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.

发现对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来预防这些认知缺陷。很遗憾， TBI 是最近参加过作战行动的军队中一种非常常见的疾病。至少 15% 部署人员受到 TBI 伤害，估计此类伤害总数高达 320,000。据估计，仅在美国，每年至少有 170 万人遭受 TBI，并且 全球每年的发病率约为 0.5%。绝大多数 TBI 都是军人经历过的 人员被归类为轻度伤害，但确实会造成严重的慢性影响。 我们寻求证明一种有效的治疗方法，可以减少或逆转长期认知障碍 轻度创伤性脑损伤 (TBI) 造成的功能障碍。因为这些伤害涉及多个 影响，有必要进一步表征治疗对持久树突和脊柱变化的影响 TBI 引起的，并增加我们对可能的治疗改变的了解，以便 TBI 患者能够 益处。在过去的几年里，我们的实验室发现了一种抗氧化剂转录激活剂 Nrf2 因子可以通过调节对健康很重要的分子机制来起到神经保护作用。 神经元。这使我们提出了一个假设：用 Nrf2 治疗轻度创伤性脑损伤 激活剂将显着改善神经元之间的连接，促进神经保护 细胞内途径，并导致 TBI 后的长期结果大大增强。我们将测试我们的 该假设具有三个具体目标： 1. 预防轻度闭合性头部损伤的慢性行为影响 通过 tBHQ 治疗，2. 轻度治疗后 tBHQ 治疗产生的持续连接变化得到改善 TBI，以及 3. 识别 TBI 治疗后引起的可能影响长期的分子变化 功能。我们将检查轻度 TBI 后分子和长期认知功能的变化 通过小鼠闭合性头部撞击损伤模型。我们将使用一个完善的 TBI 模型，涉及一个封闭的 包含旋转的头部损伤模型。我们将使用任一车辆治疗受伤和假伤组 或 tBHQ。行为测试将在受伤后 1、6 和 12 个月进行。大脑样本也将被 收集并检查树突复杂性、脊柱密度和神经元数量。最后，水平 神经病理学通路标记物将在早期和晚期（12 个月）时间点进行检查，所有这些都是为了研究 伤后治疗的效果。这样我们就可以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，治疗将如何影响具有持久性的分子事件 受伤后的后果，轻度治疗后长时间治疗后树突复杂性会发生什么变化 损伤，以及治疗引起的特定调节因素变化的影响程度 对下游神经元功能的影响。阐明轻度创伤性脑损伤后治疗的效果 受伤后一年多的时间将帮助我们确定慢性病问题的有效治疗方案 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