Preventing TBI-Induced Chronic Functional Loss with a Neuroprotective Antioxidant

使用神经保护性抗氧化剂预防 TBI 引起的慢性功能丧失

• 批准号: 9567849
• 负责人: Bruce A. Citron
• 金额: --
• 依托单位: VA NEW JERSEY HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9567849
• 关键词: Affect; Aftercare; Antioxidants; Anxiety; Behavioral; Biological Process; Brain; Brain Injuries; Central Nervous System Diseases; Chronic; Closed head injuries; Cognitive deficits; Data Reporting; Dendritic Spines; Diffusion Magnetic Resonance Imaging; Event; Family; Goals; Golgi Apparatus; Head; Health; Healthcare Systems; Human Resources; Impaired cognition; Impairment; Incidence; Inflammatory Response; Injury; Knowledge; Long-Term Effects; Measures; Memory; Messenger RNA; Military Personnel; Modeling; Molecular; Mus; Nerve Degeneration; Neurons; Outcome; Pathway interactions; Patients; Play; Prevention; Problem Solving; Process; Proteins; Reporting; Research; Role; Rotation; Sampling; Signal Transduction; Stains; Testing; Therapeutic; Time; Traumatic Brain Injury; Treatment Effectiveness; Treatment Efficacy; Up-Regulation; Vertebral column; behavior test; brain circuitry; cognitive function; combat; cytokine; density; effective therapy; experience; functional loss; head impact; improved; indexing; injured; interest; mild traumatic brain injury; neuron loss; operation; prevent; therapeutic target; transcription factor; treatment effect

It is very important to uncover therapeutic strategies to combat the chronic effects of traumatic brain injury (TBI) because currently, there are no effective treatments to prevent these cognitive deficits. Unfortunately, TBI is a very common affliction of military forces that have served in recent combat operations. At least 15% of deployed personnel receive a TBI and the total number of such injuries has been estimated as high as 320,000. In the US alone it is estimated that at least 1.7 million people suffer a TBI each year and the worldwide incidence is approximately 0.5% per year. The vast majority of TBIs experienced by military personnel are classified as mild injuries, but these do result in significant, chronic effects. We seek to demonstrate an effective treatment that could reduce or reverse the long-term cognitive dysfunction that is produced by mild traumatic brain injury (TBI). Because these injuries involve multiple effects, it is necessary to further characterize the treatment effects on the lasting dendritic and spine changes induced by TBI and add to our knowledge of therapeutic changes that are possible so that TBI patients will benefit. Over the past several years, our lab has discovered that an activator of an antioxidant transcription factor, Nrf2, can be neuroprotective by regulating molecular mechanisms that are important to the health of neurons. This has led us to formulate a hypothesis that treatment of mild traumatic brain injury with the Nrf2 activator will result in significant improvement on the connections between neurons, promote neuroprotective intracellular pathways, and result in greatly enhanced long-term outcomes following TBI. We will test our hypothesis with three specific aims: 1. Prevention of the chronic behavioral effects of mild closed head injury by tBHQ treatment, 2. Improvement of persistent connectivity changes produced by tBHQ treatment after mild TBIs, and 3. Identify molecular changes induced by the post TBI treatment that could influence long-term function. We will examine changes to molecular and long-term cognitive function after mild TBI accomplished by the closed head impact injury model in mice. We will use a well-established TBI model involving a closed head injury model that does include rotation. We will treat injured and sham injured groups with either vehicle or tBHQ. Behavioral tests will be conducted at 1, 6, and 12 months after injury. Brain samples will also be collected and examined for dendritic complexity, spine density, and neuron numbers. Finally, levels of neuropathological pathway markers will be examined at early and late (12 month) time points, all to study the effects of the post-injury treatment. In this way we will answer several key questions about the treatment of the long-term effects of mild traumatic brain injury, how the treatment will affect molecular events that have lasting consequences after injury, what happens to dendritic complexity after treatment at lengthy times after mild injury, and the extent to which the treatment induced changes in specific regulatory factors can have an effect on downstream neuronal function. Elucidating the effects of the treatment after mild traumatic brain injuries over a year following the injury will help us determine an effective therapeutic solution to the problem of chronic TBI effects.

发现治疗策略来对抗创伤性脑损伤的慢性影响是非常重要的。 (TBI)，因为目前还没有有效的治疗方法来预防这些认知缺陷。不幸的是， 在最近的作战行动中服役的军队中，脑外伤是一种非常常见的疾病。至少15% 部署的人员会受到创伤，据估计，这类伤害的总数高达 32万。仅在美国，估计每年至少有170万人患有脑损伤，而且 全球发病率约为每年0.5%。绝大多数的脑损伤是由军队经历的 人员被归类为轻伤，但这些伤害确实会导致严重的慢性影响。 我们试图证明一种有效的治疗方法，可以减少或逆转长期认知能力 由轻度创伤性脑损伤(TBI)引起的功能障碍。因为这些损伤涉及多个 疗效，有必要进一步表征治疗对持续树突和棘状改变的效果。 并增加了我们对可能的治疗变化的了解，从而使脑外伤患者 利益。在过去的几年里，我们的实验室发现一种抗氧化剂转录的激活剂 因子Nrf2可以通过调节对健康至关重要的分子机制来起到神经保护作用 神经元。这导致我们提出了一个假设，即用NRF2治疗轻度创伤性脑损伤 激活剂将显著改善神经元之间的连接，促进神经保护 细胞内途径，并大大提高了脑外伤后的长期疗效。我们将测试我们的 有三个具体目的的假说：1.预防轻度闭合性脑损伤的慢性行为影响 通过TBHQ治疗，2.改善TBHQ治疗后轻度持续连接性改变 以及3.确定脑外伤后治疗引起的可能影响长期疗效的分子变化 功能。我们将检查轻度脑外伤后分子和长期认知功能的变化。 采用小鼠闭合性头部撞击伤模型。我们将使用一个成熟的TBI模型，该模型涉及一个封闭的 包括旋转的头部损伤模型。我们将用任何一种车辆治疗受伤和假受伤的群体 或者是TBHQ。行为测试将在受伤后1、6和12个月进行。大脑样本也将被 收集并检查树突的复杂性、棘突密度和神经元数量。最后， 将在早期和晚期(12个月)检测神经病理途径标记物，所有这些都是为了研究 伤后治疗的效果。通过这种方式，我们将回答有关治疗的几个关键问题 轻度创伤性脑损伤的长期影响，治疗将如何影响已经持续的分子事件 损伤后的后果，轻度损伤后长时间治疗后树突状细胞的复杂性发生了什么 损伤，以及治疗引起的特定调节因素的变化可以产生影响的程度 下游神经元功能。浅谈轻型颅脑损伤后的治疗效果 受伤后的一年多将帮助我们确定一个有效的治疗方案来解决慢性 TBI效应。