N-Acetylcysteine Amide (NACA) Prevents Retinal Degeneration by Up-Regulating Reduced Glutathione Production and Reversing Lipid Peroxidation

Abstract

Oxidative stress plays a critical role in accelerating retinal pigment epithelial dysfunction and death in degenerative retinal diseases, including age-related macular degeneration. Given the key role of oxidative stress-induced retinal pigment epithelial cell death and secondary photoreceptor loss in the pathogenesis of age-related macular degeneration, we hypothesized that a novel thiol antioxidant, N-acetylcysteine amide (NACA), might ameliorate cellular damage and subsequent loss of vision. Treatment of human retinal pigment epithelial cells with NACA protected against oxidative stress-induced cellular injury and death. NACA acted mechanistically by scavenging existing reactive oxygen species while halting production of reactive oxygen species by reversing lipid peroxidation. Furthermore, NACA functioned by increasing the levels of reduced glutathione and the phase II detoxification enzyme glutathione peroxidase. Treatment of mice exposed to phototoxic doses of light with NACA maintained retinal pigment epithelial cell integrity and prevented outer nuclear layer cell death as examined by histopathologic methods and rescued photoreceptor function as measured by electroretinography. These observations indicate that NACA protects against oxidative stress-induced retinal pigment epithelial and photoreceptor cell death in vitro and in vivo. The data suggest that NACA may be a novel treatment in rescuing retinal function and preventing vision loss secondary to retinal degenerative diseases, including age-related macular degeneration.

GDF15 is elevated in mice following retinal ganglion cell death and in glaucoma patients

“…Given the strong association between neuroinflammation and glaucomatous optic neuropathy (7), we performed a retinal cytokine/growth factor-focused PCR array consisting of 88 genes (ILs, TNF and TGF superfamilies, growth factors, interferons, chemokines, and others) to identify factors whose expression correlates specifically with RGC death. In order to identify factors unique to RGC death, we used 3 different murine models of disease: optic nerve crush (ONC) as a model of axonal injury and RGC-specific death as seen in glaucoma, light-induced retinal degeneration (RD) as a model of photoreceptor-specific cell death, and endotoxin-induced uveitis (EIU) as a model of ocular inflammation (8)(9)(10). By comparing the retinal gene expression profiles associated with these 3 murine models of disease and focusing specifically on factors that are uniquely identified in the ONC model but not the RD and EIU models, we could identify the factors that were uniquely associated with RGC death.…”

“…Light exposure to induce RD was performed as previously described (9). Briefly, 6-week-old 129S1/SvImJ mice were dark adapted overnight.…”

The role of N-acetylcysteine amide in defending primary human retinal pigment epithelial cells against tert-butyl hydroperoxide- induced oxidative stress

“…12,[26][27][28] Our results are in agreement with previous studies which reported an increase in GSH levels after NACA incubation and a decrease in GSH levels upon TBHP treatment in an ARPE cell line. 11,14 Importantly, changes in the GR activity were also observed. GR regenerates GSH from GSSG and plays an important role in GSH homeostasis.…”

“…In an animal model, phototoxicity-induced photoreceptor cell death and photoreceptor dysfunction were prevented by NACA. 14 The experiments reported here utilized primary cultures of human retinal pigment epithelial cells (HRPEpiC), the best available in vitro model for studying RPE-related disorders. Because we attempted to mimic a human disease and provide a solution using a "disease-in-the-dish" model, choosing the most representative cell model was critical.…”

“…It has demonstrated efficacy in numerous in vitro and animal models of other oxidative stress-related conditions, including drug-induced RPE damage and cataracts. [11][12][13][14][15] Our lab has demonstrated that NACA prevented retinal degeneration in vitro and in animal models.14 The immortalized ARPE-19 cell line was used as an in vitro model because primary human RPE cells were not available at the time. ROS generation and lipid peroxidation induced by tert-butyl hydroperoxide (TBHP) were reversed by pretreatment with NACA.…”