Preventing TBI-Induced Chronic Functional Loss with a Neuroprotective Antioxidant

描述(由申请人提供)： 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，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。至少有15%的部署人员受到了创伤，据估计，受伤总人数高达32万人。仅在美国，估计每年至少有170万人遭受脑外伤，全球发病率约为每年0.5%。军事人员经历的绝大多数创伤性脑损伤被归类为轻伤，但这些伤情确实会导致严重的慢性影响。我们寻求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影响，因此有必要进一步确定对脑外伤引起的持久树突状和脊椎改变的治疗效果，并增加我们对可能的治疗变化的了解，从而使脑外伤患者受益。在过去的几年里，我们的实验室发现，抗氧化剂转录因子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保护神经。这导致我们提出了一种假设，即使用Nrf2激活剂治疗轻度创伤性脑损伤将显著改善神经元之间的连接，促进神经保护性细胞内通路，并极大地提高脑外伤后的长期结果。我们将通过三个具体的目标来验证我们的假设：1.通过TBHQ治疗预防轻度闭合性脑损伤的慢性行为效应，2.改善轻度脑损伤后TBHQ治疗所产生的持续性连通性变化，以及3.确定脑损伤后治疗所引起的可能影响长期功能的分子变化。我们将通过闭合性头部撞击伤小鼠模型检测轻度脑外伤后分子和长期认知功能的变化。我们将使用一个成熟的颅脑损伤模型，包括一个包含旋转的闭合性头部损伤模型。我们将用车辆或TBHQ治疗受伤和假受伤的群体。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，并检查树突复杂性、棘突密度和神经元数量。最后，在损伤早期和晚期(12个月)检测神经病理通路标记物的水平，以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，即轻度创伤性脑损伤的长期影响的治疗，治疗将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状细胞的复杂性发生了什么变化，以及治疗引起的特定调节因子的变化对下游神经元功能的影响程度。阐明损伤后一年多的轻度创伤性脑损伤的治疗效果将有助于我们确定有效的治疗方案来解决慢性脑创伤的影响问题。

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.