GP-1447, an inhibitor of aldose reductase, prevents the progression of diabetic cataract in rats.
We examined the effects of GP-1447 (3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]-5-methylphenyl acetic acid) on existing cataracts and sorbitol content in the lens in rats with streptozotocin-induced diabetes. GP-1447 is an inhibitor of aldose reductase, which is the first enzyme in the polyol pathway. Cataracts in the central region of the lens were observed in 7 of 14 eyes (50%) by the fifth week after induction of diabetes, and development of mature cataracts was observed in most lenses by the ninth week. In diabetic rats that received GP-1447 treatment beginning in the fifth week after induction of diabetes, progression of cataracts was observed for 1 week after initiation of treatment. Thereafter, the severity of cataracts did not change substantially. Sorbitol levels in the lens peaked during the first week of diabetes, and this increase was maintained during the 9-week observation period. Elevated sorbitol levels in the lenses of diabetic rats gradually declined after GP-1447 treatment was started on the fifth week after induction of diabetes. Cataracts and sorbitol elevation were not observed in the lenses of controls or diabetic rats treated with GP-1447 immediately after induction of diabetes. These results suggest that the polyol pathway plays an important role in both the appearance and progression of cataracts in diabetic rats. Inhibition of aldose reductase could significantly prevent progression of existing cataracts.
Department of Molecular Pharmacology, School of Pharmaceutical Sciences, Kitasato University, Minato-ku, Tokyo, Japan.
Ken
K
Kawakubo
Asami
A
Mori
Kenji
K
Sakamoto
Tsutomu
T
Nakahara
Kunio
K
Ishii
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002386:Cataract / Q000378:metabolism / Q000517:prevention & control*; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D007908:Lens, Crystalline / Q000378:metabolism; D008297:Male; D010648:Phenylacetates / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D012160:Retina / Q000378:metabolism; D013012:Sorbitol / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use*
D001786:Blood Glucose; D004791:Enzyme Inhibitors; C106125:GP 1447; D010648:Phenylacetates; D013844:Thiazoles; D013012:Sorbitol; D000449:Aldehyde Reductase