Reduction of potassium currents and phosphatidylinositol 3-kinase-dependent AKT phosphorylation by tumor necrosis factor-(alpha) rescues axotomized retinal ganglion cells from retrograde cell death in vivo

J Neurosci. 2001 Mar 15;21(6):2058-66. doi: 10.1523/JNEUROSCI.21-06-02058.2001.

Abstract

Tumor-necrosis-factor-alpha (TNF-alpha) prevented secondary death of retinal ganglion cells (RGCs) after axotomy of the optic nerve in vivo. This RGC rescue was confirmed in vitro in a mixed retinal culture model. In accordance with our previous findings, TNF-alpha decreased outward potassium currents in RGCs. Antagonism of the TNF-alpha-induced decrease in outward potassium currents with the potassium channel opener minoxidilsulfate (as verified by electrophysiology) abolished neuroprotection. Western blot analysis revealed an upregulation of phospho-Akt as a consequence of TNF-alpha-induced potassium current reduction. Inhibition of the phosphatidylinositol 3-kinase-Akt pathway with wortmannin decreased TNF-alpha-promoted RGC survival. These data point to a functionally relevant cytokine-dependent neuroprotective signaling cascade in adult CNS neurons.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / metabolism
  • Axotomy
  • Blotting, Western
  • Brain-Derived Neurotrophic Factor / metabolism
  • Cell Death / drug effects
  • Cell Survival / drug effects
  • Cells, Cultured
  • Drug Administration Routes
  • Enzyme Inhibitors / pharmacology
  • Female
  • Minoxidil / analogs & derivatives
  • Minoxidil / pharmacology
  • Patch-Clamp Techniques
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation / drug effects
  • Potassium Channels / drug effects
  • Potassium Channels / metabolism*
  • Protein Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Tumor Necrosis Factor / genetics
  • Receptors, Tumor Necrosis Factor / metabolism
  • Receptors, Tumor Necrosis Factor, Type I
  • Retinal Ganglion Cells / drug effects
  • Retinal Ganglion Cells / metabolism*
  • Signal Transduction / drug effects
  • Tumor Necrosis Factor-alpha / administration & dosage
  • Tumor Necrosis Factor-alpha / metabolism*
  • Up-Regulation

Substances

  • Antigens, CD
  • Brain-Derived Neurotrophic Factor
  • Enzyme Inhibitors
  • Phosphoinositide-3 Kinase Inhibitors
  • Potassium Channels
  • Proto-Oncogene Proteins
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Type I
  • Tumor Necrosis Factor-alpha
  • minoxidil sulfate ester
  • Minoxidil
  • Akt1 protein, rat
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt