Inhibition of chronic neuroinflammation reduces neurological deficits after TBI

抑制慢性神经炎症可减少 TBI 后的神经功能缺损

• 批准号: 10222610
• 负责人: BOGDAN ADRIAN STOICA
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10222610
• 关键词: Acute; Area; Attenuated; Biochemical; Caring; Cause of Death; Chronic; Clinical; Clinical Trials; Cognitive deficits; Conflict (Psychology); Devices; Emergency Care; Emergency Situation; Ensure; Event; Exercise; Experimental Animal Model; Exposure to; Goals; Heat-Shock Proteins 70; Human Resources; Impaired cognition; Inflammatory; Injury; Intervention; Investigation; Lead; Left; Mediating; MicroRNAs; Microglia; Mild Concussions; Military Personnel; Modeling; Modernization; Molecular; Mood Disorders; Mus; Nerve Degeneration; Nervous System Physiology; Neurologic Deficit; Neurologic Dysfunctions; Neurological outcome; Neuronal Plasticity; Operative Surgical Procedures; Organ; PARP inhibition; Pathway interactions; Patients; Pharmacology; Physiological; Population; Probability; Process; Research; Research Design; Supportive care; Survivors; System; TBI treatment; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Trauma; Traumatic Brain Injury; Traumatic CNS injury; Up-Regulation; Validation; Veterans; acute care; attenuation; clinical application; clinical practice; clinical translation; controlled cortical impact; design; disability; effective therapy; experience; extracellular vesicles; improved; inhibitor/antagonist; injured; microvesicles; motor deficit; motor impairment; neuroinflammation; neuron loss; neuroprotection; neurotoxicity; progressive neurodegeneration; repaired; response; targeted treatment; treatment strategy

Traumatic brain injury (TBI) is a major cause of long-term disability in active-duty personnel and Veterans. Improvements in body armor have greatly reduced injuries to the vital organs and advances in emergency surgery have saved countless lives. Unfortunately, neurological dysfunctions following TBI represent one area where relatively little progress was made. TBI ranging from mild (concussions) to severe are produced in large numbers on the modern battlefield, especially as result of exposure to improvised explosive devices (IED) and paradoxically, improvements in other areas of emergency care has greatly increased the numbers of warfighters that live to experience the long-term negative effects of TBI. In spite of significant research efforts, no treatments for TBI have been shown to be to be clinically effective. At present, most acute post-TBI care is limited to supportive interventions and avoidance of repeat injuries with the hope that unaided physiological repair mechanisms will, over time improve the neurological dysfunctions. Unfortunately, large numbers of Veterans that have suffered TBI are left to cope with chronic neurological deficits including motor and cognitive impairments. It is imperative to propose and validate therapeutic strategies that would positively impact this large group of patients of particular importance to the VA system. Research has shown that TBI initiates multiple cascades of secondary molecular changes that cause delayed and progressive tissue damage, which lead to neurological dysfunction. Both intrinsic neuronal cell death mechanisms and secondary neurotoxicity following neuroinflammation are thought to contribute to the neuronal loss following brain trauma. Although much of the research focus has been directed at elucidating relatively early cellular and molecular events, experimental evidence suggests that the pathobiological processes initiated by TBI may continue for as long as a year or more after trauma- contributing to progressive neurodegeneration and chronic neurological deficits. Recent evidence suggests that persistent neuroinflammation following central nervous system (CNS) trauma lasts for months and even years, and may be responsible for chronic neurodegeneration and chronic neurological dysfunction. The goal of the proposed research is to demonstrate that the chronic secondary injury processes initiated by TBI and the secondary neurological deficits are not irreversible and represent a prime target for therapeutic intervention. This proposal is designed to test the hypothesis that delayed exercise and/or pharmacologic approaches targeting key secondary injury mechanisms can effectively reduce neuronal loss and neuroinflammation, and promote neuroplasticity responses resulting in attenuation of neurological dysfunction following TBI. The proposed studies designed to test our hypothesis will use a well-established animal experimental model of TBI, controlled cortical impact (CCI) in mice. This experimental TBI model mimics key pathophysiological mechanisms of the clinical TBI, and successful validation of our hypotheses in this model should increase the probability of clinical application. The proposed studies will determine: 1) Late exercise initiated after brain trauma attenuates neurological dysfunction, reduces chronic neuronal loss, and neuroinflammation following experimental TBI; 2) Late GGA administration initiated after brain trauma attenuates neurological dysfunction, reduces chronic neuronal loss, and neuroinflammation following experimental TBI; 3) Late PJ34 administration initiated after brain trauma attenuates neurological dysfunction, reduces chronic neuronal loss, and neuroinflammation following experimental TBI; and 4) Late combination intervention including the administration PJ34 or GGA with exercise after brain trauma attenuates neurological dysfunction, reduces chronic neuronal loss, and neuroinflammation following experimental TBI. .

创伤性脑损伤（TBI）是现役人员长期残疾的主要原因 退伍军人。身体装甲的改善大大减少了重要的器官的伤害和进步 紧急手术挽救了无数生命。不幸的是，TBI之后的神经功能障碍 代表一个相对较少进展的领域。 TBI从轻度（脑震荡）到严重 在现代战场上大量生产，特别是由于即兴暴露 爆炸装置（IED）和自相矛盾的是，其他急诊室的改善已大大改善 增加了活体经历TBI长期负面影响的战士的数量。尽管 重大的研究工作，对TBI的治疗尚未证明是有效的。现在， 大多数急性TBI护理仅限于支持性干预措施，并避免重复受伤 随着时间的流逝，这种独立的生理修复机制将改善神经功能障碍。 不幸的是，遭受TBI的大量退伍军人应对慢性神经系统 缺陷，包括运动和认知障碍。必须提出和验证治疗性 将对VA系统特别重要的大批患者产生积极影响的策略。 研究表明，TBI启动了多个次级分子变化的级联，导致延迟 和进行性组织损伤，导致神经功能障碍。两种固有的神经元细胞死亡 神经炎症后的机制和二次神经毒性被认为有助于神经元 脑创伤后的损失。尽管大部分研究重点是针对相对阐明的 早期的细胞和分子事件，实验证据表明病理生物学过程 TBI发起的创伤后可能会持续一年或更长时间 神经变性和慢性神经系统缺陷。最近的证据表明持久 中枢神经系统（CNS）创伤后持续数月甚至几年，神经炎症 负责慢性神经变性和慢性神经功能障碍。提议的目标 研究表明，TBI和次级发起的慢性继发损伤过程 神经缺陷不是不可逆的，并且代表了治疗干预的主要目标。这个建议 旨在测试延迟锻炼和/或药理方法的假设。 次要损伤机制可以有效地减少神经元丧失和神经炎症，并促进 神经可塑性反应导致TBI后神经功能障碍的衰减。提议 旨在检验我们的假设的研究将使用建立的TBI动物实验模型， 小鼠受控皮质冲击（CCI）。该实验性TBI模型模仿关键病理生理学 临床TBI的机制以及在此模型中成功验证我们的假设应增加 临床应用的概率。拟议的研究将确定：1）大脑后开始的晚期运动 创伤会减轻神经功能障碍，减少慢性神经元丧失和神经炎症之后的神经炎症 实验性TBI； 2）GGA晚期给药后脑创伤后启动了神经功能障碍， 实验性TBI后，减少了慢性神经元丧失和神经炎症； 3）PJ34晚期管理 脑创伤后启动会减轻神经功能障碍，减少慢性神经元丧失，并 实验性TBI后神经炎症； 4）晚期组合干预包括 脑外伤后的给药PJ34或GGA通过锻炼减弱神经功能障碍，减少 实验性TBI后，慢性神经元丧失和神经炎症。 。