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.

Lutein Attenuates Both Apoptosis and Autophagy upon Cobalt (II) Chloride-Induced Hypoxia in Rat Műller Cells

“…Moreover, several in vitro studies also demonstrated that suppression of both apoptosis and autophagy enhanced cell survival [22,41]. Apart from apoptosis, CoCl 2 -induced hypoxia also triggered autophagy in rat cardiomyoblasts (H9c2) and retinal ganglion cells (RGC-5) cell line [22,42]. A study reported that the anti-apoptotic protein Bcl-2 acts as a pro-survival protein and negatively regulates autophagy, indicating the crosstalk between apoptosis and autophagy [43].…”

N-acetylcysteine stimulates protein synthesis in enterocytes independently of glutathione synthesis

“…6). Similarly, Yang et al (2012) reported that NAC increased the amounts of phosphorylated mTOR and Akt proteins in RGC-5 cells but these authors did not measure protein synthesis. The underlying mechanism whereby NAC affects the expression of these proteins is still unknown.…”

“…Conversely, BSO or diethylmaleate reduced cell proliferation and GSH concentration without affecting protein synthesis, while promoting protein physiological fluid and is readily transported by cells (Lai et al 2012;Lee et al 2013). Therefore, NAC provides a direct and convenient means to increase the intracellular concentration of glutathione (GSH, the reduced form of glutathione) in many tissues and cell types (Yang et al 2012).…”

2-Iminobiotin for the treatment of perinatal asphyxia

“…N-acetylcysteine-mediated neuroprotection is also mediated by targeting the hypoxia-inducible factor-1a pathway and counteracting the autophagic cell death [80]. It has low toxicity and it is able to cross the placenta and blood--brain barrier [81].…”