9
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      Neutral sphingomyelinase activation precedes NADPH oxidase-dependent damage in neurons exposed to the proinflammatory cytokine tumor necrosis factor-α.

      Journal of Neuroscience Research
      Animals, Apoptosis, drug effects, Cell Membrane, metabolism, Ceramides, Cerebral Cortex, cytology, Chick Embryo, Drug Interactions, Enzyme Inhibitors, pharmacology, Growth Cones, physiology, Humans, Magnesium, NADPH Oxidase, Neurites, Neuroblastoma, pathology, Neurons, enzymology, Palmitates, Phosphotransferases (Alcohol Group Acceptor), RNA, Small Interfering, Reactive Oxygen Species, Sphingomyelin Phosphodiesterase, Tumor Necrosis Factor-alpha, toxicity

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Inflammation accompanied by severe oxidative stress plays a vital role in the orchestration and progression of neurodegeneration prevalent in chronic and acute central nervous system pathologies as well as in aging. The proinflammatory cytokine tumor necrosis factor-α (TNFα) elicits the formation of the bioactive ceramide by stimulating the hydrolysis of the membrane lipid sphingomyelin by sphingomyelinase activities. Ceramide stimulates the formation of reactive oxygen species (ROS) and apoptotic mechanisms in both neurons and nonneuronal cells, establishing a link between sphingolipid metabolism and oxidative stress. We demonstrated in SH-SY5Y human neuroblastoma cells and primary cortical neurons that TNFα is a potent stimulator of Mg(2+) -dependent neutral sphingomyelinase (Mg(2+) -nSMase) activity, and sphingomyelin hydrolysis, rather than de novo synthesis, was the predominant source of ceramide increases. Mg(2+) -nSMase activity preceded an accumulation of ROS by a neuronal NADPH oxidase (NOX). Notably, TNFα provoked an NOX-dependent oxidative damage to sphingosine kinase-1, which generates sphingosine-1-phosphate, a ceramide metabolite associated with neurite outgrowth. Indeed, ceramide and ROS inhibited neurite outgrowth of dorsal root ganglion neurons by disrupting growth cone motility. Blunting ceramide and ROS formation both rescued sphingosine kinase-1 activity and neurite outgrowth. Our studies suggest that TNFα-mediated activation of Mg(2+) -nSMase and NOX in neuronal cells not only produced the neurotoxic intermediates ceramide and ROS but also directly antagonized neuronal survival mechanisms, thus accelerating neurodegeneration. Copyright © 2011 Wiley Periodicals, Inc.

          Related collections

          Author and article information

          Comments

          Comment on this article