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Effect of Epalrestat, an Aldose Reductase Inhibitor, on the Generation of Oxygen-Derived Free Radicals in Neutrophils from Streptozotocin-Induced Diabetic Rats¹

First Department of Internal Medicine, Gunma University School of Medicine, 3–39-22, Maebashi Gunma, 371, Japan

Address all correspondence and requests for reprints to: Noriyuki Sato, M.D., Ph.D., First Department of Internal Medicine, Gunma University School of Medicine, 3–39-22, Showa, Maebashi, Gunma, 371, Japan. E-mail: satonori{at}sb.gunma-u.sc.jp

Neutrophil function is impaired by a known mechanism in diabetic patients, thus increasing susceptibility to infections. We studied the effect of epalrestat, an aldose reductase inhibitor, on the generation of oxygen-derived free radicals and cytosolic sorbitol concentration in neutrophils from streptozotocin-induced diabetic rats. There were four groups: treated and untreated control and diabetic rats. Treated groups were given 0.075% epalrestat in their diet for 4 weeks from the induction of diabetes and were untreated for the subsequent 4 weeks. Oxygen radicals were measured as chemiluminescence amplified by a luciferin analog [Cypridina luciferin analog-dependent chemiluminescence (CLA-DCL), which is dependent on O₂^- generation] and luminol (L)-DCL, which is highly dependent on OCl^- generation) in response to formyl-methonyl-leucyl-phenylalanine. Diabetes resulted in a significant decrease in CLA/L-DCL and a significant increase in sorbitol (P < 0.01); there was a negative correlation between sorbitol and CLA-DCL (P < 0.05) in diabetic groups. The 4-week treatment with epalrestat in the diabetic group completely prevented the increase in sorbitol and partially improved the CLA-DCL, although L-DCL was not significantly affected. After 4 weeks off treatment, CLA-DCL decreased and sorbitol increased. Treatment had no effect on serum insulin or glucose concentration. We conclude that an increase in sorbitol in neutrophils causes, in part, an impaired generation of O₂^-. Epalrestat improves the impaired O₂^- generation by preventing the sorbitol increase in streptozotocin-induced diabetic rats.