Inhibition of chronic neuroinflammation reduces neurological deficits after TBI

创伤性脑损伤是现役人员长期致残的主要原因， 退伍军人。防弹衣的改进大大减少了对重要器官的伤害，并在 紧急手术拯救了无数人的生命。不幸的是，颅脑损伤后的神经功能障碍 这是一个进展相对较小的领域。颅脑损伤从轻度(脑震荡)到重度 在现代战场上大量生产，尤其是由于接触到即兴制作的 爆炸装置(IED)和矛盾的是，在其他紧急护理领域的改进已经大大 增加了活着经历TBI长期负面影响的战斗人员的数量。尽管 尽管有大量的研究工作，但没有任何治疗方法被证明在临床上是有效的。目前， 大多数急性颅脑损伤后的护理仅限于支持性干预和避免重复受伤，希望 这种独立的生理修复机制将随着时间的推移改善神经功能障碍。 不幸的是，大量遭受脑外伤的退伍军人只能应付慢性神经系统疾病。 包括运动和认知障碍在内的缺陷。提出并验证治疗方法势在必行 对VA系统特别重要的这一大群患者产生积极影响的策略。 研究表明，脑损伤启动了多个二级分子变化的级联反应，导致延迟 和进行性组织损伤，导致神经功能障碍。两者都是固有的神经细胞死亡 神经炎症后的机制和继发性神经毒性被认为是导致神经元 脑部创伤后的损失。尽管许多研究的重点都是为了阐明相对 早期的细胞和分子事件，实验证据表明病理生物学过程 创伤性脑损伤可能会持续一年或更长时间--有助于进展 神经退行性变和慢性神经缺陷。最近的证据表明，顽固的 中枢神经系统(CNS)创伤后的神经炎症持续数月甚至数年，并可能 对慢性神经变性和慢性神经功能障碍负责。建议的目标是 研究表明，由脑外伤和继发性脑损伤引发的慢性继发性损伤过程 神经功能障碍并不是不可逆转的，是治疗干预的主要目标。这项建议 旨在测试这样一种假设，即延迟运动和/或药物方法针对关键 继发性损伤机制可以有效减少神经元丢失和神经炎症，并促进 神经可塑性反应导致脑外伤后神经功能障碍的减轻。建议数 旨在验证我们的假设的研究将使用建立良好的脑外伤动物实验模型， 控制小鼠皮质撞击(CCI)。这个实验性的脑损伤模型模拟了关键的病理生理学 临床脑损伤的机制，以及我们的假说在该模型中的成功验证，应该会增加 临床应用的可能性。这项拟议的研究将确定：1)在大脑开始后开始的晚期运动 创伤可减轻神经功能障碍，减少慢性神经元丢失和随后的神经炎症 实验性脑创伤；2)脑创伤后开始的晚期GGA给药减轻神经功能障碍， 减少实验性脑损伤后的慢性神经元丢失和神经炎症；3)晚期应用PJ34 脑创伤后启动可减轻神经功能障碍，减少慢性神经元丢失，并 实验性脑损伤后的神经炎症；4)晚期联合干预，包括 脑外伤后运动后应用PJ34或GGA可减轻神经功能障碍，减少 实验性脑外伤后慢性神经元丢失和神经炎症。 。

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. .