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
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, CD / genetics
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Antigens, CD / metabolism
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Axotomy
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Blotting, Western
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Brain-Derived Neurotrophic Factor / metabolism
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Cell Death / drug effects
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Cell Survival / drug effects
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Cells, Cultured
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Drug Administration Routes
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Enzyme Inhibitors / pharmacology
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Female
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Minoxidil / analogs & derivatives
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Minoxidil / pharmacology
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Patch-Clamp Techniques
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation / drug effects
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Potassium Channels / drug effects
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Potassium Channels / metabolism*
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-akt
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Rats
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Rats, Sprague-Dawley
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Receptors, Tumor Necrosis Factor / genetics
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Receptors, Tumor Necrosis Factor / metabolism
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Receptors, Tumor Necrosis Factor, Type I
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Retinal Ganglion Cells / drug effects
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Retinal Ganglion Cells / metabolism*
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Signal Transduction / drug effects
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Tumor Necrosis Factor-alpha / administration & dosage
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Tumor Necrosis Factor-alpha / metabolism*
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Up-Regulation
Substances
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Antigens, CD
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Brain-Derived Neurotrophic Factor
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Enzyme Inhibitors
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Phosphoinositide-3 Kinase Inhibitors
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Potassium Channels
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Proto-Oncogene Proteins
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Receptors, Tumor Necrosis Factor
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Receptors, Tumor Necrosis Factor, Type I
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Tumor Necrosis Factor-alpha
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minoxidil sulfate ester
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Minoxidil
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Akt1 protein, rat
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt