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.