects on glia.
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.
authors.affiliation: Molecular Neuroscience Group, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Institute of Biomedical Research (West), Edgbaston, Birmingham B15 2TT, UK. z.ahmed.1@bham.ac.uk
authors.forename: Zubair
authors.initials: Z
authors.lastname: Ahmed
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Jacques
authors.forename: Martin
authors.initials: M
authors.lastname: Berry
authors.forename: Ann
authors.initials: A
authors.lastname: Logan
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000502:physiology; D002227:Carbazoles / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002490:Central Nervous System / Q000166:cytology / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D005727:Ganglia, Spinal / Q000166:cytology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D026121:Indole Alkaloids / Q000494:pharmacology; D009186:Myelin Sheath / Q000378:metabolism; D009409:Nerve Crush / Q000379:methods; D009414:Nerve Growth Factors / Q000378:metabolism; D009457:Neuroglia / Q000737:chemistry / Q000502:physiology*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects*; D011799:Quinazolines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D009418:S100 Proteins / Q000378:metabolism; D014162:Transfection / Q000379:methods; D020032:Tyrphostins / Q000494:pharmacology*
chemical_list: D002227:Carbazoles; D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D026121:Indole Alkaloids; D009414:Nerve Growth Factors; C509204:PD168393; D011799:Quinazolines; D034741:RNA, Small Interfering; D009418:S100 Proteins; D020032:Tyrphostins; C101044:RTKI cpd; C049985:staurosporine aglycone; D000242:Cyclic AMP; D066246:ErbB Receptors