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B.A. Nagel, M.J. Richards, S.J. Fliesler; Optic Nerve Hypomyelination in a Rat Model of Smith–Lemli–Opitz Syndrome . Invest. Ophthalmol. Vis. Sci. 2005;46(13):3166.
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Purpose: We previously described progressive retinal degeneration in a rat model of Smith–Lemli–Opitz Syndrome (SLOS) (Fliesler et al., Arch. Ophthalmol. 122:1190, 2004). SLOS involves defective cholesterol (Chol) biosynthesis, with abnormal and excessive accumulation of 7–dehydrocholesterol (7DHC) in all bodily tissues. Here, we evaluated the status of optic nerve myelination in this animal model, with and without dietary cholesterol supplementation, in comparison with age– and sex–matched control rats. Methods: Sprague Dawley rats were treated with AY9944, an inhibitor of the affected enzyme in SLOS, as previously described (Fliesler et al., 2004) for up to 11 wk; control litters (group C) received no drug. All animals were maintained on dim cyclic lighting (12L:12D, 20–40 lux) and fed water ad lib. At weaning, the drug–treated group was subdivided into Chol–free (group A) vs. 2% Chol–fed (group AC) diet groups. Under deep anesthesia, whole body perfusion with mixed aldehyde fixative was performed, and optic nerves were excised, embedded in plastic resin, and thin sections were examined by electron microscopy, with quantitative morphometric analysis. Tissues from companion cohorts were subjected to sterol analysis. Results: Compared to controls, treatment groups A and AC showed a ca. 55% decrease in total optic nerve myelin area and a ca. 37% decrease in axon caliber (mean cross–sectional area). Mean 7DHC/Chol mole ratios were– Serum: C, 0; A, 8.28 ± 1.87; AC, 0.11 ± 0.01 [A vs. AC, p < 0.001]; optic nerve: C, 0; A, 5.00 ± 1.27; AC, 4.25 ± 0.90 [A vs. AC, p = 0.403]. Conclusions: Marked optic nerve hypomyelination occurs in this rat model of SLOS. Dietary cholesterol supplementation profoundly alters systemic (serum) sterol composition, but has no significant effect on the myelin sterol profile, and does not ameliorate hypomyelination in this model.
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