Molecular mechanisms of Notch1-mediated neuronal cell death in ischemic stroke

Abstract

Stroke is a devastating neurological disease with high mortality rate and has profound implications for health economics and resources globally. There is a sense of urgency for scientists to discover a pharmacological target in stroke that could modulate multiple molecular cell injury mechanisms since many therapeutic agents that targeted only a single injury mechanism result in disappointing outcomes in human clinical trials. During stroke, cerebral ischemia triggers a number of membrane bound receptor-mediated signaling cascades that can activate many downstream kinases and transcription factors known to induce neuronal apoptosis. The activation of the membrane receptor Notch1 and its signaling pathway is seen in the infarcted brain, which is shown to deteriorate the outcome of ischemic stroke.Notch1 is a transmembrane receptor that regulates cell fate decisions in the developing nervous system and adult brain. Binding of Notch's ligands leads to the proteolytic cleavage of Notch1 by γ-secretase and the generation of Notch1 intracellular domain (NICD1), which is able to translocate to the nucleus and regulate transcription of its downstream genes. Although Notch1 has been demonstrated to worsen stroke outcome by stimulating the infiltration of pro-inflammatory leukocytes and microglia-induced inflammatory responses, the molecular mechanisms of Notch1 in neurons following ischemic stroke in the induction of pro-apoptotic cascades are still not yet fully established.The present studies aim to investigate the role of γ-secretase-mediated Notch signaling pathway in the induction of neuronal cell death through its modulation with the nuclear factor-κB (NF-κB) pathway, the collaboration with hypoxia-inducible factor-1α (HIF-1α) pathway, and its contribution to the mitogen activated protein kinase (MAPK) pathway, which are all crucial in the induction of neuronal apoptosis. It also aims to observe the modulation of the pro-apoptotic proteins that are activated as a result of Notch1 activation in neurons following ischemic stroke.The present studies demonstrate that the inhibition of Notch1 activation using γ-secretase inhibitors protect neuronal cells against ischemia-induced cell death by targeting an apoptotic marker, cleaved caspase-3, NF-κB subunits p65, p50 and pro-apoptotic BH3-only protein, Bcl-2 interacting mediator of cell death (Bim). In addition, treatment of mice with the γ-secretase inhibitor reduces NICD1, phosphorylated-p65 and Bim expression levels, with reduced infarct size and improved functional outcome in a mouse model of focal ischemic stroke. These findings II suggest that γ-secretase-mediated Notch signaling endangers neurons after ischemic stroke by modulating the NF-κB-Bim pathway.Additional findings suggest that the HIF-1α pathway, a global regulation pathway of cellular response to hypoxia, is able to interact with Notch1 and modulate its signaling during ischemic stroke. Treatment with either a HIF-1α inhibitor or a γ-secretase inhibitor protects neurons against ischemic stress and...

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