Insulin-like growth factor I, but not neurotrophin-3, sustains Akt activation and provides long-term protection of immature oligodendrocytes from glutamate-mediated apoptosis

Mol Cell Neurosci. 2002 Jul;20(3):476-88. doi: 10.1006/mcne.2002.1149.

Abstract

Glutamate toxicity is a major contributor to death of oligodendroglia in diverse CNS disorders. The goal of these studies was to investigate the mechanisms of glutamate toxicity and trophic factor protection of the immature pro-oligodendroblast (pro-OL). Glutamate induced time- and dose-dependent DNA fragmentation and caspase-3 activation in pro-OLs. IGF-I or NT-3, but not CNTF, prevented apoptosis of pro-OLs by 24 h via a PI3-kinase-dependent pathway; however, only IGF-I protected pro-OLs from glutamate toxicity through 48 h. Long-term protection of pro-OLs by IGF-I was correlated with sustained activation of Akt while NT-3 activation of Akt was transient. The differential ability of IGF-I and NT-3 to maintain Akt activation was due to differences in receptor activation and stability. In the presence of NT-3, TrkC phosphorylation and protein expression decreased significantly while activation of the IGF-IR was maintained in the pro-OLs in the presence of IGF-I.

Publication types

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

MeSH terms

  • Animals
  • Animals, Newborn
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Cell Differentiation / drug effects
  • Cell Differentiation / physiology
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Cells, Cultured
  • Enzyme Activation / physiology
  • Glutamic Acid / toxicity*
  • Insulin-Like Growth Factor I / physiology*
  • Neurotrophin 3 / physiology*
  • Oligodendroglia / cytology*
  • Oligodendroglia / drug effects
  • Oligodendroglia / enzymology*
  • Protein-Serine-Threonine Kinases*
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Rats

Substances

  • Neurotrophin 3
  • Proto-Oncogene Proteins
  • Glutamic Acid
  • Insulin-Like Growth Factor I
  • Protein-Tyrosine Kinases
  • Akt1 protein, rat
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt