Epidermal growth factor receptor inhibitor ameliorates excessive astrogliosis and improves the regeneration microenvironment and functional recovery in adult rats following spinal cord injury

Abstract

BackgroundAstrogliosis is a common phenomenon after spinal cord injury (SCI). Although this process exerts positive effects on axonal regeneration, excessive astrogliosis imparts negative effects on neuronal repair and recovery. Epidermal growth factor receptor (EGFR) pathway is critical to the regulation of reactive astrogliosis, and therefore is a potential target of therapeutics to better control the response. In this report, we aim to investigate whether blocking EGFR signaling using an EGFR tyrosine kinase specific inhibitor can attenuate reactive astrogliosis and promote functional recovery after a traumatic SCI.MethodThe astrocyte scratch injury model in vitro and the weight-drop SCI model in vivo were used as model systems. PD168393 was used to inhibit EGFR signaling activation. Astrocytic activation and phosphorylated EGFR (pEGFR) were observed after immunofluorescence staining and Western blot analysis. The rate of proliferation was determined by immunofluorescence detection of BrdU-incorporating cells located next to the wound. The levels of TNF-α, iNOS, COX-2 and IL-1β in the culture medium under different conditions were assayed by ELISA. Western blot was performed to semi-quantify the expression of EGFR/pEGFR, glial fibrillary acid protein (GFAP) and chondroitin sulfate proteoglycans (CSPGs). Myelin was stained by Luxol Fast Blue Staining. Cresyl violet eosin staining was performed to analyze the lesion cavity volume and neuronal survival following injury. Finally, functional scoring and residual urine recording were performed to show the rats’ recovery.ResultsEGFR phosphorylation was found to parallel astrocyte activation, and EGFR inhibitor PD168393 potently inhibited scratch-induced reactive astrogliosis and proinflammatory cytokine/mediator secretion of reactive astrocytes in vitro. Moreover, local administration of PD168393 in the injured area suppressed CSPGs production and glial scar formation, and resulted in reduced demyelination and neuronal loss, which correlated with remarkable hindlimb motor function and bladder improvement in SCI rats.ConclusionsThe specific EGFR inhibitor PD168393 can ameliorate excessive reactive astrogliosis and facilitate a more favorable environment for axonal regeneration after SCI. As such, EGFR inhibitor may be a promising therapeutic intervention in CNS injury.

miR‐22‐3p enhances the intrinsic regenerative abilities of primary sensory neurons via the CBL/p‐EGFR/p‐STAT3/GAP43/p‐GAP43 axis

“…However, the conclusions from these studies are controversial. They applied EGFR inhibitors in injured spinal cord, and concluded entirely different results (Erschbamer, Pernold, & Olson, ; Q. Han et al, ; Li et al, ; Li et al, ; B. Liu & Neufeld, ; White et al, ). Inspiringly, EGFR activation exerts positive role in neurons (Ahmed, Read, Berry, & Logan, ; Wildering, Hermann, & Bulloch, ; Xu et al, ).…”

Rehabilitative Surgery

“…Many investigators subsequently confirmed beneficial effects of treatments that break down or reduce CSPG production [32,79,93,113,116,125,152,161,195,360,361]. In 2006, Barritt et al reported that ChABC promotes sprouting in intact and injured spinal cords [16].…”

Nucleolin inhibitor GroA triggers reduction in epidermal growth factor receptor activation: Pharmacological implication for glial scarring after spinal cord injury

“…Previous studies have showed that activation of EGFR in astrocytes at the injury site increases their reactivity, and therefore mediates glial scar formation (Liu and Neufeld ; Li et al . , ). We have previously demonstrated that in glioblastoma, GroA, an aptamer that inhibits cell surface nucleolin, prevented EGF‐induced receptor activation and its downstream signalling followed by reduced cell proliferation (Goldshmit et al .…”