title: N-acetylcysteine protects against hypoxia mimetic-induced autophagy by targeting the HIF-1α pathway in retinal ganglion cells.
abstract: Hypoxia-induced retinal ganglion cell (RGC) death has been proposed to be the critical event in the pathophysiology of glaucoma. Therefore, delaying or halting RGC degeneration, known as neuroprotection, is a novel and promising approach with potential clinical applications for treating glaucoma. In this study, we investigate hypoxia-induced cell death of RGCs and the underlying mechanisms of N-acetylcysteine (NAC) as a neuroprotectant. To establish a model for chemical hypoxia-induced cell death, RGC-5 cells were treated with the hypoxia mimetic cobalt chloride (CoCl2). Following CoCl2 exposure, significant levels of apoptotic and autophagic cell death were observed in RGC-5 cells, evidenced by lysosome dysfunction and autophagosome formation. Pretreating RGC-5 cells with NAC significantly counteracted the autophagic cell death. NAC-mediated neuroprotection was attributed to the direct scavenging of reactive oxygen species and was mediated by targeting the hypoxia-inducible factor-1α pathway via the BNIP3 and PI3K/Akt/mTOR pathways. These results provide insights into the degeneration of RGCs and present a potential clinical application for NAC as a neuroprotectant.
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Yang
authors.forename: Panpan
authors.initials: P
authors.lastname: Tan
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.forename: Xu
authors.initials: X
authors.lastname: Zhu
authors.forename: Yongyao
authors.initials: Y
authors.lastname: Cui
authors.forename: Liang
authors.initials: L
authors.lastname: Zhu
authors.forename: Xuemei
authors.initials: X
authors.lastname: Feng
authors.forename: Hong
authors.initials: H
authors.lastname: Qi
authors.forename: Jun
authors.initials: J
authors.lastname: Zheng
authors.forename: Ping
authors.initials: P
authors.lastname: Gu
authors.forename: Xianqun
authors.initials: X
authors.lastname: Fan
authors.forename: Hongzhuan
authors.initials: H
authors.lastname: Chen
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage*; D000818:Animals; D000831:Animals, Newborn; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003035:Cobalt / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000378:metabolism*
chemical_list: C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D003035:Cobalt; C018021:cobaltous chloride; D000111:Acetylcysteine