title: Protective effect of lipoic acid against oxidative stress is mediated by Keap1/Nrf2-dependent heme oxygenase-1 induction in the RGC-5 cellline.
abstract: Oxidative stress plays a key role in neurodegeneration of CNS neurons such as in Alzheimer disease, Parkinson's disease and glaucoma. R-α-lipoic acid (R-LA) has been shown to have a neuroprotective effect through its antioxidant activity. However, the mechanism underlying its neuroprotection is totally unknown in retinal neurons. In this study, we show that R-LA has a dramatic neuroprotective effect against oxidative stress-induced death of the retinal neuronal RGC-5 cell line. We observed that R-LA induces the expression of heme oxygenase-1 (HO-1) by promoting the translocation of NF-E2-related factor 2 (Nrf2) to the nucleus. We examined the mechanism underlying HO-1 induction by R-LA by focusing on downstream signaling pathways. We found that R-LA activates Akt, and HO-1 induction by R-LA (involving Nrf2 translocation to the nucleus) was suppressed by phosphoinositide 3-kinase (PI3K) inhibitors. In addition, R-LA produced reactive oxygen species (ROS), including hydrogen peroxide. Pretreatment with a ROS scavenger or a NADPH oxidase inhibitor suppressed R-LA-induced Nrf2 translocation to the nucleus and HO-1 induction. These results suggest that ROS production triggered by R-LA might modify Kelch-like ECH-associated protein (Keap1), which in turn induces HO-1 expression through the PI3K signaling pathway. Furthermore, R-LA significantly attenuated cell death and accumulation of 4-hydroxy-2-nonenal (4HNE) in the retina induced by optic nerve injury in vivo through an HO-1 activity-dependent mechanism. These data demonstrate for the first time that R-LA exerts a neuroprotective effect against oxidative stress in retinal neurons in vitro and in vivo by inducing HO-1 through Keap1/Nrf2 signaling.
authors.affiliation: Department of Molecular Neurobiology, Graduate School of Medicine, Kanazawa University, Kanazawa 920-8640, Japan. koriyama@med.kanazawa-u.ac.jp
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Koriyama
authors.forename: Yuya
authors.initials: Y
authors.lastname: Nakayama
authors.forename: Seiichi
authors.initials: S
authors.lastname: Matsugo
authors.forename: Satoru
authors.initials: S
authors.lastname: Kato
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D015151:Immunoblotting; D007150:Immunohistochemistry; D000072019:Kelch-Like ECH-Associated Protein 1; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D008063:Thioctic Acid / Q000494:pharmacology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D018696:Neuroprotective Agents; D008063:Thioctic Acid; D051547:Heme Oxygenase-1