Omega 3 fatty acids, acute neuroprotection via mitochondria

Omega 3 脂肪酸，通过线粒体提供急性神经保护

• 批准号: 10447712
• 负责人: RICHARD JOSEPH DECKELBAUM
• 金额: $ 57.88万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10447712
• 关键词: Acute; Address; Affect; Anabolism; Animals; Apoptotic; Attenuated; BAX gene; Bioenergetics; Blood; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Buffers; Cardiovascular Diseases; Cell Death; Cell Membrane Permeability; Cerebrum; Cessation of life; Clinical; Complex; Coupled; Docosahexaenoic Acids; Eicosapentaenoic Acid; Electric Conductivity; Emulsions; Event; Failure; Functional disorder; Gender; Human; Hypoxic-Ischemic Brain Injury; In Vitro; Injections; Inner mitochondrial membrane; Ischemia; Ischemic Brain Injury; Ischemic Stroke; Liver; Measures; Mediating; Mediator of activation protein; Membrane; Metabolism; Microscopy; Mitochondria; Mitochondrial Matrix; Mus; Neurologic; Neurons; Omega-3 Fatty Acids; Organ; Outer Mitochondrial Membrane; Oxidative Phosphorylation; Pathologic; Pathway interactions; Permeability; Pharmacology; Plasma; Property; Protons; Recovery; Reperfusion Injury; Reperfusion Therapy; Reporting; Research; Respiration; Rodent Model; Role; Severities; Spleen; Stroke; Testing; Therapeutic; Time; Tissues; Triglycerides; attenuation; base; cell injury; clinical application; improved; in vivo; innovation; ischemic injury; mitochondrial dysfunction; mitochondrial membrane; natural hypothermia; neonatal hypoxic-ischemic brain injury; neonatal stroke; neurobehavioral; neuroprotectin D1; neuroprotection; novel; novel therapeutic intervention; patch clamp; preservation; prevent; therapeutic target; translational impact; translational study

Project Summary Neonatal stroke and hypoxia-ischemia (HI) brain injury remains a leading cause of a lifelong neurological handicap. The only currently accepted approach is post-ischemic hypothermia. However, no exact therapeutic mechanisms of this approach are known. A growing body of experimental evidence showed that omega-3 (n-3) fatty acids (FAs) and their bioactive metabolites protect developing brain against HI-reperfusion injury. Using triglyceride emulsions we showed that docosahexaenoic acid (DHA) provided strong neuroprotection against HI brain injury in different rodent models. This neuroprotection was associated with increased DHA content in cerebral mitochondria, preserved mitochondrial function in reperfusion and coupled with a dramatic (3 to 15 fold) elevation of DHA metabolites, neuroprotectin D1 (NPD1) and other specialized pro-resolving mediators (SPMs), specifically in the ischemic brain. We have reasoned that beneficial action of DHA may be exerted by its metabolites. Among tested SPMs, only NPD1 significantly attenuated HI brain damage in mice. Administration of NPD1 also suppressed activation of Ca2+ induced mitochondrial membrane permeability transition pore (mPTP) and apoptotic death pathway by blocking BAX-mitochondria interaction. In this renewal application, we hypothesize that DHA-derived bioactive mediator, NPD1 a) modifies the matrix mitochondrial membrane properties that attenuate activation of mPTP, b) prevents mitochondrial outer membrane interaction with BAX. These effects attenuate post-ischemic secondary energy failure and mitochondrial apoptotic cell death pathway, contributing/explaining the neuroprotective mechanisms afforded by DHA. This hypothesis will be tested in three specific aims. Aim 1: To determine the role of exogenous NPD1 and DHA in attenuation of BAX-driven mitochondrial cell death following HI brain injury. In this aim, we will compare the potency of DHA or NPD1 in limiting BAX-mediated cellular death. Given that both compounds demonstrated beneficial changes in mitochondrial functions (Ca2+ buffering and respiration (DHA) and Ca2+ buffering (NPD1)) after HI insult, we were focused on determining the fate of exogenous DHA and its metabolite, NPD1 by tracing deuterated 2H10-DHA in the ischemic brain, and mitochondria/mitoplasts isolated from the ischemic hemisphere. Aim 2: To determine the origin of increased brain NPD1 after acute injection of DHA and distribution of NPD1 and exogenous DHA following HI injury). Finally, in Aim 3, we will determine potential actions of NPD1 or/and DHA on preserving an integrity of the inner mitochondrial membrane, directly testing electrical conductance driven by the presence or absence of permeability transition. Our proposal is a translational study with a focus on specific mechanisms of neuroprotection targeting post-ischemic mitochondria using innovative approaches toward an understanding a temporal role of mitochondrial permeability transition in secondary energy failure and cell injury. Translational impacts are defined by the neuroprotective strength and clinical utility of DHA metabolites, rather than DHA itself.

项目摘要 新生儿中风和缺氧缺血（HI）脑损伤仍然是终身神经系统的主要原因 障碍。当前唯一接受的方法是缺血后体温过低。但是，没有确切的治疗性 这种方法的机制是已知的。越来越多的实验证据表明，omega-3（n-3） 脂肪酸（FAS）及其生物活性代谢产物可保护发育中的大脑免受重灌注损伤。使用 甘油三酸酯乳液我们表明二十六烯酸（DHA）为HI提供了强烈的神经保护作用 不同啮齿动物模型中的脑损伤。该神经保护与DHA含量增加有关 大脑线粒体，在再灌注中保留的线粒体功能，并与戏剧性（3至15倍）结合 DHA代谢产物，神经保护素D1（NPD1）和其他专门的促分解介质（SPMS）的升高 特别是在缺血性大脑中。我们认为DHA的有益行动可能由其作用 代谢物。在经测试的SPM中，只有NPD1显着减弱了小鼠的HI脑损伤。行政 NPD1的of也抑制了Ca2+诱导的线粒体膜通透性过渡孔的激活 （MPTP）和凋亡的死亡途径通过阻塞Bax-Mitochria相互作用。在此续签应用中，我们 假设DHA衍生的生物活性介质NPD1 a）修饰基质线粒体膜 减弱MPTP激活的特性，b）防止线粒体外膜与Bax的相互作用。 这些作用减弱了缺血后的次要能量衰竭和线粒体凋亡细胞死亡途径， 促进/解释DHA提供的神经保护机制。该假设将在三个 具体目标。目标1：确定外源性NPD1和DHA在衰减中的作用 HI脑损伤后线粒体细胞死亡。在此目标中，我们将比较DHA或NPD1的效力 限制Bax介导的细胞死亡。鉴于两种化合物都表现出有益的变化 HI侮辱后，线粒体功能（CA2+缓冲和呼吸（DHA）和Ca2+缓冲（NPD1）），我们是 专注于确定外源性DHA及其代谢产物的命运，NPD1通过追踪氘代2H10-DHA中的命运 缺血性大脑和线粒体/线粒体从缺血性半球分离出来。目标2：确定 急性注射DHA和NPD1和外源性DHA的分布后，脑NPD1增加的起源 受伤后）。最后，在AIM 3中，我们将确定NPD1或/和DHA在保存一个方面的潜在行动 内部线粒体膜的完整性，直接测试由存在或 没有渗透性过渡。我们的建议是一项翻译研究，侧重于 使用创新方法来理解A 线粒体通透性过渡在二次能量衰竭和细胞损伤中的时间作用。翻译 影响是由DHA代谢物的神经保护强度和临床实用性而不是DHA本身来定义的。