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Steven J Fliesler, Neal S Peachey, Nadav I. Weinstock, Josi Herron, Kelly M. Hines, Libin Xu; Rescue of retinal degeneration in a rat model of Smith-Lemli-Opitz Syndrome. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2491. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
The AY9944 rat model of Smith-Lemli-Opitz syndrome (SLOS) exhibits progressive retinal degeneration, which is partially ameliorated by feeding a high-cholesterol (Chol) diet (Fliesler et al., 2004, 2007). Here, we tested the hypothesis that combined dietary Chol plus antioxidants would provide an improved therapeutic intervention over Chol alone, sparing the retinal degenerative phenotype in this SLOS model.
Pregnant rats were treated with AY9944 to generate the SLOS model, as previously described (Fliesler et al., 2004, 2007). Upon weaning, rat pups (N=10-12/group) were randomized to three dietary groups: AY1 (normal rat chow); AY2 (the AY1 chow supplemented with 2% (w/w) Chol); and AY3 (the AY2 chow supplemented with vitamins E (500 IU/kg) and C (1.43 g/kg), plus Se nitrite (3.4 mg/kg) (Chen & Tappel, 1995)). Control group: age-matched untreated rats, fed normal rat chow. At PN80-82 days, electroretinograms (ERGs) were obtained; animals were euthanized, and tissues were harvested for biochemical and histological analyses. Quantitative data (mean/S.D.) were statistically compared using Student’s t-test (significance: p≤0.05) or one-way ANOVA.
Treated rats on the AY1 diet exhibited massive retinal degeneration; the AY2 diet provided substantial, but incomplete, sparing from histological damage, while retinal histology of rats fed the AY3 diet was comparable to that of untreated controls. Rod and cone ERG amplitudes were markedly reduced, relative to age-matched controls, for rats fed the AY1 diet, were less affected (but not normal) for rats fed the AY2 diet, and were comparable to untreated controls for rats fed the AY3 diet. Retinal oxysterol levels were increased >160-fold, relative to untreated controls, for rats fed the AY1 diet, declined by ~18% on the AY2 diet (rel. to the AY1 group), and by ~37% (rel. to the AY1 group) on the AY3 diet. Retinal 7DHC/Chol was >5 for rats on the AY1 diet (<0.01 for controls); AY2 and AY3 diets reduced the 7DHC/Chol >2-fold.
Combined dietary high-Chol plus antioxidant supplementation provides a substantially improved therapeutic intervention over Chol alone with regard to sparing loss of retinal structure and function, correlating with reductions in retinal oxysterol and 7DHC/Chol levels, in the AY9944 SLOS rat model. These results have translational implications for improving the clinical management of SLOS patients.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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