Age-related alterations to NADPH oxidase and glial cell activation after spinal cord injury

Henry M. Jackson Fdn For The Adv Mil/Med, Rockville MD

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Abstract

? DESCRIPTION (provided by applicant): Over 250,000 people in the US are currently living with disabilities related to spinal cord injury (SCI). The number of SCI's among the aging population has been steadily increasing since the 1980's, and is associated with high rates of co-morbidities. Oxidative stress and reactive oxygen species (ROS) are increased in aging tissue and have been causally implicated in tissue damage and chronic inflammation in the central nervous system (CNS). These stressors influence the activity of glial cells, contributing to the delayed recovery to SCI seen in the aging population. No work to date has examined age-related alterations in glial cell response to SCI. The NADPH oxidase (NOX) family of enzymes is suggested to play a modulatory role in microglial/macrophage activation, inflammation and tissue damage through the production of ROS, and is chronically up-regulated after SCI. NOX, microglia and astrocytes all show altered profiles with increased inflammatory morphology and basal activation states in both human and rodent aged populations. Thus, we hypothesize that age-related upregulation in NOX activity and expression leads to increased proinflammatory glial cell activation states, resulting in exaggerated glial responses and diminished recovery to spinal cord injury. To test this hypothesis, we propose three specific aims. In aim 1, we will characterize basal glial cell activation states and NOX expression and activity in the aging rodent spinal cord. In this aim, we will use double labeled immunohistochemistry and biochemical techniques to characterize NOX and glial cell activation state in 3 and 12 month aged rats. In aim 2, we will demonstrate the effects of aging on NOX expression and activity, glial cell activation, lesion size and functional recovery after spinal cod injury. In this aim, we will assess NOX and glial cell activation after a moderate contusion SCI in 3 and 12 month aged rats using immunohistochemistry, biochemistry, RT-qPCR and functional assessment. In aim 3, we will evaluate the effect of inhibition of NOX activity and expression on basal glial activation and response to injury. In this aim, we will assess the modulatory effects o NOX on microglia and astrocyte activation in aged rats using a NOX2 specific inhibitor. This effect will be investigated using immunohistochemistry, biochemistry, subcellular fractionation and functional assessment. The data generated in these aims will help to guide researchers and clinicians in more effective diagnosis and may provide important insight into potential future therapeutic targets for SCI in the aging population.