N-3 Fatty Acids and Outcomes in Pediatric Traumatic Brain Injury

描述（由申请人提供）：创伤性脑损伤（TBI）是一种主要的公共卫生问题，其后果包括长期功能丧失或死亡。因此，有必要改进治疗方法和其他方法来改善TBI的预后，特别是对于特别容易遭受这种伤害的幼儿。创伤性脑损伤的机制包括炎症、血脑屏障破坏和神经元死亡。n-3多不饱和脂肪酸（PUFA）二十二碳六烯酸（DHA）具有抗炎和抗凋亡活性。饮食n-3 PUFA含量会影响DHA的水平，这些DHA会被纳入组织，包括大脑，在大脑中DHA会持续积累到至少生命的第二年。美国人的饮食中n-3 PUFAs含量明显较低；因此，美国人的组织DHA水平特别低。急性给予DHA可改善脊髓损伤和中风动物模型的预后。然而，尚不清楚DHA是否对TBI有益，也不清楚饮食n-3含量以及组织DHA水平是否会影响TBI的结果。PIs的总体目标是改善幼儿创伤性脑损伤的预后。本应用程序的目的是确定饮食n-3 PUFA含量的影响，急性DHA治疗，以及它们的相互作用对幼儿创伤性脑损伤大鼠模型的结果。pi假设低饮食n-3 PUFA含量将与较差的TBI预后有关，TBI后急性DHA治疗将改善预后，急性DHA治疗和饮食n-3 PUFA含量将相互作用影响TBI预后。一种结合营养和神经生物学方法的创新方法将用于实现以下具体目标：1)确定饮食中n-3 PUFA含量对TBI结局的影响；2)确定急性DHA给药对喂食不同n-3 PUFA含量饮食的大鼠TBI结局的影响。将评估血脑屏障的破坏，这是创伤性脑损伤后病理后遗症的核心，以及功能性运动缺陷和恢复。预期的结果包括DHA治疗和/或增加饮食中n-3 PUFA含量在改善儿童TBI预后方面的潜在效用，以及对DHA在中枢神经系统中炎症、维持血脑屏障和神经元存活/死亡方面的作用的更深入的了解。这些发现可能会为未来的临床研究奠定基础，从而导致新的治疗和/或预防性干预措施，以改善儿童创伤性脑损伤的预后。这些数据也将形成一个平台，从这个平台上启动DHA在TBI中有益作用的机制的扩展基础研究，这可能会导致TBI治疗干预的新靶点的确定。

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is a major public health concern with consequences including long-term loss of function or death. Accordingly, there is a significant need for improved treatments and other means for improving outcomes in TBI, especially in small children who are particularly likely to suffer such an injury. Mechanisms of TBI include inflammation, blood-brain barrier disruption, and neuronal death. The n-3 polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) has anti- inflammatory and anti-apoptotic activities. Diet n-3 PUFA content influences the levels of DHA that are incorporated into tissues, including the brain, where DHA continues to accumulate into at least the second year of life. The American diet is notably low in n-3 PUFAs; thus, Americans are at particular risk of having low tissue DHA levels. Acute administration of DHA improves outcomes in animal models of spinal cord injury and stroke. However, it is not known whether DHA has beneficial effects in TBI or whether diet n-3 content, and thus tissue DHA levels, influence TBI outcomes. The PIs' overall goal is to improve outcomes of TBI in young children. The objective of this application is to determine the effects of diet n-3 PUFA content, acute DHA treatment, and their interaction on outcomes in a rat model of TBI in toddlers. The PIs hypothesize that low diet n-3 PUFA content will be associated with poorer TBI outcomes, that acute DHA treatment after TBI will improve outcomes, and that acute DHA treatment and diet n-3 PUFA content will interact to affect outcomes in TBI. An innovative approach, integrating nutritional and neurobiological methods will be used to pursue the following Specific Aims: 1) Determine the effects of diet n-3 PUFA content on outcomes of TBI and 2) Determine the effects of acute DHA administration on outcomes of TBI in rats fed diets varying in n-3 PUFA content. Disruption of the blood-brain barrier, which is central to the pathological sequelae after TBI, and functional motor deficits and recovery, will be assessed. Expected outcomes include readily translatable findings on the potential utility of DHA treatment and/or increased dietary n-3 PUFA content in improving outcomes in pediatric TBI, and greater understanding of the role of DHA in the central nervous system with respect to inflammation, maintenance of the blood-brain barrier, and neuronal survival/death. Such findings may be anticipated to form a basis for future clinical studies that lead to novel therapeutic and/or preventative interventions to improve outcomes in pediatric TBI. These data will also form a platform from which to launch expanded basic studies of mechanisms underlying the beneficial effects of DHA in TBI, which may be anticipated to lead to the identification of novel targets for therapeutic intervention in TBI. Relevance: Traumatic brain injury affects at least 1.4 million Americans each year and is a significant cause of death and long-term disability. Children 0-4 years old are at the highest risk. This study seeks to identify means to improve outcomes of TBI in young children.