Phosphatidylinositol 3-kinase and Akt effectors mediate insulin-like growth factor-I neuroprotection in dorsal root ganglia neurons

FASEB J. 2004 Oct;18(13):1544-6. doi: 10.1096/fj.04-1581fje. Epub 2004 Aug 19.


Insulin-like growth factor-I (IGF-I) protects neurons of the peripheral nervous system from apoptosis, but the underlying signaling pathways are not well understood. We studied IGF-I mediated signaling in embryonic dorsal root ganglia (DRG) neurons. DRG neurons express IGF-I receptors (IGF-IR), and IGF-I activates the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. High glucose exposure induces apoptosis, which is inhibited by IGF-I through the PI3K/Akt pathway. IGF-I stimulation of the PI3K/Akt pathway phosphorylates three known Akt effectors: the survival transcription factor cyclic AMP response element binding protein (CREB) and the pro-apoptotic effector proteins glycogen synthase kinase-3beta (GSK-3beta) and forkhead (FKHR). IGF-I regulates survival at the nuclear level through accumulation of phospho-Akt in DRG neuronal nuclei, increased CREB-mediated transcription, and nuclear exclusion of FKHR. High glucose increases expression of the pro-apoptotic Bcl protein Bim (a transcriptional target of FKHR). However, IGF-I does not regulate Bim or anti-apoptotic Bcl-xL protein expression levels, which suggests that IGF-I neuroprotection is not through regulation of their expression. High glucose also induces loss of the initiator caspase-9 and increases caspase-3 cleavage, effects blocked by IGF-I. These data suggest that IGF-I prevents apoptosis in DRG neurons by regulating PI3K/Akt pathway effectors, including GSK-3beta, CREB, and FKHR, and by blocking caspase activation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Caspase 3
  • Caspase 9
  • Caspases / metabolism
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cell Survival / drug effects
  • Cells, Cultured
  • Cytosol / drug effects
  • Cytosol / metabolism
  • DNA-Binding Proteins / metabolism
  • Forkhead Transcription Factors
  • Ganglia, Spinal / cytology*
  • Ganglia, Spinal / embryology
  • Glucose / antagonists & inhibitors
  • Glucose / pharmacology
  • Insulin-Like Growth Factor I / pharmacology*
  • Mitogen-Activated Protein Kinases / metabolism
  • Nerve Tissue Proteins / metabolism
  • Neurons / cytology
  • Neurons / drug effects*
  • Neurons / enzymology
  • Neurons / metabolism
  • Neuroprotective Agents / pharmacology*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation / drug effects
  • Protein Serine-Threonine Kinases / metabolism*
  • Protein Transport / drug effects
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Rats
  • Signal Transduction / drug effects


  • DNA-Binding Proteins
  • Forkhead Transcription Factors
  • Nerve Tissue Proteins
  • Neuroprotective Agents
  • Proto-Oncogene Proteins
  • Foxo1 protein, rat
  • Insulin-Like Growth Factor I
  • Akt1 protein, rat
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinases
  • Casp3 protein, rat
  • Casp9 protein, rat
  • Caspase 3
  • Caspase 9
  • Caspases
  • Glucose