Inhibition of NADPH oxidase activation in oligodendrocytes reduces cytotoxicity following trauma

Joshua T. Johnstone, Paul D. Morton, Arumugam R. Jayakumar, Andrea L. Johnstone, Han Gao, Valerie Bracchi-Ricard, Damien D Pearse, Michael D Norenberg, John R. Bethea

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Spinal cord injury is a debilitating neurological disorder that initiates a cascade of cellular events that result in a period of secondary damage that can last for months after the initial trauma. The ensuing outcome of these prolonged cellular perturbations is the induction of neuronal and glial cell death through excitotoxic mechanisms and subsequent free radical production. We have previously shown that astrocytes can directly induce oligodendrocyte death following trauma, but the mechanisms regulating this process within the oligodendrocyte remain unclear. Here we provide evidence demonstrating that astrocytes directly regulate oligodendrocyte death after trauma by inducing activation of NADPH oxidase within oligodendrocytes. Spinal cord injury resulted in a significant increase in oxidative damage which correlated with elevated expression of the gp91 phox subunit of the NADPH oxidase enzyme. Immunohistochemical analysis confirmed the presence of gp91 phox in oligodendrocytes in vitro and at 1 week following spinal cord injury. Exposure of oligodendrocytes to media from injured astrocytes resulted in an increase in oligodendrocyte NADPH oxidase activity. Inhibition of NADPH oxidase activation was sufficient to attenuate oligodendrocyte death in vitro and at 1 week following spinal cord injury, suggesting that excitotoxicity of oligodendrocytes after trauma is dependent on the intrinsic activation of the NADPH oxidase enzyme. Acute administration of the NADPH oxidase inhibitor apocynin and the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate channel blocker 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione significantly improved locomotor behavior and preserved descending axon fibers following spinal cord injury. These studies lead to a better understanding of oligodendrocyte death after trauma and identify potential therapeutic targets in disorders involving demyelination and oligodendrocyte death.

Original languageEnglish
Article numbere80975
JournalPLoS One
Volume8
Issue number11
DOIs
StatePublished - Nov 19 2013

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NADPH Oxidase
Oligodendroglia
Cytotoxicity
cytotoxicity
Chemical activation
Wounds and Injuries
Spinal Cord Injuries
spinal cord
death
astrocytes
Astrocytes
Propionates
Cell death
Enzymes
Free Radicals
oligodendroglia
NAD(P)H oxidase (H2O2-forming)
quinoxalines
nervous system diseases
neuroglia

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Johnstone, J. T., Morton, P. D., Jayakumar, A. R., Johnstone, A. L., Gao, H., Bracchi-Ricard, V., ... Bethea, J. R. (2013). Inhibition of NADPH oxidase activation in oligodendrocytes reduces cytotoxicity following trauma. PLoS One, 8(11), [e80975]. https://doi.org/10.1371/journal.pone.0080975

Inhibition of NADPH oxidase activation in oligodendrocytes reduces cytotoxicity following trauma. / Johnstone, Joshua T.; Morton, Paul D.; Jayakumar, Arumugam R.; Johnstone, Andrea L.; Gao, Han; Bracchi-Ricard, Valerie; Pearse, Damien D; Norenberg, Michael D; Bethea, John R.

In: PLoS One, Vol. 8, No. 11, e80975, 19.11.2013.

Research output: Contribution to journalArticle

Johnstone, JT, Morton, PD, Jayakumar, AR, Johnstone, AL, Gao, H, Bracchi-Ricard, V, Pearse, DD, Norenberg, MD & Bethea, JR 2013, 'Inhibition of NADPH oxidase activation in oligodendrocytes reduces cytotoxicity following trauma', PLoS One, vol. 8, no. 11, e80975. https://doi.org/10.1371/journal.pone.0080975
Johnstone JT, Morton PD, Jayakumar AR, Johnstone AL, Gao H, Bracchi-Ricard V et al. Inhibition of NADPH oxidase activation in oligodendrocytes reduces cytotoxicity following trauma. PLoS One. 2013 Nov 19;8(11). e80975. https://doi.org/10.1371/journal.pone.0080975
Johnstone, Joshua T. ; Morton, Paul D. ; Jayakumar, Arumugam R. ; Johnstone, Andrea L. ; Gao, Han ; Bracchi-Ricard, Valerie ; Pearse, Damien D ; Norenberg, Michael D ; Bethea, John R. / Inhibition of NADPH oxidase activation in oligodendrocytes reduces cytotoxicity following trauma. In: PLoS One. 2013 ; Vol. 8, No. 11.
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