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.
Department of Pharmacology and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul, Korea.
Yumi
Y
Kim
Endan
E
Li
Seungjoon
S
Park
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000502:physiology; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology*; D016627:Oxidopamine / Q000633:toxicity; D016716:PC12 Cells; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013565:Sympatholytics / Q000633:toxicity
D000975:Antioxidants; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; C495637:Nfe2l2 protein, rat; D017382:Reactive Oxygen Species; D013565:Sympatholytics; D007334:Insulin-Like Growth Factor I; D016627:Oxidopamine; D051547:Heme Oxygenase-1