A new strategy for protection from cerebral ischemia

预防脑缺血的新策略

• 批准号: 8217282
• 负责人: YING XIA
• 金额: $ 36.75万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 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 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8217282
• 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; Electroacupuncture; Electroencephalogram; Employee Strikes; Event; Family; Funding; Grant; Health; Home environment; Homeostasis; Hospitals; Hypoxia; Individual; Inflammatory; Inflammatory Response; Injury; Investigation; Ischemia; Ischemic Brain Injury; 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; 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(申请人提供)：缺血性脑损伤，如中风，在美国是导致神经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损伤。近年来，我们对电针治疗脑缺血的作用进行了令人兴奋的观察。最显著的发现是，电针可显著减少大脑中动脉闭塞所致的脑梗塞，这依赖于电针引发的脑内细胞/分子事件。由于我们和其他人的研究表明：1)激活增量阿片受体(DOR)可减轻缺氧/缺血引起的离子稳态的破坏，从而触发神经元的凋亡和死亡；2)DOR上调增强了细胞内的生存信号；3)阿片受体的激活抑制了炎症反应，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的抑制在很大程度上减弱了电针诱导的抗缺血损伤的保护作用，这可能是电针诱导的保护作用在多个水平上的细胞和分子调节的结果。具体地说，它可能依赖于DOR的上调以及DOR介导的离子稳态的稳定和生存/死亡信号的调节。这一设想的基本假设是，电针主要通过上调DOR和DOR介导的神经元细胞和分子信号转导来保护脑缺血。结合分子、转基因和电生理方法，本研究旨在实现3个具体目标：1)研究电针是否通过上调DOR对脑缺血起保护作用；2)研究电针的保护作用是否由DOR介导的离子稳态稳定所介导；3)研究电针的保护作用是否依赖于DOR介导的对脑缺血炎症反应的抑制。该项目的结果数据可能提供关于电针诱导的脑缺血保护机制的重要信息，并可能为卒中的治疗方案提供新的线索。公共卫生相关性： 在美国，中风是导致神经性残疾和死亡的主要原因。然而，到目前为止，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/治疗中风的新方法，我们最近对电针(EA)对中风损伤的影响进行了令人兴奋的观察。最惊人和令人惊讶的发现是，电针在没有任何其他治疗的情况下，通过小针，通过调节三角洲阿片受体(一种细胞膜蛋白)，显著减少了中风引起的脑损伤。此外，功能研究表明，电针促进中风后大脑功能的恢复。因此，我们的发现表明电针治疗中风具有重要的治疗潜力。在这一应用中，我们建议使用包括分子、转基因和电生理方法在内的现代技术来测试三个特定的假说，以探索电针预防中风的潜在机制。我们的初步研究表明，这一建议是可行的，很可能会在电针诱导的保护作用方面产生重要信息，并最终为中风的新治疗方式提供线索。