Docosahexaenoic Acid (DHA) and Neonatal Neuroprotection.

二十二碳六烯酸 (DHA) 和新生儿神经保护。

• 批准号: 8191805
• 负责人: JOHN D BARKS
• 金额: $ 19.44万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8191805
• 关键词: Acute; Address; Affect; American; Anti-Inflammatory Agents; Anti-inflammatory; Asphyxia; Asphyxia Neonatorum; Attenuated; Biological Markers; Blood; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Caring; Carotid Arteries; Cerebral Ischemia-Hypoxia; Cerebral Palsy; Cessation of life; Chronic; Clinical; Clinical Research; Collaborations; Combined Modality Therapy; Consumption; Data; Diet; Dietary Fats; Dietary Fatty Acid; Docosahexaenoic Acids; Dose; Effectiveness; Epidemic; Epidemiology; Erythrocytes; Essential Fatty Acids; Evaluation; Exposure to; Fatty Acids; Fatty acid glycerol esters; Functional disorder; Future; Goals; Health; Human; Hypoxia; Impaired cognition; Infant; Inflammation; Inflammatory; Injection of therapeutic agent; Injury; Investigation; Ischemia; Ischemic-Hypoxic Encephalopathy; Laboratories; Life; Ligation; Lipid Biochemistry; Lipid Peroxidation; Lipids; Live Birth; Marines; Measurement; Meat; Mediating; Modality; Modeling; Neonatal; Neonatal Brain Injury; Neonatology; Neurology; Obesity; Oils; Omega-3 Fatty Acids; Oral; Outcome; Outcome Measure; Oxygen; Pathogenesis; Patients; Perinatal; Perinatal Brain Injury; Perinatal Hypoxia; Pilot Projects; Plasma; Play; Polyunsaturated Fatty Acids; Positioning Attribute; Predisposition; Pregnant Women; Property; Protocols documentation; Public Health; Randomized Clinical Trials; Rattus; Regimen; Research Personnel; Risk; Rodent; Rodent Model; Role; Supplementation; Survivors; Therapeutic; Thinking; Third Pregnancy Trimester; Translating; Translations; Treatment Efficacy; burden of illness; clinical application; clinical care; clinically relevant; cost; disability; disability burden; effective therapy; epidemiologic data; experience; fatty acid oxidation; fetal; fetal medicine; functional outcomes; high risk; indexing; injured; insight; ischemic lesion; multidisciplinary; natural hypothermia; neonatal hypoxic-ischemic brain injury; neonate; nervous system development; neuropathology; neuroprotection; novel; novel therapeutics; peroxidation; pilot trial; pre-clinical; prenatal; prevent; research study; response; therapeutic effectiveness; translational study

DESCRIPTION (provided by applicant): This R21 application addresses complementary important questions about a novel therapeutic modality for perinatal neuroprotection. Although therapeutic hypothermia reduces death or disability after perinatal asphyxia, over 40% of treated infants have poor outcomes. There is an urgent need for more effective thera- pies for perinatal asphyxia and a greater understanding of factors that influence the efficacy of therapeutic cooling. The polyunsaturated fatty acid docosahexaenoic acid (DHA) has intrinsic neuroprotective properties and is under investigation as an oral supplement for pregnant women in several settings. The goal of this proposal, submitted in response to PA-10-069, is to determine the impact of DHA on the neuroprotective efficacy of therapeutic hypothermia in a well-characterized neonatal rodent model of hypoxic-ischemic brain injury. Our laboratory has over 20 years of experience with this model, elicited by unilateral carotid artery ligation and exposure to 8% oxygen in 7 day old (P7) rats. Of particular importance for this proposal, we developed protocols for evaluation of interactions between moderate hypothermia and other therapies that incorporate neuropathological and functional outcome measures. In preliminary studies, DHA was administered parenterally, rather than orally, to neonatal (P7) rats; DHA had neuroprotective properties. This finding provided compelling proof of principle that systemic fatty acid composition influenced susceptibility to neonatal hypoxic-ischemic brain injury. Moreover, our most recent data demonstrate that a single injection of DHA increased the neuroprotective efficacy of subsequent brief moderate hypothermia. We are excited about the potential to translate these findings to clinical studies. Essential prerequisites include: (i) evaluate interactions between DHA supplementation and hypothermia in hypoxic-ischemic neuropathology; (ii) determine the extent to which chronic maternal or acute neonatal DHA supplementation, hypothermia, or both, change brain DHA composition before and after neonatal hypoxia-ischemia, (iii) determine if plasma and/or red blood cell DHA composition reflects neonatal brain DHA composition; (iv) determine effect of DHA, hypothermia, or both, on hypoxia-ischemia-induced fatty acid peroxidation. Aim 1 will evaluate the impact of a range of acute DHA doses or a chronic maternal DHA regimen in P7 rats that undergo hypoxic-ischemic lesioning and hypothermia to identify both optimal combination therapies and potential deleterious interactions. Aim 2 will determine the impact of selected DHA+cooling combination therapies on brain DHA composition. All experiments will be performed on the background of a clinically relevant high fat maternal diet. Results of these studies will provide novel insights about the impact of manipulations of fatty acids on susceptibility to hypoxic-ischemic brain injury, and may also identify unforeseen risks of combination therapy. These studies represent an essential building block for future clinical studies to determine the impact of dietary fatty acids on neonatal brain integrity and susceptibility to perinatal hypoxic-ischemic injury. PUBLIC HEALTH RELEVANCE: The aim of this study is to determine whether the composition of diet-derived fats in the developing brain could alter the effectiveness of therapeutic hypothermia, a new therapy for babies born with abnormal brain function (asphyxia) that is a result of disruption in oxygen delivery prior to delivery. Factors that either limit or enhance the effectiveness of cooling for these babies are not well understood; our preliminary studies in neonatal rodents suggest that fats might play a role. Considering the current obesity crisis, this is an important public health issue because about 4-16,000 babies/yr are affected by asphyxia, with a high risk of disability and estimated care costs for disability of about $1,000,000/patient/yr.

描述（由申请人提供）：该 R21 申请解决了有关围产期神经保护的新型治疗方式的补充重要问题。尽管低温治疗可减少围产期窒息后的死亡或残疾，但超过 40% 的接受治疗的婴儿结局不佳。迫切需要更有效的围产期窒息治疗方法，并更好地了解影响治疗性降温效果的因素。多不饱和脂肪酸二十二碳六烯酸 (DHA) 具有内在的神经保护特性，目前正在研究在多种情况下将其作为孕妇的口服补充剂。该提案是针对 PA-10-069 提交的，其目的是确定 DHA 对缺氧缺血性脑损伤的新生儿啮齿动物模型中低温治疗的神经保护功效的影响。我们的实验室在该模型方面拥有 20 多年的经验，通过对 7 日龄 (P7) 大鼠进行单侧颈动脉结扎并暴露于 8% 的氧气来诱导。对于该提案特别重要的是，我们制定了评估中度低温与其他疗法之间相互作用的方案，其中包括神经病理学和功能结果测量。在初步研究中，新生 (P7) 大鼠通过肠胃外而非口服方式施用 DHA； DHA 具有神经保护特性。这一发现提供了令人信服的原理证明，即全身脂肪酸组成影响新生儿缺氧缺血性脑损伤的易感性。此外，我们最新的数据表明，单次注射 DHA 可以提高随后短暂中度低温的神经保护功效。 我们对将这些发现转化为临床研究的潜力感到兴奋。基本先决条件包括：(i) 评估缺氧缺血神经病理学中 DHA 补充与低温之间的相互作用； (ii) 确定慢性母体或急性新生儿 DHA 补充、低温或两者兼而有之，在新生儿缺氧缺血前后改变大脑 DHA 成分的程度，(iii) 确定血浆和/或红细胞 DHA 成分是否反映了新生儿大脑DHA成分； (iv) 确定 DHA、低温或两者对缺氧缺血诱导的脂肪酸过氧化的影响。目标 1 将评估一系列急性 DHA 剂量或慢性母体 DHA 方案对经历缺氧缺血性损伤和低温的 P7 大鼠的影响，以确定最佳联合疗法和潜在的有害相互作用。目标 2 将确定选定的 DHA+冷却联合疗法对大脑 DHA 成分的影响。所有实验都将在临床相关的高脂肪母亲饮食的背景下进行。这些研究的结果将为了解脂肪酸操作对缺氧缺血性脑损伤易感性的影响提供新的见解，并且还可能确定联合治疗的不可预见的风险。这些研究为未来的临床研究奠定了重要的基础，以确定膳食脂肪酸对新生儿大脑完整性和围产期缺氧缺血性损伤易感性的影响。 公共健康相关性：本研究的目的是确定发育中大脑中饮食来源的脂肪成分是否会改变低温治疗的有效性，低温治疗是一种新疗法，用于治疗因出生时大脑功能异常（窒息）而导致的婴儿。分娩前氧气输送中断。限制或增强这些婴儿降温效果的因素尚不清楚；我们对新生啮齿动物的初步研究表明脂肪可能发挥了作用。考虑到当前的肥胖危机，这是一个重要的公共卫生问题，因为每年约有 4-16,000 名婴儿受到窒息的影响，残疾风险很高，预计残疾护理费用约为每名患者每年 1,000,000 美元。