Carbonyl Scavenging for Traumatic Brain Injury

描述(申请人提供)：我们的实验室已经证明，在创伤性脑损伤(TBI)后的最初72小时内，过亚硝酸根(PN)的产生是通过脂质过氧化(LP)和神经毒性蛋白质修饰而产生的有效的反应性氮物种(RNS)的产生，过氧亚硝酸盐(PN)通过含LP衍生的含酮基醛(4-HNE)和丙烯醛与线粒体和其他细胞元件结合而导致神经毒性蛋白质修饰。这种氧化损伤 导致脑线粒体呼吸受损和钙(Ca++)缓冲减少，从而加重脑损伤后神经细胞内钙超载、钙蛋白介导的神经元细胞骨架降解、神经退行性变和神经功能损害。最近，一种新的抗氧化剂方法被发现用于治疗中枢神经系统(CNS)后损伤，以减轻并可能逆转氧化损伤，包括清除LP衍生的羰基化合物(“羰基清除”)，防止其神经毒性作用。来自其他实验室和我们自己的初步支持表明，某些临床上使用的含有肼功能基团的药物可以与4-HNE或丙烯醛共价结合，从而防止它们的神经毒性。拟议的3AIM项目将使用苯肼，一种长期使用的含有肼的抗抑郁剂，已被发现是一种有效的羰基清除剂，作为一种工具来研究在分离的 大鼠脑线粒体和大鼠控制性皮质冲击性脑损伤模型。具体地说，该项目将从神经元线粒体和细胞骨架保护以及改善慢性运动和认知恢复以及减少创伤后神经退行性变的能力方面定义苯乙肼“羰基清除”的神经保护药理学(例如作用机制、剂量反应和治疗窗口)。由于苯乙肼有很长的临床使用历史，而且对人类的安全性有很好的了解，因此将有助于将该药物的使用转化为临床脑损伤试验。

DESCRIPTION (provided by applicant): Our laboratory has documented that generation of the potent reactive nitrogen species (RNS) peroxynitrite (PN) is responsible for oxidative damage by lipid peroxidation (LP) and neurotoxic protein modification by binding of LP-derived carbonyl-containing aldehydes such as 4-hydroxynoneal (4-HNE) and acrolein to mitochondrial and other cellular elements during the first 72 hrs after traumatic brain injury (TBI). This oxidative damage causes brain mitochondrial respiratory compromise and decreased calcium (Ca++) buffering which worsens post-TBI neuronal intracellular Ca++ overload, calpain-mediated neuronal cytoskeletal degradation, neurodegeneration and neurological impairment. Recently, a novel antioxidant approach for post-central nervous system (CNS) injury for decreasing, and possibly reversing, oxidative damage has been identified that involves scavenging the LP-derived carbonyl compounds ("carbonyl scavenging") preventing their neurotoxic effects. Preliminary support from other laboratories and our own has shown that certain clinically used drugs that contain hydrazine function groups can covalently bind to 4-HNE or acrolein and prevent their neurotoxicity. The proposed 3 Aim project will employ phenelzine, a long used hydrazine-containing anti-depressant that contains has been found to be an effective carbonyl scavenger, as a tool to investigate the antioxidant neuroprotective effects of carbonyl scavenging in isolated rat brain mitochondria and the rat controlled cortical impact TBI model. Specifcally, the project will define the neuroprotective pharmacology (e.g. mechanism of action, dose-response and therapeutic window) of phenelzine's "carbonyl scavenging" in terms of neuronal mitochondrial and cytoskeletal protection along with the ability to improve chronic motor and cognitive recovery and to decrease post-traumatic neurodegeneration. Since phenelzine has a long history of clinical use and a well understood human safety profile, the translation of the drug's use into clinical TBI trials would be facilitated.