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: 9038791
• 负责人: Bruce A. Citron
• 金额: --
• 依托单位: BAY PINES VA MEDICAL CENTER
• 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 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9038791
• 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; Solutions; Staining method; Stains; Study models; Testing; Therapeutic; Time; Traumatic Brain Injury; Treatment Effectiveness; 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

DESCRIPTION (provided by applicant): 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 wil 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.

描述（由申请人提供）： 发现治疗策略来对抗创伤性脑损伤（TBI）的慢性影响非常重要，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，TBI是在最近的战斗行动中服役的军队的一种非常常见的痛苦。至少有15%的部署人员接受TBI，估计此类受伤的总人数高达320，000人。仅在美国，估计每年至少有170万人遭受TBI，全球发病率约为每年0.5%。军事人员经历的绝大多数TBI被归类为轻度伤害，但这些确实会导致显著的慢性影响。我们试图证明一种有效的治疗方法，可以减少或逆转由轻度创伤性脑损伤（TBI）产生的长期认知功能障碍。由于这些损伤涉及多种效应，因此有必要进一步描述TBI引起的持久树突和脊柱变化的治疗效果，并增加我们对可能的治疗变化的了解，以便TBI患者受益。在过去的几年里，我们的实验室已经发现，抗氧化转录因子Nrf2的激活剂可以通过调节对神经元健康至关重要的分子机制来发挥神经保护作用。这使我们提出了一个假设，即用Nrf2激活剂治疗轻度创伤性脑损伤将导致神经元之间的连接的显著改善，促进神经保护性细胞内通路，并导致TBI后大大增强的长期结果。我们将测试我们的假设有三个具体目标：1。通过tBHQ治疗预防轻度闭合性脑损伤的慢性行为效应，2。轻度TBI后tBHQ治疗产生的持续连接性变化的改善，以及3.确定TBI后治疗诱导的可能影响长期功能的分子变化。我们将通过小鼠闭合性头部撞击损伤模型研究轻度TBI后分子和长期认知功能的变化。我们将使用一个完善的TBI模型，包括一个闭合性头部损伤模型，包括旋转。我们将用车辆或tBHQ治疗受伤和假受伤组。行为测试将在受伤后1、6和12个月进行。还将收集大脑样本，并检查树突的复杂性，棘密度和神经元数量。最后，将在早期和晚期（12个月）时间点检查神经病理学通路标志物的水平，所有这些都是为了研究损伤后治疗的效果。通过这种方式，我们将回答几个关键问题：轻度创伤性脑损伤的长期影响的治疗，治疗如何影响损伤后具有持久后果的分子事件，轻度损伤后长时间治疗后树突复杂性发生了什么，以及治疗诱导的特定调节因子变化对下游神经元功能的影响程度。阐明轻度创伤性脑损伤后一年内的治疗效果将有助于我们确定一种有效的治疗方案，以解决慢性TBI影响的问题。