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.