Neuroprotection after TBI

创伤性脑损伤是军人和退伍军人致残的主要原因之一。这个 脑外伤对幸存退伍军人的影响通常在最初受伤后的几十年内都可以看到。氧化应激和 内质网(ER)应激在几个小时内开始并持续数天，是已知的 导致脑外伤后长期神经功能障碍的神经元死亡。重要的氧化应激与内质网应激 相互促进，协同行动。因此，这项提议的目标是测试控制氧化 应激和内质网应激对颅脑损伤后有一定的保护作用。氧化应激主要由活性氧引起。 (ROS)。因此，我们将测试一种联合疗法，它可以最大限度地减少ROS的产生(通过抑制NADPH氧化酶 NOX2)，同时促进ROS的释放(通过诱导抗氧化转录因子Nrf2) 减少脑损伤，促进脑外伤后更好的运动和认知恢复。我们将使用组合键 载脂蛋白(NOX2抑制剂)和TBHQ(Nrf2诱导剂)在不同年龄的男性和女性中的变化 TBI。此外，脑损伤后内质网功能的破坏导致启动内质网的未折叠蛋白的积累 应激并诱导ROS的产生。一个主要的内质网应激途径是由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联合疗法与Salubrine(抑制 PERK途径)对脑损伤后的脑保护和促进功能恢复有较好的疗效。我们会 还测试了联合疗法对两种男性的长期后果和保护机制 以及患有脑外伤的女性。作为颅脑损伤的长期并发症，帕金森病的发展 (PD)，我们将测试急性期的联合治疗是否将慢性期的PD倾向降至最低 在TBI之后。 我们将验证抗氧化剂联合疗法保护大脑并促进长期 颅脑损伤后不同年龄男女的功能获得。我们进一步假设防止氧化 应激和内质网应激共同作用更有效地保护大脑，促进神经功能恢复 在TBI之后。我们还假设，控制氧化应激可降低帕金森氏症的发病倾向 颅脑损伤后疾病(PD)病理改变。 ·目标1将测试抗氧化剂的最低有效剂量、机会窗、年龄和性别的影响 脑外伤后联合(apocynin+TBHQ)治疗。 ·Aim 2将测试添加Salubrine是否会增加抗氧化剂组合的保护大脑和促进 颅脑损伤后功能恢复较好。 ·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 最佳综合疗法的功能、灰质和白质损伤及其可能的保护机制 在TBI之后。这一目标将进一步测试联合治疗是否降低了帕金森病样发作的敏感性 颅脑损伤后慢性期的病理改变。 总体而言，本项目将帮助我们找到一种将继发性脑损伤降至最低的药物组合，并 通过减少脑创伤后氧化应激和内质网应激来减少脑损伤后的神经功能障碍。长期目标是 提供一种治疗方法，帮助遭受脑外伤的服务人员和退伍军人。 拟议工作与退伍军人管理局病人护理任务的相关性：每年，数千名服务人员 将遭受创伤性脑损伤，许多幸存下来的人将与长期功能赤字作斗争。目前有 &gt；30万美国退伍军人遭受了脑外伤。这种毁灭性的疾病对退伍军人的负面影响是 在经济损失和生活质量方面，这对家庭和社会都是巨大的。成功完成 建议进行哪些研究，以确定能更好地恢复脑外伤存活者功能的药物组合 患者将对退伍军人有极大的帮助。

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.