Insulin-Like Growth Factor-1 Inhibits 6-Hydroxydopamine-Mediated Endoplasmic Reticulum Stress-Induced Apoptosis via Regulation of Heme Oxygenase-1 and Nrf2 Expression in PC12 Cells

Endoplasmic reticulum (ER) stress and oxidative stress appear to play a critical role in the progression of Parkinson's disease (PD). Insulin-like growth factor (IGF)-1, a 70-amino acid polypeptide trophic factor, acts as a potent neurotrophic, neurogenic, and neuroprotective/anti-apoptotic factor. In this study, we investigated the protective mechanisms of IGF-1 in rat pheochromocytoma PC12 cells exposed to the PD-related neurotoxin 6-hydroxydopamine (6-OHDA). The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) coordinates expression of genes required for free radical scavenging, detoxification of xenobiotics, and maintenance of redox potential. Exposure of cells to 6-OHDA resulted in an increase in ER-stress-induced apoptotic cell death, which was significantly reduced by treatment of cells with IGF-1. IGF-1 treatment significantly increased BiP and C/EBP homologous protein expression in 6-OHDA-treated cultures. IGF-1 protected cells from 6-OHDA-induced insult by inhibiting intracellular reactive oxygen species generation. Compared with vehicle-treated controls, the expression of Nrf2 and heme oxygenase-1 (HO-1) was increased in 6-OHDA-treated cells. IGF-1 significantly up-regulated HO-1 in cells exposed to 6-OHDA. These results suggest that IGF-1 augment cellular anti-oxidant defense mechanism, at least in part, through the up-regulation of HO-1 expression.