Necrostatins for traumatic brain injury

描述（由申请人提供）： 创伤性脑损伤（TBI）是45岁以下成年人的头号杀手，幸存者每年的康复费用高达数十亿美元。目前还没有专门针对TBI幸存者的长期认知缺陷和其他神经系统后遗症的治疗方法。Necrostatin-1是一种新型程序性坏死的小分子抑制剂，称为坏死性凋亡，即使在CCI后给药，也能显著改善损伤后细胞死亡和Morris水迷宫缺陷。药代动力学数据表明，necrostatin-1具有良好的脑渗透性和半衰期，而necrostatin-5在体外抑制坏死性凋亡的作用几乎是necrostatin-1的两倍。总之，这些数据表明，necrostatin-1，并可能其他necrostatin，可能是临床上有用的药物治疗创伤性脑损伤后的认知缺陷。这项R21申请的目标是获得临床前原理数据证明，这些数据将证明将necrostatin-1或necrostatin-5（以及可能的其他necrostatin）用于严重TBI患者的临床试验是合理的。为了实现这一目标，我们提出了以下具体目标：（1）确定CCI之前静脉内施用的Necrostatin-1和Necrostatin-5对创伤后认知结果的剂量反应;（2）确定CCI之后静脉内施用的Necrostatin-1和Necrostatin-5对创伤后认知结果的治疗窗;和（3）确定在CCI的三个损伤严重程度水平下，坏死抑制素对组织病理学（细胞渗透性和轴突损伤）以及对运动和认知功能的影响。结果的措施，提出了莫里斯水迷宫的表现，前庭功能（线夹测试），和组织病理学。在所有目标中，还将评估性别影响。R21申请中的积极发现将应用于UO 1申请，旨在将坏死抑制素用于TBI患者的临床试验。 公共卫生相关性： 拟议项目的工作可以为创伤性脑损伤患者提供新的治疗方法。这种特定的药物治疗可能会减少脑细胞死亡，并改善长期幸存者的学习和记忆，从而提高他们的生活质量。

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is the number one killer of adults under 45 years of age, with rehabilitative costs for survivors in the billions of dollars annually. Currently there are no treatments specific for long-term cognitive deficits and other neurological sequelae in survivors of TBI. Necrostatin-1 is a small molecule inhibitor of a novel form of programmed necrosis, termed necroptosis, which strikingly improves postinjury cell death as well as Morris water maze deficits even when administered after CCI. Pharmacokinetic data suggest a favorable brain penetration and half-life for necrostatin-1, while necrostatin-5 is almost twice as potent an inhibitor of necroptosis in vitro as necrostatin-1. Together, these data suggest that necrostatin-1, and possibly other necrostatins, may be clinically useful agents for the treatment of cognitive deficits after traumatic brain injury. The goal of this R21 application is to obtain preclinical proof of principle data that will justify carrying forward necrostatin-1 or necrostatin-5 (and potentially other necrostatins) into clinical trials for patients with severe TBI. To accomplish this goal we propose the following Specific Aims: (1) Determine the dose response of necrostatin-1 and necrostatin-5 administered intravenously before CCI on posttraumatic cognitive outcome; (2) Determine the therapeutic window of necrostatin-1 and necrostatin-5 administered intravenously after CCI on posttraumatic cognitive outcome; and (3) Determine the effects of necrostatins on histopathology (cellular permeability and axonal injury), and on motor and cognitive function at three injury severity levels of CCI. Outcome measures proposed are Morris water maze performance, vestibulomotor function (wire grip test), and histopathology. In all Aims, gender effects will also be assessed. Positive findings in this R21 application will be applied towards a UO1 application intended to bring necrostatins to clinical trials for patients with TBI. PUBLIC HEALTH RELEVANCE: Work in the proposed project could render a new treatment for patients with traumatic brain injury. This specific drug therapy might reduce brain cell death as well as improve learning and memory in long term survivors, and thereby improve their quality of life.