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Mitochondrial-Targeted Therapeutics for Treatment of Spinal Cord Injury

线粒体靶向疗法治疗脊髓损伤

基本信息

批准号：
8655180
负责人：
Alexander George Rabchevsky
金额：
$ 32.16万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-15 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8655180
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

项目摘要

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）在美国是一个长期的医疗保健问题，除了适度有效的甲基强的松龙外，目前临床上没有可用于治疗急性SCI的神经保护干预。我们发表的数据和初步结果表明，氧化损伤的关键线粒体酶和随后的线粒体功能障碍是关键的神经病理后遗症后SCI。该提案侧重于直接靶向线粒体功能障碍作为挫伤SCI的新型治疗干预，其基本概念是SCI诱导的兴奋性毒性增加线粒体Ca 2+循环/过载和活性氧（ROS）的产生，最终导致线粒体功能障碍和谷胱甘肽（GSH）耗尽。我们的方法是双管齐下的，旨在利用一种新型的、渗透细胞的抗氧化剂和GSH前体NACA（N-乙酰半胱氨酸的酰胺形式）以及一种用于能源生产的替代生物燃料底物乙酰基-l-肉毒碱（ALC）减少线粒体活性氧的产生。SCI后。我们发表的和初步的数据表明，NACA和ALC都改善了大鼠挫伤SCI后的线粒体生物能量学，并且长期NACA或ALC治疗增加了损伤后的组织保护。计划中的实验旨在测试新的假设，即减少对关键线粒体蛋白的氧化损伤将维持线粒体生物能量学，从而导致挫伤SCI后增加神经保护和改善功能恢复。具体而言，我们将：1）表征参与生物能量学的特定线粒体蛋白的氧化损伤，并测试NACA治疗改善SCI后线粒体氧化损伤的假设，2）测试NACA和ALC的组合治疗将协同作用以保持SCI后线粒体稳态的假设，和3）检验NACA和ALC联合治疗将增加SCI后的组织保留并促进长期功能恢复的假设。重要的是，该应用是建立在利用我们已经开发的用于从损伤的脊髓中分离突触（神经元）和非突触（索马和神经胶质）线粒体的几种新技术，以及证明神经保护和后肢功能恢复的显著改善之间的显著相关性的L1/L2挫伤SCI范例的基础上。总的来说，拟议的实验将确定关键的线粒体事件，这些事件可能是药物干预的潜在新靶点，以更有效地治疗SCI和其他CNS损伤。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Delivery of mitoceuticals or respiratory competent mitochondria to sites of neurotrauma.

DOI：
10.1016/j.mito.2022.11.001
发表时间：
2023-01
期刊：
MITOCHONDRION
影响因子：
4.4
作者：
Patel, Samir P.;Michael, Felicia M.;Gollihue, Jenna L.;Hubbard, W. Brad;Sullivan, Patrick G.;Rabchevsky, Alexander G.
通讯作者：
Rabchevsky, Alexander G.

Intraspinal Plasticity Associated With the Development of Autonomic Dysreflexia After Complete Spinal Cord Injury.

椎管内可塑性与脊髓完全损伤后自主神经反射异常的发展相关。