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， 老兵防弹衣的改进大大减少了对重要器官的伤害， 急诊手术挽救了无数生命不幸的是，脑外伤后的神经功能障碍 这是一个进展相对较小的领域。TBI范围从轻度（脑震荡）到重度 在现代战场上大量产生，特别是由于暴露在临时的 爆炸装置（IED）和矛盾的是，在其他领域的紧急护理的改善，大大 增加了幸存下来的战士的数量，以体验TBI的长期负面影响。尽管 尽管进行了大量的研究工作，但没有TBI的治疗显示出临床有效。目前， 大多数急性TBI后护理仅限于支持性干预和避免重复损伤， 独立的生理修复机制会随着时间的推移改善神经功能障碍。 不幸的是，大量遭受TBI的退伍军人被留下来科普慢性神经系统疾病。 包括运动和认知障碍在内的缺陷。必须提出并验证治疗方案， 这些策略将对VA系统特别重要的这一大群患者产生积极影响。 研究表明，创伤性脑损伤引发了继发性分子变化的多个级联， 和渐进性组织损伤，导致神经功能障碍内源性神经元细胞死亡 神经炎症后的机制和继发性神经毒性被认为有助于神经元 脑外伤后的损失虽然大部分的研究重点一直是针对阐明相对 早期的细胞和分子事件，实验证据表明， 由TBI引发的可能持续长达一年或更长时间的创伤后-有助于进行性 神经变性和慢性神经缺陷。最近的证据表明， 中枢神经系统（CNS）创伤后的神经炎症持续数月甚至数年，并且可能 导致慢性神经变性和慢性神经功能障碍。建议的目标 研究表明，TBI引发的慢性继发性损伤过程和继发性 神经缺陷不是不可逆的，并且代表治疗干预的主要目标。这项建议 旨在检验延迟运动和/或药理学方法靶向关键的假设， 继发性损伤机制可以有效地减少神经元损失和神经炎症，并促进 神经可塑性反应导致TBI后神经功能障碍的减弱。拟议 设计用于检验我们假设的研究将使用完善的TBI动物实验模型， 对照皮质撞击（CCI）。该实验性TBI模型模拟了TBI的关键病理生理学变化。 临床TBI的机制，以及我们在该模型中假设的成功验证， 临床应用的可能性。拟议的研究将确定：1）大脑后开始的晚期运动 创伤减轻了神经功能障碍，减少了慢性神经元丢失， 实验性TBI; 2）脑外伤后开始的晚期GGA给药减轻了神经功能障碍， 减少实验性TBI后的慢性神经元损失和神经炎症; 3）晚期PJ 34给药 在脑创伤后启动，减轻神经功能障碍，减少慢性神经元丢失， 实验性TBI后的神经炎症;和4）晚期联合干预，包括 在脑创伤后与运动一起施用PJ 34或GGA减轻了神经功能障碍， 慢性神经元损失和实验性TBI后的神经炎症。 .