Insulin like growth factor-1 prevents 1-mentyl-4-phenylphyridinium-induced apoptosis in PC12 cells through activation of glycogen synthase kinase-3beta

Toxicology. 2010 Apr 30;271(1-2):5-12. doi: 10.1016/j.tox.2010.01.001. Epub 2010 Jan 12.

Abstract

Dopaminergic neurons are lost mainly through apoptosis in Parkinson's disease. Insulin like growth factor-1 (IGF-1) inhibits apoptosis in a wide variety of tissues. Here we have shown that IGF-1 protects PC12 cells from toxic effects of 1-methyl-4-phenylpyridiniumion (MPP(+)). Treatment of PC12 cells with recombinant human IGF-1 significantly decreased apoptosis caused by MPP(+) as measured by acridine orange/ethidium bromide staining. IGF-1 treatment induced sustained phosphorylation of glycogen synthase kinase-3beta (GSK-3beta) as shown by western blot analysis. The anti-apoptotic effect of IGF-1 was abrogated by LY294002, which indirectly inhibits phosphorylation of GSK-3beta. Lithium chloride (LiCl), a known inhibitor of GSK-3beta, also blocked MPP(+)-induced apoptosis. Finally, although IGF-1 enhanced phosphorylation of extracellular signal-regulated kinases ERK1 and 2 (ERK1/2), PD98059, a specific inhibitor of ERK1/2, did not alter the survival effect of IGF-1. Thus, our findings indicate that IGF-1 protects PC12 cells exposed to MPP(+) from apoptosis via the GSK-3beta signaling pathway.

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / antagonists & inhibitors*
  • Animals
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Blotting, Western
  • Cell Survival
  • Chromones / pharmacology
  • Enzyme Activation / drug effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Flavonoids / pharmacology
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 / metabolism*
  • Glycogen Synthase Kinase 3 beta
  • Insulin-Like Growth Factor I / pharmacology*
  • Lithium Chloride / pharmacology
  • Morpholines / pharmacology
  • Neurotoxins / antagonists & inhibitors*
  • PC12 Cells
  • Parkinson Disease / enzymology
  • Parkinson Disease / metabolism
  • Parkinson Disease / pathology*
  • Protein Kinase Inhibitors / pharmacology
  • Rats
  • Recombinant Proteins / pharmacology

Substances

  • Chromones
  • Flavonoids
  • Morpholines
  • Neurotoxins
  • Protein Kinase Inhibitors
  • Recombinant Proteins
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Insulin-Like Growth Factor I
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, rat
  • Extracellular Signal-Regulated MAP Kinases
  • Glycogen Synthase Kinase 3
  • Lithium Chloride
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one