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 gamma-secretase and the resulting Notch activation may endanger neurons by modulating NF-kappaB and HIF-1alpha pathways. Notch signaling can also modulate MAPK-related pathways. However, the role of gamma-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 gamma-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. gamma-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 gamma-secretase inhibitors as therapy for ischemic stroke.
Cheng, Y-L., Choi, Y., Seow, W. L., Manzanero, S., Sobey, C. G., Jo, D-G., & Arumugam, T. V. (2014). Evidence that neuronal Notch-1 promotes JNK/c-Jun activation and cell death following ischemic stress. Brain Research, 1586, 193 - 202. https://doi.org/10.1016/j.brainres.2014.08.054