Inhibition of chronic neuroinflammation reduces neurological deficits after TBI

创伤性脑损伤（TBI）是现役人员和人员长期残疾的主要原因 退伍军人。防弹衣的改进大大减少了对重要器官的伤害，并且技术进步 紧急手术挽救了无数生命。不幸的是，TBI 后的神经功能障碍 代表了进展相对较小的一个领域。 TBI 范围从轻微（脑震荡）到严重 在现代战场上大量生产，特别是由于暴露于临时 爆炸装置（IED），矛盾的是，紧急护理其他领域的改进极大地促进了 增加了遭受 TBI 长期负面影响的战士人数。尽管 尽管进行了大量的研究工作，但尚未证明 TBI 的治疗方法具有临床效果。目前， 最紧急的 TBI 后护理仅限于支持性干预和避免重复受伤，希望 随着时间的推移，独立的生理修复机制将改善神经功能障碍。 不幸的是，大量患有 TBI 的退伍军人不得不应对慢性神经系统疾病 缺陷，包括运动和认知障碍。提出并验证治疗方法势在必行 将对这一大群对 VA 系统特别重要的患者产生积极影响的策略。 研究表明，TBI 会引发多个级联的次级分子变化，从而导致延迟 和进行性组织损伤，导致神经功能障碍。两种内源性神经细胞死亡 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。尽管大部分研究重点都是为了阐明相对 早期细胞和分子事件，实验证据表明病理生物学过程 TBI 引发的创伤可能会在创伤后持续一年或更长时间，从而导致进展 神经退行性变和慢性神经功能缺损。最近的证据表明，持续 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。拟议的目标 研究的目的是证明 TBI 引发的慢性继发性损伤过程和继发性损伤 神经功能缺陷并非不可逆转，是治疗干预的主要目标。这个提议 旨在检验延迟运动和/或针对关键关键药物的药物方法的假设 继发性损伤机制可有效减少神经元丢失和神经炎症，促进 神经可塑性反应导致 TBI 后神经功能障碍的减弱。拟议的 旨在检验我们假设的研究将使用成熟的 TBI 动物实验模型， 小鼠受控皮质冲击（CCI）。该实验性 TBI 模型模拟了关键的病理生理学 临床 TBI 的机制以及我们在该模型中的假设的成功验证应该会增加 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 创伤减轻神经功能障碍，减少慢性神经元损失和随后的神经炎症 实验性创伤性脑损伤； 2) 脑外伤后开始晚期 GGA 给药可减轻神经功能障碍， 减少实验性 TBI 后的慢性神经元损失和神经炎症； 3) PJ34 管理晚 脑外伤后启动可减轻神经功能障碍，减少慢性神经元损失，并且 实验性 TBI 后的神经炎症； 4) 后期联合干预，包括 脑外伤后服用 PJ34 或 GGA 并配合运动可减轻神经功能障碍，减少 慢性神经元损失和实验性 TBI 后的神经炎症。 。

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. .