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.

Age increases reactive oxygen species production in macrophages and potentiates oxidative damage after spinal cord injury

“…We also observed that other unidentified cells also account for ~20% ROS production at 7 dpi. These unidentified cells may be oligodendrocytes, as activation of NOX has been detected in oligodendrocytes after SCI and inhibition of NOX activity attenuates excitotocicity of oligodendrodytes (Johnstone et al, 2013). However, the most prominent gp91 phox co-localization occurred in macrophage/microglia (TomL-positive cells) at 3 and 7 dpi.…”

Demyelination as a rational therapeutic target for ischemic or traumatic brain injury

“…However, normal communication between astrocytes and oligodendrocytes through CXs is interrupted in pathological conditions, thereby resulting in oligodendrocyte death and subsequent demyelination. Activated astrocytes can also exacerbate oligodendrocyte cell death by reducing extracellular zinc concentrations, which then initiates NADPH oxidase activation within oligodendrocytes through stimulation of Ca 2+ -permeable AMPA receptors (Johnstone et al, 2013). These results show that activated astrocytes exert both positive and negative influences on oligodendrocyte pathophysiology, similar to the dual-faced nature of microglia discussed below.…”

Zonisamide-loaded triblock copolymer nanomicelles as a novel drug delivery system for the treatment of acute spinal cord injury

“…8,9 Therefore, therapeutically targeting oxidative enzymes will prevent axonal demyelination, preserve oligodendrocyte integrity and spare neuronal loss. 10 Zonisamide (1,2-benzisoxazole-3-methanesulfonamide; ZNS) is an antiepileptic drug that has already been approved for clinical use. Several clinical studies have reported the wide clinical spectrum of ZNS against both psychiatric and neurological disorders.…”