DIABETIC-LIKE RETINOPATHY AMELIORATED WITH THE ALDOSE REDUCTASE INHIBITOR WAY-121,509

Purpose. To evaluate the efficacy of WAY-121,509, a potent new aldose reductase inhibitor (ARI), in preventing the retinopathy that develops in the galactose-fed rat model of diabetic ocular complications. Meth ods. Sprague-Dawley rats were randomized into treatment and duration g roups and fed diets with either 50% starch or 50% galactose with or wi thout WAY-121,509 (25 mg/kg body weight per day). Progression of catar acts was monitored by slit-lamp biomicroscopy. After durations of 4, 8 , 16, and 24 months, levels of plasma glucose and glycated hemoglobin, as well as erythrocyte and retinal galactose and galactitol, were mea sured in rats of each group. Retinal vasculatures of the 24-month rats were isolated by elastase digestion and analyzed by computer-assisted morphometry. Results. Mature, diabetic-like cataracts developed withi n 5 weeks in all the galactose-fed, untreated rats, but only nonprogre ssive anterior cortical opacities were present in lenses of 85% of the ARI-treated galactosemic animals after 3 months. Plasma glucose remai ned the same in all groups. Erythrocyte and retinal galactose and glyc ated (galactosylated) hemoglobin were elevated with galactosemia and w ere unaffected by ARI treatment. Erythrocyte and retinal galactitol le vels were decreased by 91% and 95%, respectively, with inhibitor treat ment. At 24 months, capillary length, width, density, the number of mi croaneurysms, and the percent of capillary length involved in intraret inal microvascular abnormalities, expressed as hypercellular channels with diameters >20 mu m, were significantly increased by galactosemia and were attenuated in the galactose-fed, ARI-treated group. Conclusio ns. A dose of WAY-121,509 sufficient to reduce retinal polyol levels b y 95% ameliorated the development of galactose-induced cataracts and d iabetic-like retinopathy but was insufficient to prevent early lens op acifications or all the diabetic-like retinal microangiopathies.