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（由申请人提供）：诸如中风之类的缺血性脑损伤是美国神经疾病和死亡的主要原因。但是，没有保护大脑免受缺血性损伤的有效策略。最近，我们对电针（EA）对脑缺血的影响进行了令人兴奋的观察。最引人注目的发现是，EA由于脑部中动脉的阻塞而显着减少了脑梗塞，这取决于大脑中EA触发的细胞/分子事件。由于我们的研究和其他研究表明，1）激活三角洲 - 阿片受体（DOR）的激活减弱了离子稳态的低氧/缺血性破坏，从而触发神经元细胞凋亡和死亡； 2）DOR上调增强了细胞内存活信号； 3）阿片受体激活抑制炎症反应，例如，产生在缺血性损伤中起关键作用的炎性细胞因子； 4）DOR抑制很大程度上会减弱EA诱导的缺血性损伤的保护，EA诱导的保护很可能代表了大脑中多个水平下细胞和分子调节的结果。具体而言，这可能取决于DOR上调以及离子稳态的DOR介导的稳定以及生存/死亡信号的调节。该提案的一般假设是，EA主要通过DOR上调和神经元中细胞和分子信号的DOR介导的调节来预防脑缺血。用分子，转基因和电生理学方法来保护细胞和分子信号传导。 2）研究EA保护是否是通过基于DOR的离子稳态稳定介导的； 3）研究EA保护是否依赖于DOR介导的炎症反应对缺血的抑制作用。该项目的结果数据可能会产生有关EA引起的保护免受脑缺血的基础机制的重要信息，并可能为中风治疗溶液提供新的线索。 公共卫生相关性： 中风是美国神经残疾和死亡的主要原因。但是，迄今为止尚无有效的疗法来保护大脑免受中风诱发的脑损伤。为了寻求预防/治疗中风的新方法，我们最近就电穴（EA）对中风引起的损伤的影响进行了令人兴奋的观察。最令人惊讶的发现是，通过小针，没有任何其他治疗方法，通过调节三角洲 - 阿片受体（细胞膜蛋白），通过小针不受任何其他治疗，可以显着减少中风诱导的脑损伤。此外，功能研究表明，EA促进了中风后脑功能的恢复。因此，我们的发现表明了中风中EA的重要治疗潜力。在此应用中，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假设，以探索EA保护抗中风的基础机制。我们的初步研究表明，该提案是可行的，很可能会产生有关EA引起的保护的重要信息，并最终阐明了中风的新治疗方式。