An aldose reductase inhibitor
Tolrestat is an aldose reductase inhibitor (IC50 = 35 nM for the bovine lens enzyme).1 Dietary administration of tolrestat decreases sciatic nerve galactitol accumulation in a rat model of galactosemia (ED50 = 7.3 mg/kg per day) and sciatic nerve sorbitol accumulation (ED50 = 4.8 mg/kg per day) in a rat model of diabetes induced by streptozotocin . It also decreases urinary total protein exretion in a rat model of STZ-induced diabetes when administered at a dose of 25 mg/kg per day.2 Topical administration of tolrestat (2 and 3% in 10 μl four times per day) decreases levels of galactitol in the lens of and inhibits cataract formation in rats fed a high-galactose diet.3
1.Sestanj, K., Bellini, F., Fung, S., et al.N-[5-(trifluoromethyl)-6-methoxy-1-naphthalenyl]thioxomethyl]- N-methylglycine (Tolrestat), a potent, orally active aldose reductase inhibitorJ. Med. Chem.27(3)255-256(1984) 2.McCaleb, M.L., McKean, M.L., Hohman, T.C., et al.Intervention with the aldose reductase inhibitor, tolrestat, in renal and retinal lesions of streptozotocin-diabetic ratsDiabetologia34(10)695-701(1991) 3.Banditelli, S., Boldrini, E., Vilardo, P.G., et al.A new approach against sugar cataract through aldose reductase inhibitorsExp. Eye Res.69(5)533-538(1999)
Animal experiment: | For a period of four days, rats weighing about 70 g are given unlimited access to water and Chow supplemented with 20% (wt/wt) galactose and tolrestat at various dose levels. Rats used as control receive chow containing galactose (20%, wt/wt) or glucose (20%, wt/wt). The rats are killed; the lenses and sciatic nerves are removed and homogenized in 5% trichloroacetic acid; the deproteinized extracts are then analyzed for galactitol by a modification of a method for glycerol determination. The values obtained in the group fed 20% glucose are used for background correction. |
参考文献: [1]. Sestanj K, et al. N-[5-(trifluoromethyl)-6-methoxy-1-naphthalenyl]thioxomethyl]- N-methylglycine (Tolrestat), a potent, orally active aldose reductase inhibitor. J Med Chem. 1984 Mar;27(3):255-6. | |
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