Docosahexaenoic Acid (DHA) and Neonatal Neuroprotection.

二十二碳六烯酸 (DHA) 和新生儿神经保护。

基本信息

批准号：
8307279
负责人：
JOHN D BARKS
金额：
$ 23.09万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2014-01-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8307279
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

项目摘要

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.

描述（由申请人提供）：此R21应用程序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。尽管治疗性体温过低会减少围产期窒息后的死亡或残疾，但超过40％的患者的预后较差。迫切需要对围产期窒息的更有效的疾病，并对影响治疗冷却功效的因素有更深入的了解。多不饱和脂肪酸二十六烯酸（DHA）具有内在的神经保护特性，并正在研究中，作为孕妇在多种情况下的口服补充。该提案的目的是针对PA-10-069提交的，目的是确定DHA对良好表征的低氧 - 缺血性脑损伤的新生儿啮齿动物模型中治疗性低温的神经保护功效的影响。我们的实验室在该模型中拥有20多年的经验，这是由单侧颈动脉连接引起的，并在7天大的大鼠（P7）大鼠中暴露于8％的氧气。对于该提案而言，我们特别重要的是，我们开发了用于评估中等低温和其他结合神经病理和功能结果指标的疗法之间相互作用的方案。在初步研究中，DHA是在肠胃外施用的，而不是口服的，是新生儿（P7）大鼠。 DHA具有神经保护特性。这一发现提供了令人信服的原则证明，即系统性脂肪酸组成影响了对新生儿缺氧 - 缺血性脑损伤的敏感性。此外，我们最近的数据表明，单一注射DHA提高了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）评估缺氧性神经病理学中DHA补充与体温过低之间的相互作用；（ii）确定慢性母体或急性新生儿DHA的补充，低温或两者兼而有之，改变了新生儿缺氧 - 缺血性缺血之前和之后的脑DHA组成，（iii）确定血浆和/或红细胞DHA组成是否反映了新生儿大脑DHA组成；（iv）确定DHA，低温或两者对低氧诱导的脂肪酸过氧化的影响。 AIM 1将评估P7大鼠中一系列急性DHA剂量或慢性母体DHA方案的影响，该疗法经历低氧 - 缺血性病变和体温过低，以鉴定最佳组合疗法和潜在的有害相互作用。 AIM 2将确定选定的DHA+冷却组合疗法对脑DHA组成的影响。所有实验将在临床相关的高脂母体饮食的背景下进行。这些研究的结果将提供有关脂肪酸操纵对缺氧 - 缺血性脑损伤的敏感性的影响的新见解，并且还可以鉴定出不可预见的联合治疗风险。这些研究代表了未来临床研究的重要组成部分，以确定饮食中脂肪酸对新生儿脑完整性的影响以及对围产期缺氧缺血性损伤的易感性。