NRSA Fellowship for A. Stewart: Role of Age on Anti-Oxidant Defense in Spinal Cord Injury: Physiological Changes and Intervention

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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 have revealed age as an important indicator of functional outcomes following SCI. Despite this, the use of younger adult animals prevails in pre-clinical SCI models. Recently, our lab has found critical evidence that demonstrates secondary injury mechanisms increase with age and result in worse functional outcomes. Specifically, we have found an up regulation of NADPH oxidase in aged macrophages within the SCI lesion, which manifests in increased reactive oxygen species (ROS) production and exacerbated tissue damage. Although not yet explored in the context of the spinal cord or SCI, age has been found to also reduce 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 aims are as follows: Aim 1: Determine the extent that intracellular anti-oxidant defense mediates protection against ROS in aged and young spinal cord. Aim 2: Determine the extent to which the therapeutic efficacy of ROS scavenging after spinal cord contusion is age-dependent. Hypothesis: The specific hypothesis for these aims are: 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. Project Narrative For the successful translation of therapeutics into humans, it is imperative to model SCI to match the aging demographic. Characterizing the redox potential of the aging spinal cord will determine the need for developing therapeutic strategies aimed at enhancing intracellular anti-oxidant defense. Further, the extent that increasing anti-oxidant defense can protect against ROS-mediated tissue damage will be explor
Effective start/end date4/1/1910/31/21


  • National Institute of Neurological Disorders & Stroke: $34,281.00


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