Abstract
Tumor necrosis factor-alpha is thought to be one of the most important inflammatory cytokines associated with the demyelinating disease multiple sclerosis. We determined whether neurotrophins could protect oligodendrocytes from tumor necrosis factor-alpha-mediated cytotoxicity. Among the neurotrophins tested, nerve growth factor was most effective at preventing cell death. Nerve growth factor also prevented the tumor necrosis factor-induced loss of mitochondrial membrane potential. Overexpression of constitutively active Akt, a downstream target of phosphatidylinositol 3-kinase, but not of constitutively active MEK, protected oligodendrocytes from tumor necrosis factor-induced injury. Moreover, overexpression of dominant-negative Akt negated the protective effects of nerve growth factor on tumor necrosis factor-mediated oligodendrocyte cytotoxicity. These findings indicate that the Akt pathway is crucial in nerve growth factor-mediated oligodendrocyte protection.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Androstadienes / pharmacology
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Animals
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Brain / 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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Chromones / pharmacology
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Culture Media, Conditioned / pharmacology
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Humans
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Immunohistochemistry
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Membrane Potentials / drug effects
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Mitochondria / metabolism
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Morpholines / pharmacology
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Nerve Growth Factor / pharmacology*
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Oligodendroglia / metabolism*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Proto-Oncogene Proteins c-akt
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Proto-Oncogene Proteins*
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Rats
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Signal Transduction*
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Tumor Necrosis Factor-alpha / pharmacology*
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Wortmannin
Substances
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Androstadienes
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Chromones
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Culture Media, Conditioned
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Morpholines
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Proto-Oncogene Proteins
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Tumor Necrosis Factor-alpha
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Nerve Growth Factor
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AKT1 protein, human
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Akt1 protein, rat
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Wortmannin