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作用

• 批准号: 8996605
• 负责人: RICHARD JOSEPH DECKELBAUM
• 金额: $ 35万
• 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 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8996605
• 关键词: Acute; Address; Affect; Aftercare; Apoptosis; Apoptotic; Attenuated; BAX gene; Blood; Brain; Brain Death; Brain Injuries; Cardiovascular Diseases; Caspase; Cause of Death; Cell Death; Cell Membrane Structures; Cell Survival; Cell membrane; Cells; Cerebrum; Child; Complex; Cytochromes; Disabled Persons; Docosahexaenoic Acids; Dose; Elements; Emulsions; Exposure to; Failure; Fatty Acids; Generations; Glucose; Habits; Health; Human; Hypoxic-Ischemic Brain Injury; In Vitro; Injection of therapeutic agent; Injury; Intravenous; Ischemia; Laboratories; Life Style; Link; Lipids; Liver; Measures; Membrane; Membrane Structure and Function; Mitochondria; Mitochondrial Matrix; Morbidity - disease rate; Mus; Myocardial Infarction; Neonatal; Neurologic; Neurons; Nonesterified Fatty Acids; Omega-3 Fatty Acids; Outcome; Outer Mitochondrial Membrane; Oxidative Stress; Oxygen; Pathway interactions; Permeability; Production; Radiolabeled; Reactive Oxygen Species; Recovery; Reperfusion Therapy; Research Personnel; Rodent; Role; Severities; Societies; Specificity; Stroke; Testing; Time; Triglycerides; attenuation; base; cell injury; clinical application; deprivation; dosage; fatty acid transport; handicapping condition; improved; in vivo; mitochondrial dysfunction; mitochondrial membrane; mortality; natural hypothermia; neonatal brain; neonate; neuroprotectin D1; neuroprotection; novel; oxidation; oxidative damage; particle; prevent; pro-apoptotic protein; radiotracer; research study; transmission process; uptake

 DESCRIPTION (provided by applicant): Hypoxic-ischemic brain injury (HI) is the major cause of permanent neurological handicap in children. Omega- 3 (n-3) fatty acids (FA), especially eicosapentaenoic (EPA) and docosahexaenoic acids (DHA), have emerged as major elements for cell membrane structure+-function. n-3 FA beneficially alter outcomes of hypoxic- ischemic (HI) brain injury in rodents. The investigators' laboratories are demonstrating that acute injectio of intravenous triglyceride (TG) emulsions enriched in DHA and EPA markedly protect rodent brains against HI injury after HI in neonatal mice. Emulsions with TG containing only DHA (triDHA) showed major neuroprotective effects, and this was not shared by emulsions containing only triEPA or n-6 TG. The neuroprotection shown by triDHA occurred when injected even at 2hr after reperfusion. Neuroprotection was associated with 1) increased brain content of neuroprotectin D1 (NPD1), 2) increased DHA in cerebral mitochondria, and 3) attenuation of mitochondrial membrane permeabilization after HI. Our overall hypothesis is that triDHA changes mitochondrial FA composition and preserves mitochondrial function after HI by limiting Ca2+ induced membrane permeabilization, a central mechanism of cell death after ischemia. A key component of our hypothesis is that beneficial effects of triDHA relate to decreasing reactive oxygen species (ROS) surges in mitochondria, limiting mitochondrial self-oxidation, thereby preserving mitochondrial membrane integrity. These hypotheses will be tested under three Specific Aims. Aim 1 will characterize how n-3 TG and their catabolites are delivered to neonatal brain after acute injection following HI injury and determine optimal dosages and FA specificity for maximum neuroprotection and compare this with hypothermia treatment. We anticipate that after injection triDHA is first taken up by liver and after repackaging into TG or FA, and/or partially catabolized to NPD1 to reach brain to promote neuroprotection. In Aim 2 we will determine whether n- 3 TG treatment after HI modifies mitochondrial FA composition and how this alleviates secondary mitochondrial dysfunction in reperfusion. We expect these experiments will confirm a major role for DHA in protecting mitochondria by decreasing mitochondrial generation of ROS, a major factor for injury to mitochondria and cells. Aim 3 will determine whether DHA-associated neuroprotection relates to increased production of NPD1 through its anti-apoptotic effects. The focus will be on the role of NPD1 interacting with mitochondria to prevent permeabilization of outer mitochondrial membranes and whether this involves translocation of anti-apoptotic pathways.

 描述（由申请人提供）：缺氧缺血性脑损伤（HI）是儿童永久性神经障碍的主要原因。Omega-3（n-3）脂肪酸（FA），尤其是二十碳五烯酸（EPA）和二十二碳六烯酸（DHA）。 ），已成为细胞膜结构+功能的主要元素，有益地改变缺氧缺血（HI）脑损伤的结果。研究人员的实验室证明，在新生小鼠发生 HI 后，静脉注射富含 DHA 和 EPA 的甘油三酯 (TG) 乳剂可显着保护啮齿类动物的大脑免受 HI 损伤。仅含有 triEPA 或 n-6 TG 的乳剂则不具备这一点。即使注射，triDHA 也能发挥神经保护作用。再灌注后 2 小时，神经保护与 1) 脑内神经保护素 D1 (NPD1) 含量增加、2) 大脑线粒体中 DHA 增加以及 3) HI 后线粒体膜通透性减弱有关。并通过限制 Ca2+ 诱导的膜透化（缺血后细胞死亡的核心机制）来保留 HI 后的线粒体功能，我们假设的一个关键组成部分是有益作用。 triDHA 的活性与线粒体中的活性氧 (ROS) 激增有关，从而限制线粒体自氧化，从而保持线粒体膜的完整性。这些假设将在三个具体目标下进行测试，目标 1 将描述 n-3 TG 及其分解代谢物的传递方式。 HI 损伤后急性注射后对新生儿大脑的影响，并确定最佳剂量和 FA 特异性以实现最大程度的神经保护，并将其与低温治疗进行比较，我们预计注射后 triDHA 首先被肝脏吸收，然后再被肝脏吸收。重新包装成 TG 或 FA，和/或部分分解为 NPD1 以到达大脑以促进神经保护。在目标 2 中，我们将确定 HI 后的 n-3 TG 治疗是否会改变线粒体 FA 组成，以及我们期望这如何减轻再灌注中的继发性线粒体功能障碍。这些实验将证实 DHA 通过减少线粒体生成 ROS 来保护线粒体，而 ROS 是线粒体和细胞损伤的主要因素，Aim 3 将确定 DHA 是否相关。神经保护与通过其抗凋亡作用增加 NPD1 的产生有关。重点是 NPD1 与线粒体相互作用以防止线粒体外膜透化的作用，以及这是否涉及抗凋亡途径的易位。