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

自20世纪70年代S以来，脊髓损伤(SCI)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，年龄是一种重要的预测因素。 脊髓损伤后的功能恢复。尽管如此，年轻成年动物的使用在临床前脊髓损伤中占主导地位 模特们。年龄依赖性炎症反应和活性氧介导的损伤越来越多 与脊髓损伤缺陷的病理生理学有关。虽然还没有在SCI的背景下进行探讨，但年龄 通过降低谷胱甘肽的水平来降低细胞的抗氧化能力，谷胱甘肽是关键的抗氧化调节物质 所有细胞内的氧化还原平衡。总体而言，ROS产量的增加与抗氧化剂的减少 防御使老化的细胞更容易受到ROS介导的损伤，并可能导致细胞死亡。 老年脊髓损伤前后氧化还原平衡的特征需要评估 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-乙酰半胱胺(NACA)治疗，它增加细胞内谷胱甘肽并导致抗- 氧化剂对ROS的保护。使用NACA或类似物的治疗已经证明是有效的 脊髓损伤动物模型治疗幼年脊髓损伤的疗效。拟议的工作将确定 脊髓损伤前后老龄和幼龄脊髓的抗氧化能力和氧化还原状态 测试NACA作为自由基清除疗法在恢复功能和改善预后方面的疗效 脊髓挫伤小鼠模型。具体的假设有两个：1)细胞内的抗氧化能力 脊髓内的损伤随着年龄的增长而减少，并且由于脊髓损伤和2)治疗而进一步减少 在脊髓损伤后使用NACA的疗效与年龄有关，并将在老龄小鼠中引起更大的治疗反应。 目标1将确定细胞内抗氧化防御在多大程度上介导了老年人对ROS的保护 和年轻的脊髓。目标2将确定清除ROS的治疗效果的程度 脊髓挫伤后是年龄依赖性的。总的来说，这些研究的数据将有助于 开发治疗所有年龄段的脊髓损伤患者的治疗方法。进一步，阐明年龄的机制-- 相关的神经退行性变将推动衰老和神经科学领域的发展。

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.