Carbonyl Scavenging for Traumatic Brain Injury

描述（申请人提供）：我们的实验室已经证明，产生有效的活性氮物质（RNS）过氧亚硝酸盐（PN）是由脂质过氧化（LP）引起的氧化损伤和通过结合LP衍生的含羰基的醛如4-羟基壬醛（4-HNE）引起的神经毒性蛋白质修饰的原因。以及丙烯醛在创伤性脑损伤（TBI）后的前72小时内转化为线粒体和其它细胞成分。这种氧化损伤 导致脑线粒体呼吸损害和钙（Ca++）缓冲减少，这导致TBI后神经元细胞内Ca++过载、钙蛋白酶介导的神经元细胞骨架降解、神经变性和神经损伤。最近，已经鉴定了一种用于中枢神经系统（CNS）损伤后的新的抗氧化剂方法，其用于减少并可能逆转氧化损伤，其涉及清除LP衍生的羰基化合物（“羰基清除”），防止其神经毒性作用。其他实验室和我们自己的初步支持表明，某些临床使用的含有肼官能团的药物可以与4-HNE或丙烯醛共价结合并防止其神经毒性。拟议的3 Aim项目将使用苯乙肼，一种长期使用的含肼抗氧化剂，其含有已被发现是有效的羰基清除剂，作为研究羰基清除的抗氧化神经保护作用的工具。 大鼠脑线粒体和大鼠皮质撞击TBI模型。具体而言，该项目将从神经元线粒体和细胞骨架保护沿着改善慢性运动和认知恢复以及减少创伤后神经变性的能力方面定义苯乙肼的“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）。由于苯乙肼具有长期的临床使用历史和良好的人体安全性，因此将该药物的使用转化为临床TBI试验将得到促进。

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.