Abstract
Neurotrophins protect neurons against glutamate excitotoxicity, but the signaling mechanisms have not been fully elucidated. We studied the role of the phosphatidylinositol 3-kinase (PI3-K) and Ras/mitogen-activated protein kinase (MAPK) pathways in the protection of cultured hippocampal neurons from glutamate induced apoptotic cell death, characterized by nuclear condensation and activation of caspase-3-like enzymes. Pre-incubation with the neurotrophin brain-derived neurotrophic factor (BDNF), for 24 h, reduced glutamate-evoked apoptotic morphology and caspase-3-like activity, and transiently increased the activity of the PI3-K and of the Ras/MAPK pathways. Inhibition of the PI3-K and of the Ras/MAPK signaling pathways abrogated the protective effect of BDNF against glutamate-induced neuronal death and similar effects were observed upon inhibition of protein synthesis. Moreover, incubation of hippocampal neurons with BDNF, for 24 h, increased Bcl-2 protein levels. The results indicate that the protective effect of BDNF in hippocampal neurons against glutamate toxicity is mediated by the PI3-K and the Ras/MAPK signaling pathways, and involves a long-term change in protein synthesis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects*
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Apoptosis / physiology
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Brain-Derived Neurotrophic Factor / pharmacology*
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Caspase 3
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Caspases / biosynthesis
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Cell Survival
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Down-Regulation / drug effects
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Extracellular Signal-Regulated MAP Kinases / metabolism*
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Glutamic Acid / toxicity*
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Hippocampus / cytology
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Hippocampus / drug effects*
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Hippocampus / enzymology
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Hippocampus / metabolism
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MAP Kinase Signaling System / drug effects
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MAP Kinase Signaling System / physiology
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Neurons / cytology
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Neurons / drug effects*
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Neurons / enzymology
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Neurons / metabolism
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Neuroprotective Agents / pharmacology*
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Phosphatidylinositol 3-Kinases / metabolism*
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Rats
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Rats, Wistar
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Transfection
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ras Proteins / metabolism
Substances
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Brain-Derived Neurotrophic Factor
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Neuroprotective Agents
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Glutamic Acid
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases
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Casp3 protein, rat
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Caspase 3
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Caspases
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ras Proteins