Abstract
Protein kinase B (PKB, or Akt), a downstream effector of phosphatidylinositol 3-kinase (PI-3-K), can play a critical role in regulating neuronal survival. Among known targets of PKB, glycogen synthase kinase-3 (GSK-3) is inhibited by PKB-mediated phosphorylation. Recent studies implicate GSK-3 as a physiologically relevant principal regulatory target of the PI-3-K/PKB survival pathway. Here we show that SB-216763 and SB-415286, selective small molecule inhibitors of GSK-3, protected cultured rat cerebellar granule neurons and hippocampal neurons against excitotoxicity mediated by NMDA and non-NMDA receptor agonists. Treatment with SB-216763 and SB-415286 was optimal when initiated 6-7 days before excitotoxin exposure. As GSK-3 can modulate transcriptional events, these results may provide insight into the identification of new neuroprotective targets.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aminophenols / pharmacology
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Animals
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Cell Survival / drug effects
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Cells, Cultured
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Central Nervous System / cytology*
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Central Nervous System / drug effects*
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Cerebellum / cytology
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Cerebellum / drug effects
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Enzyme Inhibitors / pharmacology*
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Excitatory Amino Acid Agonists / toxicity*
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Excitatory Amino Acid Antagonists / pharmacology
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Glutamic Acid / toxicity
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Glycogen Synthase Kinase 3 / antagonists & inhibitors*
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Hippocampus / cytology
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Hippocampus / drug effects
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Indoles / pharmacology
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Kainic Acid / antagonists & inhibitors
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Kainic Acid / toxicity
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Maleimides / pharmacology
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N-Methylaspartate / antagonists & inhibitors*
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N-Methylaspartate / toxicity*
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Neurons / drug effects*
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Neuroprotective Agents*
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Phosphorylation
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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, N-Methyl-D-Aspartate / agonists
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Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
Substances
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3-(3-chloro-4-hydroxyphenylamino)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione
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Aminophenols
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Enzyme Inhibitors
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Excitatory Amino Acid Agonists
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Excitatory Amino Acid Antagonists
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Indoles
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Maleimides
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Neuroprotective Agents
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Proto-Oncogene Proteins
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Receptors, N-Methyl-D-Aspartate
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SB 216763
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Glutamic Acid
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N-Methylaspartate
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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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Glycogen Synthase Kinase 3
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Kainic Acid