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Shi Bai, Yongdong Zhou, Christian Sheline; Light-induced Death Of Photoreceptor And RPE Cells: Role Of Zinc And NAD+. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5354.
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Light-induced retinal damage (LD) occurs after surgery or sun exposure. LD causes preferential superior central photoreceptor and RPE death in albino rodents and is a model of oxidation-induced neurodegeneration. Zinc accumulates in photoreceptors and RPE cells after LD, and pyruvate or nicotinamide attenuate the resultant death perhaps by restoring nicotinamide adenine dinucleotide (NAD+) levels. Here, we examined if reducing zinc in the diet of rats could attenuate subsequent LD. Also, NAD+ levels cycle with a 24-h rhythm in the periphery, and this is affected by the feeding schedule. Therefore, we measured the affect of inverting the feeding schedule on LD. We also examined the affects in mice of knocking out zinc transporter 3 (ZnT3-KO, no synaptic zinc), or metallothionein 3 (MT3-KO, reduced intracellular zinc), and the affect of nicotinamide mononucleotide adenyl-transferase-1 (NMNAT1, an NAD+ synthetic enzyme) overexpression (WldS mice) on LD.
Sprague Dawley albino rats were fed for 3 wk with a 1 ppm zinc diet, a 60 ppm zinc diet (normal level), or a 1 ppm switched to 60 ppm zinc diet (1-60 ppm, 2 wk-1 wk) and exposed to 18 kLux of white light for 4 h. Rats were switched to day only, or night only feeding 2 d prior to 4 h of LD and maintained until sacrifice at 7 d. ZnT3-KO, MT3-KO, WldS, and C57/Bl6/J control mice (all RPE65 Met/Met) were exposed to 70 kLux of white light for 50 h. Retinas were examined 7 d later by optical coherence tomography (OCT) followed by histology.
Rats fed the reduced zinc diet (1 ppm) showed less photoreceptor and RPE death after 4 h of LD compared to those fed either 60 ppm of zinc, or those switched back to normal zinc levels (1 ppm - 60 ppm). Day fed rats showed less LD compared to night fed rats. ZnT3-KO, MT3-KO and WldS mice all showed attenuated LD.
: 1) Zinc toxicity plays a role in LD-induced death of photoreceptors and RPE cells as shown by the efficacy of a reduced zinc diet and genetic knockouts that reduce synaptic or cellular zinc content. 2) NAD+ levels play a role in LD-induced death of photoreceptors and RPE cells as shown by the efficacy of a daytime feeding schedule (NAD+ levels are high at the start of LD), and genetic overexpression of the NAD+ synthetic enzyme, NMNAT1.
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