Carbonyl Scavenging for Traumatic Brain Injury

羰基清除治疗创伤性脑损伤

基本信息

批准号：
8993650
负责人：
EDWARD D. HALL
金额：
$ 32.92万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-01 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8993650
关键词：
4 hydroxynonenal Acrolein Acute Aldehydes Antihypertensive Agents Antioxidants Binding Brain Brain Injuries Buffers Calcium Calpain Cell Culture Techniques Cell membrane Chemicals Chronic Clinical Data Dose Drug usage Elements Exposure to Functional disorder Generations Health Human Hydralazine Impairment Injury Ischemia Laboratories Lesion Lipid Peroxidation Lipids Mediating Membrane Lipids Mitochondria Mitochondrial Proteins Modeling Modification Motor Mus Nerve Degeneration Neurologic Neurons Patients Peroxonitrite Pharmacology Phase Phase III Clinical Trials Phenelzine Polyunsaturated Fatty Acids Post-Translational Protein Processing Rattus Reaction Reactive Nitrogen Species Reactive Oxygen Species Recording of previous events Regimen Reperfusion Therapy Reporting Research Personnel Safety Spinal cord injury Staging Stress Stroke Testing Therapeutic Time Tissues Toxic effect Translations Traumatic Brain Injury Traumatic Subarachnoid Hemorrhage Treatment Efficacy attenuation axonal degeneration base carbonyl compound carbonyl group central nervous system injury clinically relevant cognitive function cognitive recovery controlled cortical impact cytotoxic improved in vivo injured lipid peroxidation inhibitor morris water maze mortality motor function improvement motor recovery nerve injury neurotoxic neurotoxicity novel oxidative damage perhydroxyl radical prevent protective effect respiratory tool treatment response

项目摘要

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.

描述（由申请人提供）：我们的实验室已证明，有效的活性氮物质（RNS）过氧亚硝酸盐（PN）的产生是造成脂质过氧化（LP）氧化损伤和通过与LP衍生的含羰基结合而修饰神经毒性蛋白质的原因。在创伤性脑损伤 (TBI) 后的前 72 小时内，醛类如 4-羟基壬醛 (4-HNE) 和丙烯醛进入线粒体和其他细胞元件。这种氧化损伤导致脑线粒体呼吸功能受损和钙 (Ca++) 缓冲减少，从而加剧 TBI 后神经元细胞内 Ca++ 超载、钙蛋白酶介导的神经元细胞骨架降解、神经变性和神经功能障碍。最近，已经确定了一种用于中枢神经系统（CNS）后损伤的新型抗氧化方法，用于减少甚至可能逆转氧化损伤，该方法涉及清除LP衍生的羰基化合物（“羰基清除”），以防止其神经毒性作用。其他实验室和我们自己实验室的初步支持表明，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 项目将采用苯乙肼（一种长期使用的含肼抗抑郁剂，已被发现是一种有效的羰基清除剂）作为工具，研究羰基清除在分离的神经元中的抗氧化神经保护作用。大鼠脑线粒体和大鼠控制的皮质冲击 TBI 模型。具体来说，该项目将在神经元线粒体和细胞骨架保护方面定义苯乙肼“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），以及改善慢性运动和认知恢复并减少慢性运动和认知恢复的能力。创伤后神经变性。由于苯乙肼具有悠久的临床使用历史和众所周知的人类安全性，因此将有助于将该药物的使用转化为临床 TBI 试验。