Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
6263256 | Brain Research | 2014 | 10 Pages |
â¢Notch signaling regulates cell fate decisions during embryonic development.â¢Notch activation may endanger neurons by modulating NF-κB and HIF-1α pathways.â¢Notch signaling can also modulate MAPK-related pathways.â¢The role of Notch signaling in activating MAPK in stroke is not known.â¢Our findings suggest that Notch signaling promotes JNK/cJun signaling in ischemia.
Notch signaling is a highly conserved pathway that regulates cell fate decisions during embryonic development. We have recently identified that in ischemic stroke, activity of γ-secretase and the resulting Notch activation may endanger neurons by modulating NF-κB and HIF-1α pathways. Notch signaling can also modulate MAPK-related pathways. However, the role of γ-secretase-mediated Notch signaling in activating MAPK following ischemic stroke has not been investigated. We used control and NICD1-overexpressing HEK and SH-SY5Y cell lines, and inhibitors of γ-secretase and JNK, to explore novel roles of Notch in modulating cell death following ischemic stress in vitro. Our findings indicate that expression of NICD1, JNK/cJun, p38-MAPK and the pro-apoptotic marker, cleaved caspase-3, increased during ischemic conditions. γ-Secretase inhibitors reduced ischemia-induced increase in NICD1 and JNK/p-cJun. Furthermore, NICD overexpression augmented JNK/cJun levels and cell death under these conditions. These results suggest that Notch signaling contributes to the pathogenesis of ischemic stroke, in part by promoting JNK/cJun signaling. These results provide further support for the potential use of γ-secretase inhibitors as therapy for ischemic stroke.