Light Alcohol Consumption and Ischemic Stroke

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Hong Sun, MD, PhD PROJECT SUMMARY/ABSTRACT Efforts to screen for agents that prevent and treat ischemic stroke, one of the leading causes of death and permanent disability, have not produced promising results. Interestingly, light alcohol consumption (LAC) lowers the incidence and improves the prognosis of ischemic stroke. Most recently, we found that LAC promotes cerebral angiogenesis and neurogenesis under basal conditions and following ischemic stroke. This renewal application will continue identifying the cellular mechanism underlying the neuroprotective effect of LAC. We aim to translate these findings to humans having risk factors and suffering from the consequences of ischemic stroke. In the previous grant period, we further found that LAC upregulates lipocalin-type prostaglandin D2 synthase (L-PGDS), peroxisome proliferator-activated receptor gamma (PPARg), vascular endothelial growth factor A (VEGF-A), and vascular endothelial growth factor receptor 2 (VEGFR2) in the brain. In preliminary studies, LAC-induced cerebral angiogenesis appeared to be related to an increase in L-PGDS. Based on these findings, our central hypothesis is that LAC promotes cerebral angiogenesis and neurogenesis by upregulating VEGF-A/VEGFR2 via L-PGDS-mediated PPARg activation. In specific aim #1, we propose to test the hypothesis that LAC promotes cerebral angiogenesis and neurogenesis via upregulated VEGF-A and VEGFR2. In specific aim #2, we propose to test the hypothesis that LAC promotes cerebral angiogenesis and neurogenesis via PPARg-mediated upregulation of VEGF-A and VEGFR2. In specific aim #3, we propose to test the hypothesis that LAC upregulates VEGF-A and VEGFR2 and promotes cerebral angiogenesis and neurogenesis via L-PGDS-mediated PPARg activation. The findings from these studies will have far-reaching implications, beyond that for LAC. We believe that by identifying the protective targets of LAC we will be able to apply therapy to manipulate these targets in individuals at risk for ischemic stroke.