Evidence that collaboration between HIF-1α and Notch-1 promotes neuronal cell death in ischemic stroke.

Recent findings suggest that Notch-1 signaling contributes to neuronal death in ischemic stroke, but the underlying mechanisms are unknown. Hypoxia inducible factor-1α (HIF-1α), a global regulator of cellular responses to hypoxia, can interact with Notch and modulate its signaling during hypoxic stress. Here we show that Notch signaling interacts with the HIF-1α pathway in the process of ischemic neuronal death. We found that a chemical inhibitor of the Notch-activating enzyme, γ-secretase, and a HIF-1α inhibitor, protect cultured cortical neurons against ischemic stress, and combined inhibition of Notch-1 and HIF-1α further decreased neuronal death. HIF-1α and Notch intracellular domain (NICD) are co-expressed in the neuronal nucleus, and co-immunoprecipitated in cultured neurons and in brain tissue from mice subjected to focal ischemic stroke. Overexpression of NICD and HIF-1α in cultured human neural cells enhanced cell death under ischemia-like conditions, and a HIF-1α inhibitor rescued the cells. RNA interference-mediated depletion of endogenous NICD and HIF-1α also decreased cell death under ischemia-like conditions. Finally, mice treated with inhibitors of γ-secretase and HIF-1α exhibited improved outcome after focal ischemic stroke, with combined treatment being superior to individual treatments. Additional findings suggest that the NICD and HIF-1α collaborate to engage pro-inflammatory and apoptotic signaling pathways in stroke.

Encephaloduroarteriosynangiosis with bifrontal encephalogaleo(periosteal)synangiosis in the pediatric moyamoya disease: the surgical technique and its outcomes.

METHODS: To increase the blood flow of the anterior cerebral artery (ACA) and the middle cerebral artery (MCA) territories, we modified the "ribbon" procedure in combination with encephaloduroarteriosynangiosis (EDAS). This is referred to as "EDAS with bifrontal encephalogaleo(periosteal)synangiosis (EGS)." The surgical technique, clinical outcomes, complications, extent of revascularization, and changes in CBF in 67 pediatric MMD patients were retrospectively reviewed. RESULTS: The excellent and good clinical recovery rates were 57% and 31%. The rate for complete disappearance of TIA was 63%. All the bifrontal EGS made abundant collateral vessels in the ACA territory. When the EDAS with bifrontal EGS was performed in the first operation, collaterals of EGS sites developed more on the contralateral side of the EDAS. The arachnoid opening of the medial frontal lobe in the EGS site had no effect on the results. There was a positive correlation between the clinical outcome and the extent of angiographic revascularization. Improvements in the CBF and the reserve in ACA territory were observed in 57%. CONCLUSIONS: EDAS with bifrontal EGS resulted in excellent revascularization in both the MCA and ACA territories. The clinical and hemodynamic results were also excellent. This procedure may be an effective and safe surgical modality for the prevention of ischemia in the whole territory of the anterior circulation of the brain in pediatric MMD.