Abstract
Activated epidermal growth factor receptor (EGFR) has been proposed in the pathophysiology of neurodegenerative diseases. In the present study, the anti-inflammatory effect of afatinib, an EGFR-tyrosine kinase inhibitor (EGFR-TKIs) was investigated using CTX-TNA2 cells and primary cultured astrocytes subjected to oxygen/glucose deprivation (OGD). We found that OGD induced EGFR phosphorylation and activated subsequent signaling pathways, including phosphorylation of AKT and extracellular signal-regulated kinases (ERK). Afatinib blocked OGD-induced phosphorylation of EGFR, AKT and ERK. At the same time, afatinib attenuated OGD-induced elevations in glial fibrillary acidic protein (a biomarker of activated astrocytes) and proliferating cell nuclear antigen expression (a cell proliferating biomarker) as well as hypoxia-induced migratory ability. Furthermore, afatinib decreased OGD-induced increases in cyclooxygenase-II and inducible nitric oxide synthase expression of the treated astrocytes as well as NO content in the culture medium. Moreover, afatinib attenuated OGD-induced caspase 1 activation (a biomarker of inflammasome activation) and interleukin-1β levels (a pro-inflammatory cytokine). Collectively, afatinib could block OGD-induced EGFR activation and its downstream signaling pathways in astrocytes. Moreover, afatinib attenuated OGD-induced astrocyte activation, proliferation and inflammasome activation. These data support the involvement of EGFR activation in neuroinflammation. Furthermore, EGFR-TKIs may be promising in inhibiting neuroinflammation in the CNS neurodegenerative diseases.
Highlights
Activated epidermal growth factor receptor (EGFR) has been proposed in the pathophysiology of neurodegenerative diseases
Incubation with afatinib (1–100 nM) did not induce significant increases in lactate dehydrogenase (LDH) levels in the culture medium containing primary cultured astrocytes (Fig. 1C). These data indicate that afatinib was not cytotoxic to CTX-TNA2 cells and primary cultured astrocytes
We found that afatinib (1 and 10 nM) attenuated oxygen/glucose deprivation (OGD) (12 h)-induced phosphorylation of EGFR (Fig. 2C) as well as the phosphorylation of AKT and extracellular signal-regulated kinases (ERK) in the treated CTX-TNA2 cells (Fig. 2D)
Summary
Activated epidermal growth factor receptor (EGFR) has been proposed in the pathophysiology of neurodegenerative diseases. The anti-inflammatory effect of afatinib, an EGFRtyrosine kinase inhibitor (EGFR-TKIs) was investigated using CTX-TNA2 cells and primary cultured astrocytes subjected to oxygen/glucose deprivation (OGD). We found that OGD induced EGFR phosphorylation and activated subsequent signaling pathways, including phosphorylation of AKT and extracellular signal-regulated kinases (ERK). Afatinib attenuated OGD-induced astrocyte activation, proliferation and inflammasome activation These data support the involvement of EGFR activation in neuroinflammation. EGFR activation activates PI3K-AKT and Raf-MAPK-ERK1/2 pathways[2,6,7] to generate intracellular mediators which translocate into the nucleus to regulate DNA synthesis for cell growth and proliferation as well as to modulate cell survival, migration, differentiation and death[2,7]. The anti-inflammatory effect of afatinib, a second-generation EGFR-tyrosine kinase inhibitor (EGFR-TKI), on OGD-induced neuroinflammation was studied in vitro. Due to its ability to penetrate blood brain barrier (BBB)[19], afatinib may be useful in inhibiting neuroinflammation in the CNS neurodegenerative diseases
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