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

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 GT1â...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of biological chemistry 1999-04, Vol.274 (14), p.9828
Main Authors: Stefanie Heck, Frank Lezoualc’h, Stefanie Engert, Christian Behl
Format: Article
Language:English
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 2 O 2 ). Neuroprotective concentrations of IGF-1 specifically induce the transcriptional activity and the DNA binding activity of nuclear factor κB (NF-κB), 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-κB and with degradation of the NF-κB inhibitory protein IκBα. IGF-1-mediated protection of GT1–7 cells against oxidative challenges was mimicked by overexpression of the NF-κB subunit c-Rel. Partial inhibition of NF-κB baseline activity by overexpression of a dominant-negative IκBα mutant enhanced the toxicity of H 2 O 2 in GT1–7 cells. The pathway by which IGF-1 promotes neuronal survival and activation of NF-κB 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-κB that is dependent on the PI 3-kinase pathway.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.274.14.9828