Comparisons between U18666A, Naphthalene, and Galactose on Lens Cholesterol Biosynthesis and Evaluation of Cataract Progression by Scheimpflug and Slit Lamp Exams

Abstract

Abstract: : Purpose: To investigate if disruption of lens cholesterol biosynthesis is a general feature of cataract formation and to evaluate the preclinical and histopathological progression of cataract formation using three mechanistic models of cataract formation. Methods: Female Sprague-Dawley rats (150-200g) were treated once daily with 10 mg/kg U18666A (s.c., 2 days), 500 mg/kg naphthalene (p.o., 2 days), or 50% galactose (in diet, 3 days). Lens cholesterol and palmitate biosynthesis were analyzed by incorporation of [¹⁴C]-acetate. Cataract progression studies were conducted for 6 weeks with female Sprague-Dawley and Long-Evans rats for naphthalene or Sprague-Dawley rats for galactose. Naphthalene was administered orally every other day at 1000 mg/kg after 2 acclimating doses at 500 mg/kg. For galactose, rats were fed ad libitum with a 50% galactose supplemented diet. Scheimpflug and slit lamp exams were performed twice weekly and changes in lens density were analyzed using Nidek EAS-1000 software. Lenses with initial and pronounced evidence of density changes were collected and evaluated for histopathological changes. Results: U18666A treatment significantly decreased (59%) lens cholesterol biosynthesis while no effect was observed with naphthalene or galactose. Treatment with galactose significantly increased (82%) palmitate biosynthesis while no effect was observed with U18666A or naphthalene. All naphthalene treated animals showed evidence of cataract formation using the EAS-1000 system before or concurrently with slit lamp exams. At the end of naphthalene treatment, an incomplete zonular cataract was observed in both Long-Evans (3/3) and Sprague-Dawley rats (3/3). Treatment with galactose produced changes in the anterior equatorial cortex detectable by both Scheimpflug (7/7, day 7) and slit lamp exams (7/7, day 3). Initial density changes within the lens were obscured by the margin of the iris with Scheimpflug exams on day 3. During the 5^th week, a dense nuclear opacity was present in all animals (4/4). Histopathological changes were observed in 40% of naphthalene and 100% of galactose treated animals. Conclusions: Alterations in lens cholesterol biosynthesis do not appear to be involved in the early stage of naphthalene or galactose cataract formation. Further studies with compound induced opacities need to be studied; however, Scheimpflug imaging offers several advantages over slit lamp and histologic exams: it is non-invasive, objective, and quantitative.

Keywords: cataract • pathology: experimental • drug toxicity/drug effects