Glycogen synthase kinase-3 inhibitors protect central neurons against excitotoxicity

Neuroreport. 2003 Aug 6;14(11):1467-70. doi: 10.1097/00001756-200308060-00012.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminophenols / pharmacology
  • Animals
  • Cell Survival / drug effects
  • Cells, Cultured
  • Central Nervous System / cytology*
  • Central Nervous System / drug effects*
  • Cerebellum / cytology
  • Cerebellum / drug effects
  • Enzyme Inhibitors / pharmacology*
  • Excitatory Amino Acid Agonists / toxicity*
  • Excitatory Amino Acid Antagonists / pharmacology
  • Glutamic Acid / toxicity
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors*
  • Hippocampus / cytology
  • Hippocampus / drug effects
  • Indoles / pharmacology
  • Kainic Acid / antagonists & inhibitors
  • Kainic Acid / toxicity
  • Maleimides / pharmacology
  • N-Methylaspartate / antagonists & inhibitors*
  • N-Methylaspartate / toxicity*
  • Neurons / drug effects*
  • Neuroprotective Agents*
  • Phosphorylation
  • Protein Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / agonists
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors

Substances

  • 3-(3-chloro-4-hydroxyphenylamino)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione
  • Aminophenols
  • Enzyme Inhibitors
  • Excitatory Amino Acid Agonists
  • Excitatory Amino Acid Antagonists
  • Indoles
  • Maleimides
  • Neuroprotective Agents
  • Proto-Oncogene Proteins
  • Receptors, N-Methyl-D-Aspartate
  • SB 216763
  • Glutamic Acid
  • N-Methylaspartate
  • Akt1 protein, rat
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3
  • Kainic Acid