Abstract
BackgroundSpinal cord injury (SCI) among people over age 40 has been steadily increasing since the 1980s and is associated with worsened outcome than injuries in young people. Age-related increases in reactive oxygen species (ROS) are suggested to lead to chronic inflammation. The NADPH oxidase 2 (NOX2) enzyme is expressed by microglia and is a primary source of ROS. This study aimed to determine the effect of age on inflammation, oxidative damage, NOX2 gene expression, and functional performance with and without SCI in young adult (3 months) and middle-aged (12 months) male rats.MethodsYoung adult and middle-aged rats were assessed in two groups—naïve and moderate contusion SCI. Functional recovery was determined by weekly assessment with the Basso, Beattie, and Breshnahan general motor score (analyzed two-way ANOVA) and footprint analysis (analyzed by Chi-square analysis). Tissue was analyzed for markers of oxidative damage (8-OHdG, Oxyblot, and 3-NT), microglial-related inflammation (Iba1), NOX2 component (p47PHOX, p22PHOX, and gp91PHOX), and inflammatory (CD86, CD206, TNFα, and NFκB) gene expression (all analyzed by unpaired Student’s t test).ResultsIn both naïve and injured aged rats, compared to young rats, tissue analysis revealed significant increases in 8-OHdG and Iba1, as well as inflammatory and NOX2 component gene expression. Further, injured aged rats showed greater lesion volume rostral and caudal to the injury epicenter. Finally, injured aged rats showed significantly reduced Basso–Beattie–Bresnahan (BBB) scores and stride length after SCI.ConclusionsThese results show that middle-aged rats demonstrate increased microglial activation, oxidative stress, and inflammatory gene expression, which may be related to elevated NOX2 expression, and contribute to worsened functional outcome following injury. These findings are essential to elucidating the mechanisms of age-related differences in response to SCI and developing age-appropriate therapeutics.
Highlights
Spinal cord injury (SCI) among people over age 40 has been steadily increasing since the 1980s and is associated with worsened outcome than injuries in young people
Microglial activation and pro-inflammatory gene expression is altered with age To determine if aged tissue showed basal differences in microglial activation, uninjured tissue from 3- and 12month-old rats was immunostained with the microglial marker Iba-1 (Fig. 2a) and processed for comparative RT-PCR for expression genes associated with microglial activation and NADPH oxidase 2 (NOX2) components
Overall, the results of our study suggest that increasing age leads to a pro-inflammatory environment, with alterations to microglial activation, NOX2 enzyme component expression, and an increase in oxidative stress in the cellular environment that may contribute to worsened outcomes after
Summary
Spinal cord injury (SCI) among people over age 40 has been steadily increasing since the 1980s and is associated with worsened outcome than injuries in young people. This study aimed to determine the effect of age on inflammation, oxidative damage, NOX2 gene expression, and functional performance with and without SCI in young adult (3 months) and middle-aged (12 months) male rats. There are over 250,000 people in the USA currently living with a spinal cord injury (SCI), and over 15,000 new cases are documented every year [1]. These injuries cause permanent motor, autonomic, and sensory function loss [2]. Aging causes changes to hormones and cellular function associated with increased co-morbidities, lengthened recovery time, reduced functional recovery, and prolonged chronic inflammation after SCI [6]
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