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

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

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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.

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创伤性脑损伤（TBI）后的前72小时，线粒体和其他细胞元素。这种氧化损伤导致脑线粒体呼吸道损害并减少钙（Ca ++）缓冲，这会使TBI神经元内CA ++过载后加剧，CALPAIN介导的神经元细胞骨骼降解，神经变性和神经学障碍。最近，已经确定了一种新型的中央神经系统（CNS）损伤的抗氧化剂方法，并可能逆转氧化损伤，其中涉及清除LP衍生的羰基化合物（“ Carbonyl清除”），以防止其神经毒性作用。来自其他实验室的初步支持，我们自己表明，某些含有肼功能组的临床使用的药物可以共价结合4-HNE或丙烯醛，并防止其神经毒性。拟议的3 AIM项目将采用苯嗪，这是一种已有长期使用的含氢援抑制剂的苯嗪，已被发现是一种有效的羰基清除剂，作为研究孤立的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控制的皮质影响TBI模型。 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.由于苯嗪具有悠久的临床使用史和知名的人类安全性，因此将促进该药物将其用于临床TBI试验的翻译。