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.
The proposed research is relevant to public health because determining the extent to which age affect the efficacy of therapies for SCI will facilitate the successful translation of treatments to a growing aging SCI demographic. Moreover, understanding the mechanisms that contribute to age-related neurodegeneration is important for a number of neuropathologies. Therefore, the proposed research is relevant to the part of the NIH mission that pertains to developing fundamental knowledge and applying that knowledge to foster research strategies to reduce the burden of human disabilities.
