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DK Vaughan, MJ Richards, SJ Fliesler; DMTU Protects Against Light-Induced Retinal Degeneration in an Animal Model of Smith-Lemli-Opitz Syndrome . Invest. Ophthalmol. Vis. Sci. 2002;43(13):3729.
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Purpose: Rats treated with AY9944, an inhibitor of 3ß-hydroxysterol Δ;7-reductase, exhibit markedly enhanced light-induced retinal degeneration, compared with control Sprague-Dawley rats (Fliesler et al. (2001) IOVS (ARVO Abstr.) 42: S627). We examined the protective effects of dimethylthiourea (DMTU), an antioxidant, against retinal light damage in this animal model of Smith-Lemli-Opitz syndrome (SLOS). Methods: Sprague-Dawley rats maintained in dim cyclic light (20-40 lux, 12L:12D) for 1-2 months were treated with AY9944 as described previously (Fliesler et al. (1999) IOVS 40:1792). Animals were dark-adapted 20-24 h prior to constant light exposure. Half of the rats were given an injection of DMTU (500 mg/kg, subdermal aq. soln.), 24 h and 1 h prior to light exposure. Half of the animals (±DMTU) were then exposed to intense, constant, green light (24 h, 1700 lux, 490-580 nm), while the others were maintained in darkness. All animals then were returned to dim cyclic light for 2 wk. One eye from each rat was taken for histological and quantitative morphometric analysis, while sterol analysis was performed on retinas from contralateral eyes. Results: HPLC confirmed 7-dehydrocholesterol (7DHC) as the major sterol in retinas of AY9944-treated rats; DMTU treatment reduced the levels of oxysterol products. Histology of retinas from unexposed, AY9944-treated rats was normal. In contrast, light-exposed AY9944-treated rats exhibited massive photoreceptor (PR) cell loss in both hemispheres; DMTU almost completely prevented this PR cell loss. Conclusion: DMTU protects against retinal light damage in AY9944-treated rats. These results suggest that PR loss caused by exposure to intense, constant, green light involves rhodopsin-mediated lipid oxidation, with oxysterols as significant agents in the process of cell death. The mechanism of oxysterol-induced retinal degeneration remains to be elucidated. [Supported by EY07361 (SJF).]
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