RGD Reference Report - Inhibition of EGFR/MAPK signaling reduces microglial inflammatory response and the associated secondary damage in rats after spinal cord injury. - Rat Genome Database

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Inhibition of EGFR/MAPK signaling reduces microglial inflammatory response and the associated secondary damage in rats after spinal cord injury.

Authors: Qu, WS  Tian, DS  Guo, ZB  Fang, J  Zhang, Q  Yu, ZY  Xie, MJ  Zhang, HQ  Lu, JG  Wang, W 
Citation: Qu WS, etal., J Neuroinflammation. 2012 Jul 23;9:178. doi: 10.1186/1742-2094-9-178.
RGD ID: 7204495
Pubmed: PMID:22824323   (View Abstract at PubMed)
PMCID: PMC3418570   (View Article at PubMed Central)
DOI: DOI:10.1186/1742-2094-9-178   (Journal Full-text)

BACKGROUND: Emerging evidence indicates that reactive microglia-initiated inflammatory responses are responsible for secondary damage after primary traumatic spinal cord injury (SCI); epidermal growth factor receptor (EGFR) signaling may be involved in cell activation. In this report, we investigate the influence of EGFR signaling inhibition on microglia activation, proinflammatory cytokine production, and the neuronal microenvironment after SCI. METHODS: Lipopolysaccharide-treated primary microglia/BV2 line cells and SCI rats were used as model systems. Both C225 and AG1478 were used to inhibit EGFR signaling activation. Cell activation and EGFR phosphorylation were observed after fluorescent staining and western blot. Production of interleukin-1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF alpha) was tested by reverse transcription PCR and ELISA. Western blot was performed to semi-quantify the expression of EGFR/phospho-EGFR, and phosphorylation of Erk, JNK and p38 mitogen-activated protein kinases (MAPK). Wet-dry weight was compared to show tissue edema. Finally, axonal tracing and functional scoring were performed to show recovery of rats. RESULTS: EGFR phosphorylation was found to parallel microglia activation, while EGFR blockade inhibited activation-associated cell morphological changes and production of IL-1 beta and TNF alpha. EGFR blockade significantly downregulated the elevated MAPK activation after cell activation; selective MAPK inhibitors depressed production of cytokines to a certain degree, suggesting that MAPK mediates the depression of microglia activation brought about by EGFR inhibitors. Subsequently, seven-day continual infusion of C225 or AG1478 in rats: reduced the expression of phospho-EGFR, phosphorylation of Erk and p38 MAPK, and production of IL-1 beta and TNF alpha; lessened neuroinflammation-associated secondary damage, like microglia/astrocyte activation, tissue edema and glial scar/cavity formation; and enhanced axonal outgrowth and functional recovery. CONCLUSIONS: These findings indicate that inhibition of EGFR/MAPK suppresses microglia activation and associated cytokine production; reduces neuroinflammation-associated secondary damage, thus provides neuroprotection to SCI rats, suggesting that EGFR may be a therapeutic target, and C225 and AG1478 have potential for use in SCI treatment.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Inflammation  ISOEgfr (Rattus norvegicus)7204495; 7204495associated with Spinal Cord InjuriesRGD 
Inflammation  IMP 7204495associated with Spinal Cord InjuriesRGD 

Objects Annotated

Genes (Rattus norvegicus)
Egfr  (epidermal growth factor receptor)

Genes (Mus musculus)
Egfr  (epidermal growth factor receptor)

Genes (Homo sapiens)
EGFR  (epidermal growth factor receptor)


Additional Information