Docosahexaenoic Acid (DHA) and Neonatal Neuroprotection.

描述(由申请人提供)：这份R21申请解决了关于围产期神经保护的新治疗方式的补充重要问题。尽管治疗性低温可以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。迫切需要更有效的治疗围产期窒息的药物，并更好地了解影响治疗降温效果的因素。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，目前正在多个环境中作为孕妇的口服补充剂进行研究。根据PA-10-069提交的这项提案的目的是确定DHA对具有良好特征的缺氧缺血性脑损伤新生啮齿动物模型中低温治疗的神经保护效果的影响。我们实验室已经有20多年的经验，通过结扎单侧颈动脉并暴露于7日龄(P7)大鼠的8%氧气中，建立了这种模型。对于这项建议特别重要的是，我们制定了评估亚低温和其他疗法之间相互作用的方案，这些方案结合了神经病理和功能结果测量。在初步研究中，DHA对新生大鼠(P7)进行了非肠道给药，而不是口服；DHA具有神经保护特性。这一发现提供了令人信服的证据，证明全身性脂肪酸组成影响新生儿缺氧缺血性脑损伤的易感性。此外，我们的最新数据表明，单次注射DHA增加了随后短暂中低温的神经保护效果。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)评估补充DHA与低温在缺氧缺血性神经病理中的相互作用；(Ii)确定长期补充或急性新生儿DHA补充、低温或两者兼而有之的程度，在新生儿缺氧缺血前后改变脑DHA组成；(Iii)确定血浆和/或红细胞DHA组成是否反映新生儿大脑DHA组成；(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。目的1将评估一系列急性DHA剂量或一种慢性母体DHA方案对经历缺氧缺血性损害和低温的P7大鼠的影响，以确定最佳组合疗法和潜在的有害相互作用。目的2将确定选定的DHA+降温组合疗法对脑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操纵脂肪酸对缺氧缺血性脑损伤易感性的影响提供新的见解，并可能确定联合治疗的不可预见的风险。这些研究是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大脑完整性和围产期缺氧缺血损伤的易感性的影响。

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.