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.
Highlights
Oxidative stress and reactive oxygen species (ROS) production play a predominant role in the secondary injury mechanisms of spinal cord injury (SCI) [1]
Using a transgenic mouse expressing a dominant negative form of the inhibitor of κBα (IκBα) protein under the control of the glial fibrillary acidic protein (GFAP) promoter (GFAP-IκBαdn), we showed that prevention of NF-κB activation in astrocytes significantly improved hind limb locomotor recovery and preserved myelin and axon tracts following a moderate contusion SCI [17,18] suppression of astroglial NF – κB activation after trauma resulted in a reduction in oligodendrocyte death by preventing zinc uptake by astrocytes [16]
We showed that media taken from injured WT astrocytes can elicit oligodendrocyte death in vitro, while media from injured GFAPIκBα-dn astrocytes failed to elicit oligodendrocyte death
Summary
Oxidative stress and reactive oxygen species (ROS) production play a predominant role in the secondary injury mechanisms of spinal cord injury (SCI) [1]. There are many enzymes that produce ROS, recent studies have demonstrated that under conditions of glutamate excitotoxicity, oxidative stress and free radical production are mediated by increased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity [5]. Treatment with the NADPH oxidase inhibitor apocynin, or genetic deletion of the p47 phox subunit of the NADPH oxidase complex, was sufficient to block NMDA-stimulated superoxide production and attenuate neuronal death [5]. These studies identified NADPH oxidase as a key downstream regulator of glutamate receptor-mediated excitotoxic cell death mechanisms
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