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A. M. Schimel, L. Abraham, C. Kraus, N. Ercal, R. S. Apte; A Novel Thiol Antioxidant, N-Acetylcysteine Amide, Prevents Retinal Degeneration in Rd10 Mice. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2940.
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© ARVO (1962-2015); The Authors (2016-present)
Oxidative stress plays a critical role in accelerating photoreceptor dysfunction and death in both inherited retinal degenerative diseases such as retinitis pigmentosa (RP) and in diseases of aging such as age-related macular degeneration (AMD). Given the key role of oxidative stress-induced photoreceptor loss in the pathogenesis of retinal degeneration, we hypothesized that a novel thiol antioxidant, N-acetylcysteine amide (NACA), might ameliorate cellular damage and subsequent loss of vision.
Litters of homozygous retinal degenerative rd10 mice (B6.CXB1-Pde6brd10/J) were given daily intraperitoneal injections of NACA versus vehicle from postnatal day (P)13 through P23. To assess photoreceptor viability, retinal sections were analyzed using hematoxylin and eosin staining for outer nuclear layer (ONL) cell body density at P23. ONL cell body density was quantified using histopathologic butterfly patterns of six locations: 25%, 50%, and 75% of the distance between both the superior and inferior poles and the optic nerve. In order to measure photoreceptor function, full field electroretinograms (ERGs) were recorded for all mice.
Treatment of retinal degenerative rd10 mice with intraperitoneal NACA was well tolerated without any adverse effects. Analysis of hematoxylin and eosin-stained sections demonstrated a significantly greater ONL cell body density in the NACA-treated group versus the vehicle-treated controls (p<0.001). Subgroup analysis of the histopathologic sections showed that NACA-treated mice had significantly more cells in their ONL at each of the six locations measured (p<0.001 for each). Furthermore, there was an impressive maintenance of photoreceptor activity and visual function in the NACA-treated versus vehicle-treated mice as measured by ERG (p<0.001).
Our results demonstrate that NACA, which inhibits lipid peroxidation, scavenges reactive oxygen species, and increases levels of intracellular glutathione and the enzymes that produce it, protects against oxidative stress-related damage and photoreceptor degeneration in vivo. This suggests a potential therapeutic role in the treatment of retinal degenerative diseases such as AMD and RP.
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