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Aling Dong, Rebecca Stevens, Sean Hackett, Peter A Campochiaro; Compared with N-acetylcysteine (NAC), N-Acetylcysteine Amide (NACA) Provides Increased Protection of Cone Function in a Model of Retinitis Pigmentosa. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1736.
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Retinitis pigmentosa (RP) is a major cause of blindness due to a large variety of mutations that lead to the death of rod photoreceptors. After rods die, cones gradually die from progressive oxidative damage. We previously found that N-acetylcysteine (NAC), a well-known thiol antioxidant, reduces cone cell death and preserves cone function in models of RP. N-acetylcysteine amide (NACA) is a prodrug for NAC with increased bioavailability. In this study, we compared NAC and NACA in a model of RP.
Starting at postnatal day (P) 14, rd10+/+ mice were given normal drinking water (n=6) or water containing 7mg/ml NACA or 20mg/ml NAC (n=8 for each group). Scotopic and photopic electroretinograms (ERGs) were recorded at P35 and P50. Cone density was measured at P50 in four 230 mmx 230 mm (512x512 pixels) areas located 0.5mm superior, temporal, inferior, and nasal to the center of the optic nerve in retinal flat mounts stained with fluorescein-labeled peanut agglutinin (PNA).
At P35, mean peak scotopic ERG b-wave amplitude was similar in rd10+/+ mice treated with 7mg/ml NACA or 20mg/ml NAC, and were significantly greater (about 2-fold) than those in controls. Mean peak photopic b-wave amplitude was 41% higher (p=0.024) in NACA-treated mice than NAC-treated mice and both were more than 3-fold higher than that in controls. At P50, mean peak scotopic ERG b-wave amplitude was more than 5-fold higher in NAC- or NACA-treated mice than in controls with mean b-wave amplitudes significantly greater in NACA-treated mice compared with NAC-treated mice at 10 of 11 stimulus intensities. Mean photopic ERG b-wave amplitude was 50% higher (p=0.001) at all 3 stimulus intensities in NACA-treated versus NAC-treated mice and more than 4-fold greater than controls. At P50, cone cell density was significantly greater in 3 of 4 quadrants in NACA-treated mice compared to NAC-treated mice.
Even with a substantially lower oral dose, NACA showed significantly greater preservation of cone cell function and cone survival compared with NAC in rd10+/+ mice.
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