title: Oxygen radicals elicit paralysis and collapse of spinal cord neuron growth cones upon exposure to proinflammatory cytokines.
abstract: A persistent inflammatory and oxidative stress is a hallmark of most chronic CNS pathologies (Alzheimer's (ALS)) as well as the aging CNS orchestrated by the proinflammatory cytokines tumor necrosis factor alpha (TNFα) and interleukin-1 beta (IL-1β). Loss of the integrity and plasticity of neuronal morphology and connectivity comprises an early step in neuronal degeneration and ultimate decline of cognitive function. We examined in vitro whether TNFα or IL-1β impaired morphology and motility of growth cones in spinal cord neuron cultures. TNFα and IL-1β paralyzed growth cone motility and induced growth cone collapse in a dose-dependent manner reflected by complete attenuation of neurite outgrowth. Scavenging reactive oxygen species (ROS) or inhibiting NADPH oxidase activity rescued loss of neuronal motility and morphology. TNFα and IL-1β provoked rapid, NOX-mediated generation of ROS in advancing growth cones, which preceded paralysis of motility and collapse of morphology. Increases in ROS intermediates were accompanied by an aberrant, nonproductive reorganization of actin filaments. These findings suggest that NADPH oxidase serves as a pivotal source of oxidative stress in neurons and together with disruption of actin filament reorganization contributes to the progressive degeneration of neuronal morphology in the diseased or aging CNS.
authors: Department of Chemistry and Biochemistry, University of Alaska Fairbanks, 900 Yukon Drive, Reichardt Building, Room 194, Fairbanks, AK 99775-6150, USA.
authors: Thomas B
authors: TB
authors: Kuhn
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D066146:Cell Body / Q000187:drug effects / Q000378:metabolism; D002642:Chick Embryo; D020439:Growth Cones / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D018836:Inflammation Mediators / Q000633:toxicity*; D053583:Interleukin-1beta / Q000633:toxicity*; D008954:Models, Biological; D019255:NADPH Oxidases / Q000378:metabolism; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D010243:Paralysis / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000633:toxicity*; D013116:Spinal Cord / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D018836:Inflammation Mediators; D053583:Interleukin-1beta; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D019255:NADPH Oxidases; D020830:rac1 GTP-Binding Protein