Docosahexaenoic Acid (DHA) and Neonatal Neuroprotection.

描述（由申请人提供）：该R21申请解决了关于围产期神经保护的新型治疗方式的补充重要问题。虽然治疗性低温降低了围产期窒息后的死亡或残疾，但超过40%的治疗婴儿结局不佳。目前迫切需要更有效的治疗围产期窒息和更好地了解影响治疗性冷却效果的因素。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，目前正在研究在几种情况下作为孕妇的口服补充剂。本提案是针对PA-10-069提交的，旨在确定DHA对缺氧缺血性脑损伤新生啮齿动物模型中治疗性低温的神经保护作用的影响。我们的实验室有超过20年的经验，这个模型，引起单侧颈动脉结扎和暴露于8%的氧气在7天龄（P7）大鼠。特别重要的是，这个建议，我们制定了协议，中度低温和其他疗法，包括神经病理和功能结果的措施之间的相互作用进行评估。在初步研究中，DHA是通过胃肠外而不是口服给药给新生大鼠（P7）; DHA具有神经保护特性。这一发现提供了令人信服的原则证据，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，我们最近的数据表明，单次注射DHA增加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DHA补充和低体温在缺氧-缺血性神经病理学中的相互作用;（ii）确定慢性母体或急性新生儿DHA补充、低体温或两者在新生儿缺氧-缺血前后改变脑DHA组成的程度，（iii）确定血浆和/或红细胞DHA组成是否反映新生儿脑DHA组成;（iv）确定DHA、低温或两者对缺氧-缺血诱导脂肪酸过氧化作用的影响。目的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体温过低的P7大鼠的影响，以确定最佳联合治疗和潜在的有害相互作用。目标2将确定选定的DHA+冷却组合疗法对大脑DHA组成的影响。所有实验都将在临床相关高脂肪母体饮食的背景下进行。这些研究的结果将提供新的见解的脂肪酸的操作对缺氧缺血性脑损伤的易感性的影响，也可以确定联合治疗的不可预见的风险。这些研究代表了未来临床研究的重要组成部分，以确定膳食脂肪酸对新生儿脑完整性和围产期缺氧缺血性损伤的易感性的影响。 公共卫生相关性：这项研究的目的是确定发育中的大脑中饮食来源的脂肪的组成是否会改变治疗性低温的有效性，这是一种针对出生时脑功能异常（窒息）的婴儿的新疗法，这是分娩前氧气输送中断的结果。限制或增强这些婴儿冷却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，脂肪可能起作用。考虑到目前的肥胖危机，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，具有很高的残疾风险，估计残疾护理费用约为1，000，000美元/患者/年。

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.