title: Inhibition of NADPH oxidase activation in oligodendrocytes reduces cytotoxicity following trauma.
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.
authors.affiliation: The Miami Project to Cure Paralysis, University of Miami, Miami, Florida, United States of America.
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Johnstone
authors.forename: Paul D
authors.initials: PD
authors.lastname: Morton
authors.forename: Arumugam R
authors.initials: AR
authors.lastname: Jayakumar
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Johnstone
authors.forename: Han
authors.initials: H
authors.lastname: Gao
authors.forename: Valerie
authors.initials: V
authors.lastname: Bracchi-Ricard
authors.forename: Damien D
authors.initials: DD
authors.lastname: Pearse
authors.forename: Michael D
authors.initials: MD
authors.lastname: Norenberg
authors.forename: John R
authors.initials: JR
authors.lastname: Bethea
mesh_terms: D000098:Acetophenones / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001369:Axons / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D008124:Locomotion / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D018384:Oxidative Stress; D061251:Primary Cell Culture; D011810:Quinoxalines / Q000494:pharmacology; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology
chemical_list: D000098:Acetophenones; D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D008562:Membrane Glycoproteins; D011810:Quinoxalines; D018091:Receptors, AMPA; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; C056165:acetovanillone; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases