Abstract
We designed a series of experiments to explore the neuroprotective effects of insulin. Insulin significantly inhibited the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-induced neuronal cell damage as evidenced by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium-bromide (MTT) assay. However, insulin had little affect on the AMPA-induced glial cell damage. To determine whether insulin inhibits AMPA-induced excitotoxicity, we performed grease-gap recording assays using rat brain slices. In these experiments, insulin also significantly inhibited AMPA-induced depolarization. Flow cytometry and DNA fragmentation assays showed that insulin inhibits AMPA-induced apoptosis and DNA fragmentation, respectively. Insulin stimulated protein kinase B (Akt) activity, whereas AMPA pretreatment did not alter the insulin-stimulated Akt activity. On the contrary, insulin blocked induction of SAPK/JNK, which AMPA stimulated. Taken together, these results suggest that insulin exerts neuroprotective effects by inhibiting AMPA-induced excitotoxicity and apoptosis, possibly by activating Akt and blocking SAPK/JNK.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line
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Dose-Response Relationship, Drug
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Enzyme Activation / drug effects
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Enzyme Activation / physiology
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In Vitro Techniques
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Insulin / pharmacology*
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Insulin / therapeutic use
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Male
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Nerve Degeneration / drug therapy
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Nerve Degeneration / metabolism
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Nerve Degeneration / pathology
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Neural Inhibition / drug effects*
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Neural Inhibition / physiology
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Neurons / drug effects*
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Neurons / metabolism
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Neurons / pathology
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Neuroprotective Agents / pharmacology*
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Neuroprotective Agents / therapeutic use
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Protein Serine-Threonine Kinases / metabolism*
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Protein Serine-Threonine Kinases / physiology
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins / physiology
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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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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / antagonists & inhibitors*
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / toxicity*
Substances
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Insulin
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Neuroprotective Agents
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Proto-Oncogene Proteins
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
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Akt1 protein, rat
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt