Glycogen synthase kinase-3 inhibitors protect central neurons against excitotoxicity.
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.
Facci
Laura
L
Neurophysiology and Cell Sciences, GlaxoSmithKline Research and Development Ltd., Third Avenue, Harlow, Essex CM19 5AW, UK. Laura_2_facci@gsk.com
Stevens
David A
DA
Skaper
Stephen D
SD
D000627:Aminophenols / Q000494:pharmacology; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002490:Central Nervous System / Q000166:cytology* / Q000187:drug effects*; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000633:toxicity; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology; D007608:Kainic Acid / Q000037:antagonists & inhibitors / Q000633:toxicity; D008301:Maleimides / Q000494:pharmacology; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors
C417520:3-(3-chloro-4-hydroxyphenylamino)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione; D000627:Aminophenols; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D007211:Indoles; D008301:Maleimides; D018696:Neuroprotective Agents; D011518:Proto-Oncogene Proteins; D016194:Receptors, N-Methyl-D-Aspartate; C417521:SB 216763; D018698:Glutamic Acid; D016202:N-Methylaspartate; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D007608:Kainic Acid