Carbonyl Scavenging for Traumatic Brain Injury

羰基清除治疗创伤性脑损伤

• 批准号: 8795231
• 负责人: EDWARD D. HALL
• 金额: $ 32.88万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 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/8795231
• 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; Hydrazine; 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; response; tool

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）：我们的实验室已经证明，在创伤性脑损伤（TBI）后的最初72小时内，强效活性氮物种（RNS）过氧亚硝酸盐（PN）的产生负责脂质过氧化（LP）的氧化损伤和通过将LP衍生的含羰基醛（如4-羟基壬醛（4-HNE）和丙烯醛）结合到线粒体和其他细胞元素而对神经毒性蛋白进行修饰。这种氧化损伤