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

N-3 脂肪酸和小儿创伤性脑损伤的结果

• 批准号: 7751876
• 负责人: BETH LEVANT
• 金额: $ 7.43万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-22 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7751876
• 关键词: 4 year old; Abbreviations; Acute; Affect; Aftercare; American; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Apoptotic; Behavioral; Biochemical; Blood - brain barrier anatomy; Brain; Cause of Death; Cessation of life; Child; Childhood; Clinical Research; Data; Diet; Docosahexaenoic Acids; Future; Goals; Inflammation; Injury; Intervention; Lead; Life; Maintenance; Matrix Metalloproteinases; Mediator of activation protein; Methods; Modeling; N-3 polyunsaturated fatty acid; Neuraxis; Neurobiology; Neurons; Nutritional; Omega-3 Fatty Acids; Outcome; Polyunsaturated Fatty Acids; Public Health; Rattus; Recovery; Research; Research Personnel; Risk; Role; Spinal cord injury; Stroke; Therapeutic Intervention; Tissues; Toddler; Traumatic Brain Injury; Variant; base; controlled cortical impact; disability; docosapentaenoic acid; feeding; high risk; improved; innovation; interdisciplinary approach; loss of function; motor deficit; neurochemistry; neuronal survival; novel; novel therapeutics; postnatal

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.

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，迫切需要改进治疗方法和其他手段，以改善脑外伤的治疗结果，特别是对特别有可能遭受这种伤害的儿童。脑外伤的机制包括炎症、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)具有抗炎和抗细胞凋亡活性。饮食中n-3多不饱和脂肪酸的含量会影响组织中DHA的水平，包括大脑，在大脑中，DHA至少在生命的第二年会继续积累。美国人的饮食中n-3多不饱和脂肪酸的含量明显较低；因此，美国人组织中DHA水平低的风险尤其大。急性给予DHA可改善脊髓损伤和中风动物模型的结果。然而，目前尚不清楚DHA是否对脑外伤有益处，也不知道饮食n-3含量以及组织中DHA水平是否会影响脑外伤的预后。PIs的总体目标是改善幼儿脑外伤的预后。这项应用的目的是确定饮食中n-3多不饱和脂肪酸含量、急性DHA治疗以及它们之间的交互作用对幼儿脑外伤大鼠模型预后的影响。PI假设低饮食n-3PUFA含量将与较差的TBI预后相关，TBI后急性DHA治疗将改善预后，急性DHA治疗和饮食n-3PUFA含量将交互作用影响TBI的预后。一种创新的方法，结合营养和神经生物学方法，将被用来追求以下具体目标：1)确定饮食n-3多不饱和脂肪酸含量对脑创伤结局的影响；2)确定急性DHA给药对不同n-3多不饱和脂肪酸含量饮食的大鼠脑创伤结局的影响。将评估血脑屏障的破坏，这是脑外伤后病理后遗症的核心，以及功能性运动障碍和恢复。预期结果包括：关于DHA治疗和/或增加膳食n-3多不饱和脂肪酸含量在改善儿童脑损伤预后方面的潜在效用的易于翻译的发现，以及更好地了解DHA在中枢神经系统在炎症、维持血脑屏障和神经元存活/死亡方面的作用。这些发现可能会成为未来临床研究的基础，这些研究将导致新的治疗和/或预防干预措施，以改善儿童脑外伤的预后。这些数据还将形成一个平台，从这个平台开始对DHA对脑损伤有益影响的潜在机制进行扩展的基础研究，这可能会导致确定脑损伤治疗干预的新靶点。 相关性：创伤性脑损伤每年影响至少140万美国人，是导致死亡和长期残疾的重要原因。0-4岁的儿童风险最高。本研究试图找出改善儿童脑外伤预后的方法。