Abstract
The authors investigate the effect of aldose reductase inhibitor FR74366 on diabetic cataract. Streptozocin (STZ)-induced diabetic rats were treated with eye drops of FR74366 (0.03%, 0.1%, and 0.3%) for 16 weeks. Lenses were examined using a slit lamp, and the score of lens opacity was determined on a scale of from 0 (normal lens) to 4 (matured nuclear cataract). Diabetic placebo control rats developed lens opacity linearly, beginning at 3 weeks and reaching a maximum at 8 weeks after STZ injection. Instillation of FR74366 to diabetic rats delayed the cataract formation and inhibited lens sorbitol accumulation in a dose-dependent manner. At 16 weeks after STZ injection, the score of lens opacity was more than 3 (diffuse central opacities) in diabetic placebo control rats, whereas it was less than 2 (peripheral vesicles and cortical opacities) and the lenses remained clear in animals treated with 0.3% of FR74366. Measurement of tissue drug concentrations indicated that FR74366 penetrated into the lens, where its levels were increased in a dose- and time-dependent manner. These three parameters (score of lens opacity and sorbitol and FR74366 levels) were well correlated with each other. Instillation of FR74366 also reduced the sorbitol levels in the retina. However, the sorbitol levels in the sciatic nerve and renal cortex were not changed by instillation of FR74366. Instillation or oral administration of FR74366 has not shown serious side effects in animal toxicity studies. These results suggested that instillation of FR74366 may be a useful therapeutic agent against diabetic cataract and retinopathy.