Advanced Age and Neurotrauma Diminish Glutathione and Impair Antioxidant Defense after Spinal Cord Injury

Andrew N. Stewart, Ethan P. Glaser, Caitlin A. Mott, William M. Bailey, Patrick Sullivan, Samirkumar Patel, John C. Gensel

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Advanced age at the time of spinal cord injury (SCI) exacerbates damage from reactive oxygen species (ROS). Mechanisms underlying this age-dependent response are not well understood and may arise from decreased antioxidant defense. We investigated how spinal cord levels of the antioxidant glutathione (GSH), and its regulation, change with age and SCI. GSH is used by GSH peroxidase to sequester ROS and is recycled by GSH reductase. Male and female, 4- and 14-month-old (MO) mice received a 60 kDyn contusion SCI, and the levels of GSH and its regulatory enzymes were evaluated at one and three days post-injury (dpi). The mice with SCI were treated with N-acetylcysteine-amide (NACA; 150 mg/kg), a cysteine supplement that increases GSH, to determine effects on functional and histological outcomes. GSH was decreased with older age in sham mice, and an SCI-dependent depletion was observed in 4-MO mice by three dpi. Neither age nor injury affected the abundance of proteins regulating GSH synthesis or recycling. GSH peroxidase activity, however, increased after SCI only in 4-MO mice. In contrast, GSH peroxidase activity was increased in 14-MO sham mice, indicating that spinal cords of older mice have an elevated oxidative state. Indeed, 14-MO sham mice had more oxidized protein (3-nitrotyrosine [3-NT]) within their spinal cords compared with 4-MO sham mice. Only 4-MO mice had significant injury-induced increases in 3-NT at three dpi. NACA treatment restored GSH and improved the redox environment in injured 4- and 14-MO mice at one dpi; however, three days of NACA delivery did not improve motor, sensory, or anatomical deficits at 28 dpi in 4-MO mice and trended toward toxicity in all outcomes in 14-MO mice. Our observation suggests that GSH levels at acute stages of SCI play a minimal role in age-dependent outcomes reported after SCI in mice. Collective results implicate elements of injury occurring after three dpi, such as inflammation, as key regulators of age-dependent effects.

Original languageEnglish
Pages (from-to)1075-1089
Number of pages15
JournalJournal of Neurotrauma
Volume39
Issue number15-16
DOIs
StatePublished - Aug 1 2022

Bibliographical note

Funding Information:
Funding support provided by: The Craig H. Neilsen Foundation under award #465079, the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health (NIH) under Awards: R01NS091582 and F32NS111241, as well as the National Institute on Alcohol Abuse and Alcoholism training grant T32AA027488, and the University of Kentucky Neuroscience Research Priority Area.

Publisher Copyright:
© 2022 Andrew N. Stewart et al.

Keywords

  • aging
  • neuroprotection
  • neurotrauma
  • oxidative stress
  • Redox
  • sex differences

ASJC Scopus subject areas

  • Clinical Neurology

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