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: 10174732
• 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 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10174732
• 关键词: Affect; Aftercare; Antioxidants; Anxiety; Axon; 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; TBI treatment; 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.

发现抗创伤性脑损伤的慢性影响的治疗策略非常重要 （TBI）因为目前没有有效的治疗方法可以防止这些认知缺陷。很遗憾， TBI是最近在战斗行动中服役的军事力量的非常普遍的苦难。至少15％ 部署的人员将获得TBI，此类伤害的总数估计高如 320,000。仅在美国，据估计，每年至少有170万人遭受TBI的痛苦 全球发病率约为每年0.5％。军事经历的绝大多数TBI 人员被归类为轻度伤害，但确实会导致重大的慢性影响。 我们试图展示一种有效的治疗方法，可以减少或扭转长期认知 由轻度脑损伤（TBI）产生的功能障碍。因为这些伤害涉及多重 效果，有必要进一步表征对持久树突和脊柱变化的治疗效果 由TBI诱导，并增加了我们对治疗性变化的了解，以便TBI患者将 益处。在过去的几年中，我们的实验室发现抗氧化剂转录的激活剂 因素NRF2可以通过调节对健康很重要的分子机制来具有神经保护作用 神经元。这使我们提出了一个假设，即用NRF2治疗轻度脑外伤 激活剂将显着改善神经元之间的连接，促进神经保护作用 细胞内途径，并在TBI之后导致长期结局大大增强。我们将测试我们的 假设具有三个特定目的：1。预防轻度闭合头部损伤的慢性行为影响 通过TBHQ处理，2。轻度治疗产生的持续连通性变化 TBI和3。确定TBI治疗引起的分子变化，可能会影响长期 功能。我们将检查轻度TBI完成后对分子和长期认知功能的变化 通过小鼠的闭合头部冲击损伤模型。我们将使用涉及封闭的良好的TBI模型 头部损伤模型确实包括旋转。我们将用任何一种车辆治疗受伤和假受伤的群体 或TBHQ。行为测试将在受伤后1、6和12个月进行。大脑样本也将是 收集并检查了树突复杂性，脊柱密度和神经元数。最后，水平 神经病理途径标记将在早期和晚期（12个月）的时间点进行检查，所有这些都可以研究 伤害后治疗的影响。通过这种方式，我们将回答有关处理的几个关键问题 轻度外伤性脑损伤的长期影响，治疗将如何影响持久的分子事件 受伤后的后果，在轻度后长时间治疗后的树突状复杂性发生了什么 伤害以及治疗引起的特定调节因素变化的程度可能会产生影响 在下游神经元功能上。轻度创伤性脑损伤后阐明治疗的影响 受伤后的一年多多年，将有助于我们确定慢性问题的有效治疗解决方案 TBI效应。

项目成果

Sidestream Smoke Affects Dendritic Complexity and Astrocytes After Model Mild Closed Head Traumatic Brain Injury.

• DOI: 10.1007/s10571-020-01036-5
• 发表时间: 2022-07
• 期刊: Cellular and molecular neurobiology
• 影响因子: 4
• 作者: Ratliff WA;Saykally JN;Keeley KL;Driscoll DC;Murray KE;Okuka M;Mervis RF;Delic V;Citron BA
• 通讯作者: Citron BA

Withania somnifera Extract Protects Model Neurons from In Vitro Traumatic Injury.

• DOI: 10.1177/0963689717714320
• 发表时间: 2017-07
• 期刊: Cell transplantation
• 影响因子: 3.3
• 作者: Saykally JN;Hatic H;Keeley KL;Jain SC;Ravindranath V;Citron BA
• 通讯作者: Citron BA

Exendin-4 attenuates blast traumatic brain injury induced cognitive impairments, losses of synaptophysin and in vitro TBI-induced hippocampal cellular degeneration.

• DOI: 10.1038/s41598-017-03792-9
• 发表时间: 2017-06-16
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Rachmany L;Tweedie D;Rubovitch V;Li Y;Holloway HW;Kim DS;Ratliff WA;Saykally JN;Citron BA;Hoffer BJ;Greig NH;Pick CG
• 通讯作者: Pick CG

Dendritic arbor complexity and spine density changes after repetitive mild traumatic brain injury and neuroprotective treatments.

• DOI: 10.1016/j.brainres.2020.147019
• 发表时间: 2020-11-01
• 期刊: Brain research
• 影响因子: 2.9
• 作者: Ratliff WA;Delic V;Pick CG;Citron BA
• 通讯作者: Citron BA

Neuromuscular Junction Morphology and Gene Dysregulation in the Wobbler Model of Spinal Neurodegeneration.

• DOI: 10.1007/s12031-018-1153-8
• 发表时间: 2018-09
• 期刊: Journal of molecular neuroscience : MN
• 作者: Ratliff WA;Saykally JN;Kane MJ;Citron BA
• 通讯作者: Citron BA