Insulin-like growth factor I, but not neurotrophin-3, sustains Akt activation and provides long-term protection of immature oligodendrocytes from glutamate-mediated apoptosis.
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.
Ness
Jennifer K
JK
Department of Neuroscience and Anatomy, Penn State College of Medicine, Hershey, PA 17033, USA.
Wood
Teresa L
TL
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000502:physiology; D018698:Glutamic Acid / Q000633:toxicity*; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D020933:Neurotrophin 3 / Q000502:physiology*; D009836:Oligodendroglia / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats
D020933:Neurotrophin 3; D011518:Proto-Oncogene Proteins; D018698:Glutamic Acid; D007334:Insulin-Like Growth Factor I; D011505:Protein-Tyrosine Kinases; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt