Role of Age on Anti-oxidant Defense in Spinal Cord Injury: Physiological Changes and Intervention

年龄对脊髓损伤抗氧化防御的作用：生理变化和干预

• 批准号: 9906759
• 负责人: Andrew Nathaniel Stewart
• 金额: $ 6.53万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2021-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906759
• 关键词: Affect; Age; Aging; Animal Model; Animals; Antioxidants; Biochemical Process; Biological Assay; Buthionine Sulfoximine; Cell Death; Cells; Clinical; Contusions; Data; Defense Mechanisms; Dependence; Dose; Enzymes; Equilibrium; Exposure to; Fostering; Functional disorder; Glutathione; Histologic; Homeostasis; Human; Individual; Inflammation; Inflammatory Response; Injury; Intervention; Knowledge; Laboratories; Measures; Mediating; Mediator of activation protein; Mission; Modeling; Motor; Mus; N-Acetylcysteinamide; NADPH Oxidase; Neurosciences; Older Population; Outcome; Oxidation-Reduction; Physiological; Pre-Clinical Model; Production; Public Health; Rattus; Reactive Oxygen Species; Recovery of Function; Reduced Glutathione; Reporting; Research; Role; Spinal Cord; Spinal Cord Contusions; Spinal cord injury; Testing; Therapeutic; Tissues; Translations; Treatment Efficacy; United States National Institutes of Health; Work; acetovanillone; age effect; age related; age related neurodegeneration; aged; analog; base; cell age; disability; efficacy testing; experience; experimental study; functional outcomes; functional restoration; improved; improved outcome; inhibitor/antagonist; juvenile animal; mature animal; mouse model; nervous system disorder; neuropathology; neuroprotection; pre-clinical; targeted treatment; therapy development; translational impact; treatment response; young adult

Since the 1970’s the average age that a spinal cord injury (SCI) occurs has shifted towards older populations, from age 29 to 42. Further, both clinical and pre-clinical reports reveal age as an important predictor of functional recovery following SCI. Despite this, the use of younger adult animals prevails in pre-clinical SCI models. Increasingly, age-dependent inflammatory responses and reactive oxygen species-mediated damage are implicated in the pathophysiology of SCI deficits. Although not yet explored in the context of SCI, age reduces cellular anti-oxidant capacity through diminished levels of glutathione, a critical anti-oxidant regulating redox balance within all cells. Collectively, an increase in ROS production with a decrease in anti-oxidant defense leaves aged cells more susceptible to ROS-mediated damage and can result in cell death. Characterization of redox balance within the aged spinal cord before and after injury is needed to evaluate the therapeutic potential of strategies aimed at increasing cellular anti-oxidant defense. One such strategy is treatment using N-acetylcysteineamide (NACA), which increases intracellular glutathione and results in anti- oxidant protection against ROS. Treatment using NACA, or similar analogs, have demonstrated therapeutic efficacy in animal models of SCI when used to treat young SCI conditions. The proposed work will determine the anti-oxidant capabilities and redox state of aged and young spinal cords before and after SCI, as well as test the efficacy of NACA as a free radicle scavenging treatment to restore function and improve outcomes in a contusive mouse model of SCI. The specific hypotheses are two-fold: 1) intracellular anti-oxidant capacity within the spinal cord diminishes with age and is further reduced as a consequence of SCI, and 2) treatment efficacy using NACA is age-dependent following SCI and will elicit a larger therapeutic response in aged mice. Aim 1 will determine the extent that intracellular anti-oxidant defense mediates protection against ROS in aged and young spinal cords. Aim 2 will determine the extent to which the therapeutic efficacy of ROS scavenging after spinal cord contusion is age-dependent. Collectively, the data from these studies will aid in the development of therapies to treat SCI individuals of all ages. Further, elucidating the mechanisms of age- related neurodegeneration will advance the fields of aging and neuroscience.

自20世纪70年代以来，脊髓损伤（SCI）发生的平均年龄已向老年人群转移， 从29岁到42岁此外，临床和临床前报告都显示年龄是一个重要的预测因素， SCI后的功能恢复尽管如此，在临床前SCI中使用年轻的成年动物是普遍的。 模型越来越多的年龄依赖性炎症反应和活性氧介导的损伤 与SCI缺陷的病理生理学有关。尽管尚未在SCI的背景下进行探讨， 通过减少谷胱甘肽水平降低细胞抗氧化能力，谷胱甘肽是一种关键的抗氧化调节剂， 所有细胞内的氧化还原平衡。总的来说，随着抗氧化剂的减少，ROS的产生增加， 防御使衰老细胞更容易受到ROS介导的损伤，并可能导致细胞死亡。 需要表征损伤前后老年脊髓内的氧化还原平衡，以评估损伤后脊髓内的氧化还原平衡。 旨在增加细胞抗氧化防御的策略的治疗潜力。一种这样的策略是 使用N-乙酰半胱氨酸酰胺（NACA）治疗，其增加细胞内谷胱甘肽并导致抗- 对ROS的氧化保护。使用NACA或类似物的治疗已经证明具有治疗性。 当用于治疗年轻SCI病症时，SCI动物模型的有效性。拟议的工作将决定 老年和年轻脊髓在SCI前后的抗氧化能力和氧化还原状态，以及 测试NACA作为自由基清除治疗恢复功能和改善预后的有效性， 脊髓损伤挫伤小鼠模型。具体的假设有两个方面：1）细胞内抗氧化能力 随着年龄的增长，脊髓内的神经元数量减少，并由于SCI而进一步减少，以及2）治疗 使用NACA的功效在SCI后是年龄依赖性的，并且将在老年小鼠中引起更大的治疗反应。 目的1将确定细胞内抗氧化防御介导的保护作用在多大程度上对ROS的老年人， 和年轻的脊髓目的2将确定ROS清除的治疗效果的程度 脊髓挫伤后的症状与年龄有关总的来说，这些研究的数据将有助于 开发治疗所有年龄段SCI患者的疗法。此外，阐明年龄的机制- 相关的神经变性将推动衰老和神经科学领域的发展。