Using the galactose-fed rat model for diabetic retinopathy, which was first developed in this laboratory, we designed intervention studies to test the possibility of delaying, halting, or reversing retinopathy soon after the earliest capillary lesions could be documented. Weanling male SD rats were divided into five groups, three of which received either normal lab chow or a 50% galactose diet with an aldose reductase inhibitor (ARI:ca. 11 mg/kg/day AL-3152) and two of which received 50% galactose for 6 months and then intervention, by either normal lab chow or a 50% galactose for 6 months and then intervention, by either addition of inhibitor or removal of galactose. From each rat killed at 6, 18, and 24 months, one retina was prepared for obtaining electron micrographs of capillary transections and the other was used for whole mounts of isolated retinal vessels. We captured images of whole and transacted capillaries and analyzed them using computer hardware and programs specially designed for 1,024 x 1,024 x 8-bit resolution. Based on several quantitative assessments, including basement membrane thickness, PAS stain intensity, a cellularity, dilation, tortuosity, length, and microaneurysms, the retinopathy was graded on a scale of 1 to 10. At 6 months, when intervention began, untreated galactose-fed rats exhibited a 30%, statistically significant (p<0.01) increase in capillary basement membrane thickness and grade-1 retinopathy overall. By 18 months, the same group had grade-7 retinopathy whereas rats receiving intervention with either AL-3152-enriched or galactose-free diets exhibited only grade-2 retinopathy, and rats fed control diet or galactose plus AL-3152 throughout 18 months showed none. At 24 months, untreated rats had grade-10 retinopathy, and both intervention groups had grade-8 retinopathy. Thus, intervention at 6 months delays but does not halt or reverse the progression of galactose-induced retinopathy. We plan to attempt, by dietary manipulation, to produce rat models that develop the diabetic-like retinal angiopathies sooner. Also, using cell culture, we will investigate possible mechanisms of endothelial cell proliferation and subsequent pathologies.
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