Light Alcohol Consumption and Ischemic Stroke

 描述（由申请人提供）：短暂性局灶性脑缺血是最常见的缺血性卒中类型之一。努力筛选防止脑缺血/再灌注（I/R）损伤的药剂/机制尚未产生有希望的结果。有趣的是，长期大量饮酒会增加缺血性中风的风险并产生神经退行性变，而轻度饮酒（LAC）会降低缺血性中风的风险并具有神经保护作用。本申请将集中于鉴定LAC的神经保护的细胞机制。我们的目标是将这些发现转化为患有缺血性中风后果的人类。在我们的初步研究中，我们发现LAC的神经保护作用似乎与核过氧化物酶体增殖物激活受体γ（PPARγ）的增加有关。我们还发现，LAC显着衰减短暂局灶性脑缺血诱导的炎症基因的表达和DNA断裂。此外，脂质运载蛋白型前列腺素D2合成酶（L-PGDS）和锰超氧化物歧化酶（MnSOD）被发现在大脑皮层中上调LAC。基于这些发现，我们的中心假设是LAC通过L-PGDS介导的PPARγ激活上调MnSOD来保护脑I/R损伤。在具体目标#1中，我们提出测试LAC通过上调MnSOD减弱短暂局灶性脑缺血后血管内皮细胞（VEC）炎症和神经元凋亡的假设。在具体目标#2中，我们建议检验LAC通过PPARγ介导的MnSOD上调减轻短暂局灶性脑缺血后VEC炎症和神经元凋亡的假设。在具体目标#3中，我们建议检验以下假设：LAC通过L-PGDS介导的PPARγ激活上调MnSOD并减弱短暂局灶性脑缺血后的VEC炎症和神经元凋亡。这些研究的结果将产生深远的影响，而不仅仅是对拉丁美洲和加勒比地区的影响。我们相信，通过确定LAC的保护性靶点，我们将能够在有缺血性卒中风险的个体中应用治疗来操纵这些靶点。

 DESCRIPTION (provided by applicant): Transient focal cerebral ischemia is one of the most common types of ischemic stroke. Efforts to screen for agents/mechanisms that protect against cerebral ischemia/reperfusion (I/R) injury have not produced promising results. Interestingly, chronic heavy alcohol consumption increases the risk of ischemic stroke and produces neurodegeneration, whereas light alcohol consumption (LAC) decreases the risk of ischemic stroke and is neuroprotective. The present application will focus on identifying the cellular mechanisms of neuroprotection by LAC. Our aim is to translate these findings to humans suffering from the consequences of ischemic stroke. In our preliminary studies, we found that the neuroprotective effect of LAC appeared to be related to an increase in nuclear peroxisome proliferator-activated receptor gamma (PPARγ). We also found that LAC significantly attenuated transient focal cerebral ischemia-induced expression of inflammatory genes and DNA fragmentation. Further, lipocalin-type prostaglandin D2 synthase (L-PGDS) and manganese superoxide dismutase (MnSOD) were found to be upregulated in cerebral cortex by LAC. Based on these findings, our central hypothesis is that LAC protects against cerebral I/R injury by upregulating MnSOD via L-PGDS-mediated PPARγ activation. In specific aim #1, we propose to test the hypothesis that LAC attenuates vascular endothelial cell (VEC) inflammation and neuronal apoptosis following transient focal cerebral ischemia via an upregulated MnSOD. In specific aim #2, we propose to test the hypothesis that LAC attenuates VEC inflammation and neuronal apoptosis following transient focal cerebral ischemia via PPARγ-mediated MnSOD upregulation. In specific aim #3, we propose to test the hypothesis that LAC upregulates MnSOD and attenuates VEC inflammation and neuronal apoptosis following transient focal cerebral ischemia via L-PGDS-mediated PPARγ 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.