Neuroprotection after TBI

创伤性脑损伤（TBI）是服务人员和退伍军人残疾的主要原因之一。的 TBI对幸存退伍军人的影响通常可以在最初受伤后数十年内看到。氧化应激和 在数小时内开始并持续数天的内质网（ER）应激是已知的 神经元死亡，导致TBI后长期神经功能缺损。重要的氧化应激和ER应激 相互促进，协同作用。因此，本提案的目的是测试是否控制氧化 应激和内质网应激对TBI后有益处。氧化应激主要由活性氧引起 （ROS）。因此，我们将测试最小化ROS生成的组合疗法（通过抑制NADPH氧化酶 NOX2）并伴随增强ROS的处置（通过诱导抗氧化剂转录因子Nrf2） 减少脑损伤，促进TBI后更好的运动和认知恢复。我们将使用一个组合 在不同年龄的男性和女性中， 创伤性脑损伤此外，TBI后ER功能的破坏导致启动ER的未折叠蛋白质的积累， 应激并诱导ROS产生。一个主要的ER应激途径是由PERK及其下游介导的。 凋亡基因因此，我们将测试是否将抗氧化剂组合疗法与salubrinal（抗氧化剂的抑制剂）组合。 PERK通路）提供了更好的保护脑和促进TBI后功能恢复的功效。我们将 还测试了长期后果和保护机制的联合治疗，在这两个男性 和遭受TBI的女性。脑外伤的长期并发症是帕金森病的发展 (PD)，我们将测试急性期联合治疗是否能最大限度地降低慢性期PD倾向 在TBI之后 我们将检验一种抗氧化剂联合疗法保护大脑并促进长期 TBI后不同年龄男女的功能增益。我们进一步假设， 应激和内质网应激共同作用对保护大脑和促进神经功能恢复更有效 在TBI之后我们还假设，控制氧化应激降低帕金森氏症的倾向， TBI后的疾病（PD）病理学。 ·目标1将测试抗氧化剂的最小有效剂量、机会窗口、年龄和性别的影响 夹竹桃麻素+ TBHQ联合治疗。 ·目标2将测试添加salubrinal是否会增加抗氧化剂组合保护大脑的功效，并促进 TBI后功能恢复更好。 ·目标3将测试长期结果，包括运动功能、认知功能、神经精神功能 功能、灰质和白色物质损伤以及最佳联合治疗的假定保护机制 在TBI之后这一目标将进一步测试联合治疗是否降低了PD样疾病发作的敏感性。 TBI后慢性阶段的病理学。 总的来说，目前的项目将帮助我们找到一种药物组合，最大限度地减少继发性脑损伤， 通过减少TBI后的氧化应激和ER应激来减轻TBI后的神经功能障碍。长期目标是 提供治疗，以帮助服务人员和退伍军人谁遭受创伤性脑损伤。 拟议工作与VA患者护理使命的相关性：每年，数千名服务人员 将遭受创伤性脑损伤，许多幸存者将与长期功能缺陷作斗争。目前有 美国有超过30万名退伍军人患有TBI。这种毁灭性的状况对退伍军人的负面影响是 对家庭和社会造成巨大的经济损失和生活质量。成功完成 建议进行哪些研究，以确定一种药物组合，使幸存的TBI患者的功能恢复更好 患者将对退伍军人有很大帮助。

Traumatic brain injury (TBI) is one of the leading causes of disability in service personnel and veterans. The effects of TBI in surviving veterans can often be seen for decades after the initial injury. Oxidative stress and endoplasmic reticulum (ER) stress that starts within hours and continues for days are known promoters of neuronal death that lead to long-term neurological deficits after TBI. Importantly oxidative stress and ER stress potentiate each other and act synergistically. Hence, the goal of this proposal is to test if controlling oxidative stress and ER stress is beneficial after TBI. Oxidative stress is induced mainly by the reactive oxygen species (ROS). Hence, we will test a combo therapy that minimizes generation of ROS (by inhibiting NADPH oxidase NOX2) and concomitantly potentiates disposal of ROS (by inducing the antioxidant transcription factor Nrf2) decreases brain damage and promotes better motor and cognitive recovery following TBI. We will use a combo of apocynin (NOX2 inhibitor) and TBHQ (Nrf2 inducer) in both males and females at different ages subjected to TBI. Furthermore, disruption of ER function after TBI leads to accumulation of unfolded proteins that start ER stress and also induce ROS generation. A major ER stress pathway is mediated by PERK and its downstream apoptotic genes. Hence, we will test if combining the antioxidant combo therapy with salubrinal (inhibitor of PERK pathway) provides a better efficacy to protect brain and promote functional recovery after TBI. We will also test the long-term consequences and the mechanisms of protection of the combo therapy in both males and females subjected to TBI. As a long-term complication of TBI is the development of Parkinson's disease (PD), we will test if the combo therapy during acute phase minimizes PD propensity during the chronic phase after TBI. We will test the hypothesis that an antioxidant combination therapy protects the brain and promotes long-term functional gains in both sexes at different ages after TBI. We further hypothesize that preventing oxidative stress and ER stress together is more efficacious to protect the brain and to promote neurological recovery after TBI. We also hypothesize that controlling oxidative stress decreases the propensity of Parkinson's disease (PD) pathology after TBI. • Aim 1 will test the minimal efficacious dose, window of opportunity, effect of age and sex for the antioxidant combo (apocynin + TBHQ) therapy after TBI. • Aim 2 will test if adding salubrinal increases the efficacy of antioxidant combo to protect brain and promotes better functional recovery after TBI. • Aim 3 will test the long-term outcomes including motor function, cognitive function, neuropsychiatric function, gray and white matter damage and putative mechanisms of protection for the best combo therapy after TBI. This aim will further test if the combo therapy decreases the sensitivity of onset of PD-like pathology at a chronic stage after TBI. Overall, the present project will help us to find a drug combo that minimizes secondary brain damage and neurologic dysfunction after TBI by curtailing oxidative stress and ER stress after TBI. The long-term goal is to provide a therapy to help service personnel and veterans who suffer a TBI. Relevance of the proposed work to the VA patient care mission: Every year, thousands of service personnel will suffer TBI and many of those who survive struggle with long-term functional deficits. There are currently >300,000 veterans in USA who suffered a TBI. The negative impact of this devastating condition on veterans is enormous for the families as well as society in terms of financial loss and quality of life. Successful completion of the proposed studies to identify a drug combo that leads to better recovery of functions in surviving TBI sufferers will be enormously helpful to veterans.