A new strategy for protection from cerebral ischemia

预防脑缺血的新策略

• 批准号: 7762239
• 负责人: YING XIA
• 金额: $ 8.71万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2010-05-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7762239
• 关键词: Acupuncture procedure; Attention; Attenuated; Award; Blood flow; Brain; Brain Infarction; Brain Injuries; Cell Membrane Proteins; Cerebral Ischemia; Cerebrovascular Circulation; Cerebrum; Cessation of life; Complementary and alternative medicine; Data; Early treatment; Employee Strikes; Event; Family; Funding; Grant; Home environment; Homeostasis; Hospitals; Hypoxia; Individual; Inflammatory; Inflammatory Response; Injury; Investigation; Ischemia; Ischemic Brain Injury; Knowledge; Lead; Light; Mediating; Middle Cerebral Artery Occlusion; Modality; Molecular; National Center for Complementary and Alternative Medicine; Needles; Neurologic; Neurons; Opioid; Opioid Receptor; Outcome; Patients; Play; Prevention; Production; Receptor Activation; Receptor Down-Regulation; Receptor Inhibition; Receptor Up-Regulation; Recovery; Regulation; Research; Risk; Role; Science; Scientist; Signal Transduction; Simulate; Solutions; Somatosensory Evoked Potentials; Stroke; Study Section; System; Techniques; Testing; Therapeutic; Transgenic Model; Transgenic Organisms; Travel; United States; United States National Institutes of Health; Up-Regulation; Work; acute stroke; attenuation; base; cost; cytokine; delta opioid receptor; design; disability; effective therapy; experience; neuron apoptosis; novel; novel strategies; novel therapeutics; prevent; public health relevance; receptor expression

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.

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，没有有效的策略来保护大脑免受缺血性损伤。近年来，电针对脑缺血的影响研究取得了令人振奋的进展。最引人注目的发现是，EA显着减少由于大脑中动脉闭塞引起的脑梗死，这取决于EA触发的脑中的细胞/分子事件。由于我们的研究和其他人的研究已经表明：1）δ-阿片受体（DOR）的激活减弱了引发神经元凋亡和死亡的离子稳态的缺氧/缺血破坏; 2）DOR上调增强了细胞内存活信号; 3）阿片受体激活抑制了炎症反应，例如，在缺血性损伤中起关键作用的炎性细胞因子的产生;以及4）DOR抑制在很大程度上减弱EA诱导的针对缺血性损伤的保护，EA诱导的保护很可能代表脑中多个水平的细胞和分子调节的结果。具体而言，它可能依赖于DOR上调和DOR介导的离子稳态稳定和存活/死亡信号的调节。这一建议的一般假设是，EA主要通过上调DOR以及DOR介导的神经元细胞和分子信号转导的调节来保护脑缺血。通过分子、转基因和电生理学方法，本研究旨在实现3个具体目标：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的离子稳态稳定来介导; 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。本项目的结果数据可能会产生重要的信息，EA诱导的脑缺血保护的机制，并可能提供新的线索，中风的治疗方案。 公共卫生关系： 中风是美国神经系统残疾和死亡的主要原因。然而，迄今为止还没有有效的治疗方法来保护大脑免受中风引起的脑损伤。为了寻求预防和治疗脑卒中的新方法，我们最近对电针对脑卒中损伤的影响进行了令人兴奋的观察。最引人注目和令人惊讶的发现是，EA，通过小针没有任何其他治疗，通过调节δ阿片受体（细胞膜蛋白）显着减少中风引起的脑损伤。同时，功能研究表明，电针可促进中风后脑功能的恢复。因此，我们的研究结果表明，重要的治疗潜力EA中风。在本申请中，我们建议使用现代技术，包括分子，转基因和电生理方法来测试三个具体的假设，探索潜在的EA保护中风的机制。我们的初步研究表明，这一建议是可行的，并很可能产生重要的信息EA诱导的保护，并最终阐明新的治疗模式的中风。