Insulin-like growth factor-1-mediated neuroprotection against oxidative stress is associated with activation of nuclear factor kappaB.
The role of insulin-like growth factor 1 (IGF-1) for the treatment of neurodegenerative disorders, such as Alzheimer's disease, has recently gained attention. The present study demonstrates that IGF-1 promotes the survival of rat primary cerebellar neurons and of immortalized hypothalamic rat GT1-7 cells after challenge with oxidative stress induced by hydrogen peroxide (H2O2). Neuroprotective concentrations of IGF-1 specifically induce the transcriptional activity and the DNA binding activity of nuclear factor kappaB (NF-kappaB), a transcription factor that has been suggested to play a neuroprotective role. This induction is associated with increased nuclear translocation of the p65 subunit of NF-kappaB and with degradation of the NF-kappaB inhibitory protein IkappaBalpha. IGF-1-mediated protection of GT1-7 cells against oxidative challenges was mimicked by overexpression of the NF-kappaB subunit c-Rel. Partial inhibition of NF-kappaB baseline activity by overexpression of a dominant-negative IkappaBalpha mutant enhanced the toxicity of H2O2 in GT1-7 cells. The pathway by which IGF-1 promotes neuronal survival and activation of NF-kappaB involves the phosphoinositol (PI) 3-kinase, because both effects of IGF-1 are blocked by LY294002 and wortmannin, two specific PI 3-kinase inhibitors. Taken together, our results provide evidence for a novel molecular link between IGF-1-mediated neuroprotection and induction of NF-kappaB that is dependent on the PI 3-kinase pathway.
Heck
S
S
Max Planck Institute of Psychiatry, Kraepelinstrasse 2-10, 80804 Munich, Germany.
Lezoualc'h
F
F
Engert
S
S
Behl
C
C
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D002531:Cerebellum / Q000378:metabolism*; D002867:Chromones / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000378:metabolism; D020672:I-kappa B Proteins; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D020569:Proto-Oncogene Proteins c-rel; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077191:Wortmannin
D000730:Androstadienes; D002867:Chromones; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D006861:Hydrogen Peroxide; D020672:I-kappa B Proteins; D007334:Insulin-Like Growth Factor I; D009025:Morpholines; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D020569:Proto-Oncogene Proteins c-rel; D000077191:Wortmannin; C000606206:Nfkbia protein, rat; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one