Insulin-like Growth Factor-1-mediated Neuroprotection against Oxidative Stress Is Associated with Activation of Nuclear Factor κB

• Published in: The Journal of biological chemistry Vol. 274; no. 14; pp. 9828 - 9835
• Main Authors: Heck, Stefanie, Lezoualc'h, Frank, Engert, Stefanie, Behl, Christian
• Format: Journal Article
• Language: English
• Published: 02.04.1999
• ISSN: 0021-9258
• DOI: 10.1074/jbc.274.14.9828

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 (H sub(2)O sub(2)). Neuroprotective concentrations of IGF-1 specifically induce the transcriptional activity and the DNA binding activity of nuclear factor Kappa B (NF- Kappa B), 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- Kappa B and with degradation of the NF- Kappa B inhibitory protein I Kappa B alpha . IGF-1-mediated protection of GT1-7 cells against oxidative challenges was mimicked by overexpression of the NF- Kappa B subunit c-Rel. Partial inhibition of NF- Kappa B baseline activity by overexpression of a dominant-negative I Kappa B alpha mutant enhanced the toxicity of H sub(2)O sub(2) in GT1-7 cells. The pathway by which IGF-1 promotes neuronal survival and activation of NF- Kappa B 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- Kappa B that is dependent on the PI 3-kinase pathway.