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C.M. Doshna, D.J. Baltrukonis, J.H. Fortner, J. Render, C.J. Somps; RGH–6201 Cataract Preceded by Decrease in Lens Cholesterol Biosynthesis in Rats . Invest. Ophthalmol. Vis. Sci. 2006;47(13):4109.
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© ARVO (1962-2015); The Authors (2016-present)
RGH–6201 is a central nervous system depressant that causes time– and dose–dependent cataracts in rats after 2–4 weeks of daily dosing. RGH–6201 contains a diethylaminoethoxy structural moiety associated with compounds that inhibit cholesterol biosynthesis and are cataractogenic. The purpose of this study was to determine if changes in lens cholesterol biosynthesis (LCB) precede RGH–6201–induced cataract formation in rats.
Rats were treated orally with 50 or 200 mg/kg/d RGH–6201 or vehicle control (0.5% methylcellulose). After 2 days of dosing, lenses were collected from rats in all 3 groups for analysis of LCB. LCB was analyzed by ex vivo lenticular incorporation of [14C]–acetate. In order to document cataract progression, an additional group of 8 rats was dosed with RGH–6201 for 15 days. This group was initially dosed at 200 mg/kg. However due to adverse effects, the dose was reduced to 100 mg/kg for days 3–15. Slit lamp biomicroscopic examinations and/or Scheimpflug imaging were conducted once pre–study and then on days 5, 9/10, 12, and 15. Scheimpflug images (0o, 90o, and retroillumination) were acquired from each eye using the Nidek EAS–1000 anterior segment analysis system. Subsequent densitometric image analysis was performed using EAS–1000 software. Slit lamp images (retroillumination) were captured using a Nikon FS–3V slit lamp. On day 15, eyes were collected for histopathological assessment.
RGH–6201 doses of 50 and 200 mg/kg resulted in significant inhibition of LCB (68 and 82% respectively) after only 2 days. Rats treated with RGH–6201 for 15 days showed evidence of subtle changes in lens clarity with Slit lamp exams on day 9 (5/8) and with Scheimpflug imaging on day 10 (5/8). Slit lamp exams on day 5 showed no evidence of changes. By treatment end, minimal and diffuse opacities were observed by both Scheimpflug imaging and Slit lamp exams. Histopathological changes were observed in 8/8 rats treated with RGH–6201 for 15 days.
Decreases in lens cholesterol biosynthesis may be an early indicator of RGH–6201–induced cataractogenesis in rats. The diethylaminoethoxy–group of this compound, shared by other cataractogens such as the cholesterol lowering agents triparanol and U18666A, may be responsible for the lenticular toxicity.
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