Notch signaling and neuronal death in stroke.

Ischemic stroke is a leading cause of morbidity and death, with the outcome largely determined by the amount of hypoxia-related neuronal death in the affected brain regions. Cerebral ischemia and hypoxia activate the Notch1 signaling pathway and four prominent interacting pathways (NF-κB, p53, HIF-1α and Pin1) that converge on a conserved DNA-associated nuclear multi-protein complex, which controls the expression of genes that can determine the fate of neurons. When neurons experience a moderate level of ischemic insult, the nuclear multi-protein complex up-regulates adaptive stress response genes encoding proteins that promote neuronal survival, but when ischemia is more severe the nuclear multi-protein complex induces genes encoding proteins that trigger and execute a neuronal death program. We propose that the nuclear multi-protein transcriptional complex is a molecular mediator of neuronal hormesis and a target for therapeutic intervention in stroke.