Abstract
Abstract: :
Purpose:Treatment of rats with AY9944, an inhibitor of 3 -hydroxysterol 7-reductase, causes profound alterations in retinal lipid metabolism and composition, but without apparent disruption of normal histology, ultrastructure, or electrophysiological function, up to one postnatal month (Fliesler et al. (1999) IOVS 40:1792). In this animal model of Smith-Lemli-Opitz syndrome (SLOS), we examined longer-term consequences of AY9944 treatment, with regard to electroretinographic responses (ERGs) and retinal histology/ultrastructure. Methods:Sprague-Dawley rats maintained in dim cyclic light (20-40 lux, 12L:12D) were treated with AY9944 as described previously (Fliesler et al. (1999) IOVS 40:1792), up to 10 postnatal weeks; a parallel control group received normal chow and vehicle-only injections. Rats were dark-adapted overnight. After dark- and light-adapted ERGs were recorded, one eye from each rat then was taken for histological and ultrastructural analysis, while sterol analysis was performed on retinas from contralateral eyes. Results. HPLC confirmed the dominance of 7-dehydrocholesterol (7DHC) in retinas of AY9944-treated rats, while cholesterol was ≷98% of the sterol in control retinas. Histology and ultrastructure of retinas from AY9944-treated rats were comparable to those of age-matched controls. ERG a- and b-wave amplitudes of AY9944-treated rats were significantly reduced and implicit times were longer, compared with controls. Results:HPLC confirmed the dominance of 7-dehydrocholesterol (7DHC) in retinas of AY9944-treated rats, while cholesterol was ≷98% of the sterol in control retinas. Histology and ultrastructure of retinas from AY9944-treated rats were comparable to those of age-matched controls. ERG a- and b-wave amplitudes of AY9944-treated rats were significantly reduced and implicit times were longer, compared with controls. Conclusion:AY9944 treatment causes time-dependent electrophysiological dysfunction in the retina in this SLOS animal model, without obvious histological or ultrastructural abnormalities, up to 10 postnatal weeks. These results are consistent with reported findings of retinal dysfunction in SLOS patients (Elias et al. (2000) Am. J. Hum. Genet. 67 (Suppl. 2):36).
Keywords: 316 animal model • 561 retinal degenerations: cell biology • 396 electroretinography: non-clinical