A new strategy for protection from cerebral ischemia

描述（由申请人提供）：缺血性脑损伤如中风是美国神经系统残疾和死亡的主要原因。然而，目前还没有有效的策略来保护大脑免受缺血性损伤。近年来，我们在电针治疗脑缺血方面取得了令人振奋的研究成果。最引人注目的发现是，EA显著减少了由于大脑中动脉闭塞引起的脑梗死，这取决于EA触发的大脑细胞/分子事件。由于我们的研究和其他研究已经表明：1)δ -阿片受体（DOR）的激活减弱了缺氧/缺血对离子稳态的破坏，从而引发神经元凋亡和死亡；2) DOR上调增强了细胞内生存信号；3)阿片受体激活可抑制炎症反应，如在缺血性损伤中起关键作用的炎症细胞因子的产生；4) DOR抑制在很大程度上减弱了ea诱导的对缺血性损伤的保护作用，可能ea诱导的保护作用是脑内多水平细胞和分子调控的结果。具体来说，它可能依赖于DOR的上调和DOR介导的离子稳态稳定和生存/死亡信号的调节。这一提议的一般假设是，EA主要通过DOR上调和DOR介导的神经元细胞和分子信号的调节来保护脑缺血。本研究采用分子、转基因和电生理等方法，旨在实现以下三个目标：1)研究EA是否通过DOR上调来保护脑缺血；2)研究EA保护是否通过基于dor的离子稳态稳定介导；3)研究EA保护是否依赖于dor介导的对缺血炎症反应的抑制。该项目的结果数据可能为ea诱导的脑缺血保护机制提供重要信息，并可能为中风的治疗方案提供新的线索。公共卫生相关性：

DESCRIPTION (provided by applicant): Ischemic brain injury such as stroke is a leading cause of neurological disability and death in the States. There is, however, no effective strategy to protect the brain from ischemic injury. Recently, we have made exciting observations on effect of electro-acupuncture (EA) on cerebral ischemia. The most striking finding is that EA remarkably reduces brain infarction due to the occlusion of middle cerebral artery, which is dependent on the EA-triggered cellular/molecular events in the brain. Since our studies and those of others have shown that 1) activation of delta-opioid receptor (DOR) attenuates hypoxic/ischemic disruption of ionic homeostasis that triggers neuronal apoptosis and death; 2) DOR up-regulation enhances intracellular survival signals; 3) opioid receptor activation inhibits inflammatory responses, e.g., production of inflammatory cytokines that plays a critical role in ischemic injury; and 4) DOR inhibition largely attenuates the EA-induced protection against ischemic injury, it is likely that the EA-induced protection represents the outcome of cellular and molecular regulation at multiple levels in the brain. Specifically, it may depend on DOR up-regulation and the DOR-mediated stabilization of ionic homeostasis and modulation of survival/death signals. The general hypothesis of this proposal is that EA protects against cerebral ischemia mainly through DOR up-regulation and the DOR-mediated modulation of cellular and molecular signaling in neurons.. With molecular, transgenic and electrophysiological approaches, this proposal is designed to accomplish 3 specific aims: 1) to investigate if EA protects the brain from cerebral ischemia via DOR up-regulation; 2) to investigate if the EA protection is mediated by DOR-based stabilization of ionic homeostasis; and 3) to investigate if the EA protection relies on DOR-mediated inhibition of inflammatory responses to ischemia. The outcome data of this project may yield important information on the mechanism underlying the EA-induced protection from cerebral ischemia and may provide novel clues for therapeutic solutions of stroke. PUBLIC HEALTH RELEVANCE: Stroke is a leading cause of neurological disability and death in the United States. However, there is no effective therapy to date to protect the brain from stroke-induced brain injury. To seek novel approaches to prevent/treat stroke, we have recently made exciting observations on the effect of electro- acupuncture (EA) on stroke-induced injury. The most striking and surprising finding is that EA, through little needles without any other treatment, remarkably reduces stroke-induced brain injury via the regulation of delta-opioid receptor (a cell membrane protein). Also, functional studies showed that EA promotes the recovery of brain function after stroke. Our finding thus suggests important therapeutic potential for EA in stroke. In this application, we propose to use modern techniques including molecular, transgenic and electrophysiological approaches to test three specific hypotheses for exploring mechanisms underlying the EA protection against stroke. Our preliminary studies have shown that this proposal is feasible and will very likely yield important information on the EA-induced protection and eventually shed light on new therapeutic modalities of stroke.