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M.J. Richards, B.A. Nagel, S.J. Fliesler; Lipid Hydroperoxide Formation and Retinal Degeneration in an Animal Model of Smith-Lemli-Opitz Syndrome . Invest. Ophthalmol. Vis. Sci. 2003;44(13):3548.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Defective cholesterol (Chol) biosynthesis at the level of 3ß-hydroxysterol-Δ7-reductase is associated with Smith-Lemli-Opitz syndrome (SLOS). Using rats treated with AY9944 (an inhibitor of the reductase), we have created an animal model of SLOS (Fliesler et al.,IOVS, 1999) and have shown that it exhibits a progressive retinal degeneration (Fliesler et al., ARVO, 2002) that is markedly more susceptible to "retinal light damage" than control albino rats (Fliesler et al., ARVO, 2001). Herein, we tested the hypothesis that exacerbated retinal light damage correlates with a greater formation of retinal lipid hydroperoxides (LPO) in SLOS vs. normal rats under the same environmental conditions.Methods: SLOS rats (2-mo. old, N=6-8) were generated by treating Sprague-Dawley rats with AY9944, as previously described (Fliesler et al., IOVS 40:1792, 1999). A parallel control group received vehicle injections only and no drug. Rats were maintained under dim cyclic light (12L:12D, 20-40 lux) and fed Chol-free chow and water ad lib. After a 24-h dark adaptation period, half of the rats in each group were exposed to intense, constant, green light (1700 lux, 490-580 nm, 24 h), while the remainder were kept in darkness. The light-exposed rats were then returned to darkness for 1 h, and then all animals were sacrificed. One eye of each was fixed and examined histologically, while contralateral retinas were harvested and analyzed using a Lipid Hydroperoxide (LPO) Assay Kit (Cayman Chemical Co., #705002). Results: Retinas from light-exposed control rats (CE) contained about twice the levels of LPO as retinas from non-light-exposed control rats (CN). Retina LPO levels in AY9944-treated, non-light-exposed rats (AN) were comparable to those in CE rat retinas; upon exposure to intense light, LPO levels in AY9944-treated rats (AE) increased 3-5X, relative to AN retinas. Histological analysis confirmed that photoreceptor damage and loss were far more severe (both in degree and geographic extent) in AE than in CE retinas.Conclusions: Elevated LPO levels correlate with the extent of retinal light damage in SLOS vs. normal rats. The comparable LPO levels in AN and CE retinas are consistent with prior ERG findings (Fliesler et al., ARVO, 2001): despite normal histology, AN retinas exhibit reduced scotopic ERG amplitudes, similar le to those observed in CE retinas. This suggests that, at sufficiently low levels, LPOs may cause functional abnormalities without obvious cellular damage; above such levels, both cytological and functional defects can occur.
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