Mitochondrial-Targeted Therapeutics for Treatment of Spinal Cord Injury

线粒体靶向疗法治疗脊髓损伤

• 批准号: 8688439
• 负责人: Alexander George Rabchevsky
• 金额: $ 7.42万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-15 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8688439
• 关键词: Acetylcysteine; Acute; Amides; Antioxidants; Behavioral; Bioenergetics; Carnitine; Cell Count; Cells; Collaborations; Contusions; Data; Dose; Enzymes; Event; Glutathione; Healthcare; Histopathology; Homeostasis; Impairment; Injury; Intervention; Levocarnitine Acetyl; Limb structure; Maintenance; Methylprednisolone; Mitochondria; Mitochondrial Proteins; N-Acetylcysteinamide; Neuroglia; Neurons; Outcome Measure; Oxidative Phosphorylation; Population; Production; Publishing; Rattus; Reactive Oxygen Species; Recovery; Recovery of Function; Reporting; Site; Source; Spinal cord injury; Synapses; Techniques; Testing; Therapeutic; Tissues; United States; Universities; Work; base; central nervous system injury; combinatorial; design; dosage; excitotoxicity; improved; kinematics; mitochondrial dysfunction; neuronal cell body; neuroprotection; novel; novel therapeutic intervention; oxidative damage; prevent; research study; response; therapeutic target

DESCRIPTION (provided by applicant): Spinal cord injury (SCI) is a long-term health care problem in the United States, and with the exception of the modestly effective methylprednisolone, there is currently no neuroprotective intervention clinically available for treatment of acute SCI. Our published data and preliminary results demonstrate that oxidative damage to key mitochondrial enzymes and subsequent mitochondrial dysfunction is key to the neuropathological sequalae following SCI. This proposal focuses on directly targeting mitochondrial dysfunction as a novel therapeutic intervention for contusion SCI, the fundamental concept being that SCI-induced excitotoxicity increases mitochondrial Ca2+ cycling/overload and the production of reactive oxygen species (ROS), ultimately leading to mitochondrial dysfunction and glutathione (GSH) depletion. Our approach is two-pronged, aimed at reducing mitochondrial ROS production utilizing a novel, cell-permeant antioxidant and GSH precursor, NACA (the amide form of N-acetylcysteine), as well as an alternative biofuel substrate for energy production, acetyl-l-carnitine (ALC), following SCI. Our published and preliminary data signify that both NACA and ALC improve mitochondrial bioenergetics following contusion SCI in rats, and that prolonged NACA or ALC treatment increases tissue sparing following injury. The planned experiments are designed to test the novel hypothesis that reducing oxidative damage to key mitochondrial proteins will maintain mitochondrial bioenergetics, thus leading to increased neuroprotection and improved functional recovery following contusion SCI. Specifically we will: 1) Characterize oxidative damage to specific mitochondrial proteins involved in bioenergetics and test the hypothesis that NACA treatment ameliorates mitochondrial oxidative damage following SCI, 2) Test the hypothesis that a combinatorial treatment with NACA and ALC will act synergistically to preserve mitochondrial homeostasis following SCI, and 3) Test the hypothesis that a combinatorial treatment with NACA and ALC will increase tissue sparing and promote long-term functional recovery following SCI. Critically, this application is built around the utilization of several novel techniques we have developed for isolating synaptic (neuronal) and non-synaptic (soma and glia) mitochondria from the injured spinal cord, as well as an L1/L2 contusion SCI paradigm that demonstrates a significant correlation between neuroprotection and remarkable improvements in recovery of hind limb function. Collectively, the proposed experiments will pinpoint key mitochondrial events that could be potential novel targets for pharmacological interventions to more effectively treat SCI and, perhaps, other CNS injuries.

描述（由申请人提供）：脊髓损伤（SCI）是美国的长期医疗保健问题，除了适度有效的甲基强度甲醇外，目前尚无神经保护干预术可用于临床治疗急性SCI。我们已发布的数据和初步结果表明，对关键线粒体酶的氧化损伤和随后的线粒体功能障碍是SCI后神经病理序列的关键。该提案的重点是直接靶向线粒体功能障碍作为挫伤SCI的新型治疗干预措施，基本概念是Sci诱导的兴奋毒性会增加线粒体CA2+循环/过载/过载，并且产生了反应性氧（ROS）（ROS），最终导致了线粒体质量和ghshathe and ghshath and ghshath and ghshath and ghshhath and ghshath and ghshhath。我们的方法是两管齐的，旨在利用一种新颖的细胞 - 磨损抗氧化剂和GSH前体，NACA（N-乙酰半胱氨酸的酰胺形式）以及替代生物燃料生产的替代生物生产，乙酰基） - 甲基甲氮氨酸（ALC），遵循替代生物燃料。我们发表的和初步的数据表明，NACA和ALC在大鼠挫伤后的SCI后都改善了线粒体生物能，并且长时间的NACA或ALC治疗会增加受伤后的组织保留。计划的实验旨在测试新的假设，即减少对关键的线粒体蛋白的氧化损伤将维持线粒体生物能量，从而导致神经保护层增加并改善inofusion SCI后的功能恢复。 Specifically we will: 1) Characterize oxidative damage to specific mitochondrial proteins involved in bioenergetics and test the hypothesis that NACA treatment ameliorates mitochondrial oxidative damage following SCI, 2) Test the hypothesis that a combinatorial treatment with NACA and ALC will act synergistically to preserve mitochondrial homeostasis following SCI, and 3) Test the hypothesis that a与NACA和ALC的组合治疗将在SCI后增加组织较高的组织并促进长期功能恢复。至关重要的是，这种应用是围绕我们开发的几种新型技术来隔离突触（神经元）和非突触（SOMA和GLIA）线粒体与受伤的脊髓的线粒体以及L1/L2 inopusion Sci范式的使用，这些线粒体表现出了明显的置于神经前测和隆重改善功能之间的折叠率。总的来说，提出的实验将指出关键的线粒体事件，这些事件可能是药理学干预措施的潜在新靶标，以更有效地治疗SCI以及其他中枢神经系统损伤。