Effects of Docosahexaenoic Acid on Oxidative Stress White Matter Injury and Brain Inflammation in a Pre-Clinical Model of Pediatric TBI

项目总结 创伤性脑损伤是导致儿童后天神经功能障碍的主要原因。符合条件的代理 减少氧化应激和炎症可能会减少脑损伤后的神经功能障碍，尤其是在 孩子们。二十二碳六烯酸，或DHA，是治疗儿童脑外伤的候选药物。在我们已建立的幼鼠体内 DHA治疗儿童颅脑损伤模型可改善功能预后，降低脑组织氧化应激和脑白质 受伤和发炎。DHA可作为婴儿和儿童的营养补充剂。然而，DHA 在关键知识差距被打破之前，不能在临床TBI试验中进行测试。DHA对氧化作用的影响 脑外伤后大脑中的压力、白质完整性和炎症是未知的，数据也是如此。 颅脑损伤后人体DHA的最佳剂量。DHA在未成熟大脑中的安全性和有效性无法预测 基于成人研究。相对于成人的大脑，未成熟的大脑有更强烈的炎症 反应和较小的抗氧化能力。DHA是一种直接抗氧化剂，但在高剂量时，它的许多倍数 相反，债券可能会放大儿科脑损伤后的自由基损害。我们建议解决这些未知的问题 在仔猪中应用液压冲击伤(FPI)，建立了一种成熟的儿童脑外伤模型。未成熟的猪和 人类大脑在营养、解剖和发育方面有着惊人的相似之处。仔猪fpi与啮齿动物脑损伤不同， 允许使用连续脑脊液(CSF)、尿液和血液样本进行临床相关监测。我们有 确定了中度严重的仔猪FPI的特征，并建立了DHA管理和 生物体液采样。我们假设急性DHA给药会减少氧化应激，白质 与疗效和毒性的生物标记物相关的损伤和炎症，对仔猪的影响。我们将使用 暴露于FPI或假手术的4周龄仔猪，接受两种剂量(40或200 mg/kg/天)之一的DHA治疗 或车辆(VEH)。我们将测量氧化应激、脑白质损伤和炎症的生物标记物 分别于注药后第1、3、7天采集脑脊液、尿液和血液标本。我们将比较生物标记物的结果 DHA剂量组，至第7天进行神经元死亡、脑白质损伤、炎症和 对大脑中的蛋白质、脂质和DNA造成氧化损伤。这项建议意义重大，因为它将为 在未来候选神经保护剂的临床试验中为有效性和安全性监测奠定基础，如 作为DHA，通过提供关于DHA剂量和疗效和毒性的生物标记物的数据，在脑损伤后的儿童 翻译模型。它的创新性是因为人们对急性脑损伤后的DHA知之甚少 生物标志物在儿童脑外伤中的应用研究进展。它将通过提供临床上的 设计第二阶段试验以及最终的干预性试验所需的有效性和安全性的相关措施 DHA有可能减轻儿童颅脑损伤后获得性神经损伤的负担。

PROJECT SUMMARY Traumatic brain injury (TBI) is the leading cause of acquired neurologic disability in children. Agents that decrease oxidative stress and inflammation may decrease neurologic disability after TBI, particularly in children. Docosahexaenoic Acid, or DHA, is a candidate therapy for childhood TBI. In our established rat pup model of pediatric TBI, DHA improved functional outcome and decreased brain oxidative stress, white matter injury and inflammation. DHA is available as a nutritional supplement for infants and children. However, DHA cannot be tested in clinical TBI trials until critical knowledge gaps are breached. Effects of DHA on oxidative stress, white matter integrity and inflammation in the human brain after TBI are unknown, as are data on optimal DHA dosing in humans after TBI. DHA safety and efficacy in the immature brain cannot be predicted based on adult studies. Relative to the adult brain, the immature brain has a more vigorous inflammatory response and a lesser antioxidant capacity. DHA is a direct antioxidant, but at high doses its numerous double bonds could instead magnify free radical damage after pediatric TBI. We propose to address these unknowns using fluid-percussion injury (FPI) in the piglet, a well-established model of pediatric TBI. Immature pig and human brains share striking nutritional, anatomic and developmental similarities. Piglet FPI, unlike rodent TBI, allows clinically relevant monitoring using serial cerebrospinal fluid (CSF), urine and blood sampling. We have characterized piglet FPI of moderate severity and established a methodology of DHA administration and biofluid sampling. We hypothesize that acute DHA administration will decrease oxidative stress, white matter damage and inflammation, associated with biomarkers of efficacy and toxicity, in piglets after FPI. We will use 4-week old piglets exposed to FPI or SHAM surgery, treated with one of two DHA doses (40 or 200mg/kg/day) or vehicle (VEH). We will measure biomarkers of oxidative stress, white matter damage and inflammation in CSF, urine and blood samples taken at 1, 3 and 7 days after FPI. We will compare biomarker results between DHA dosing groups, and to day 7 brain assays of neuronal death, white matter damage, inflammation and oxidative injury to proteins, lipids and DNA in the brain. This proposal is significant because it will lay the groundwork for efficacy and safety monitoring during future clinical trials of candidate neuroprotectants, such as DHA, in children after TBI by providing data on DHA dosing and biomarkers of efficacy and toxicity in a translational model. It is innovative because little is known about DHA after acute brain injury during development or about the utility of biomarkers in pediatric TBI. It will impact the field by providing clinically relevant measures of efficacy and safety needed to design a Phase II trial and, ultimately, an interventional trial of DHA with the potential to decrease the burden of acquired neurologic injury after pediatric TBI.