Effects of a Novel Potent Aldose Reductase Inhibitor, GP-1447, on Aldose Reductase Activity In Vitro and on Diabetic Neuropathy and Cataract Formation in Rats.

Ashizawa, Naoki; Yoshida, Motoyuki; Sugiyama, Yoshiko; Akaike, Nobuhide; Ohbayashi, Shigeo; Aotsuka, Tomoji; Abe, Naoki; Fukushima, Kanako; Matsuura, Akihiro

doi:10.1254/jjp.73.133

Cited by 31 publications

(26 citation statements)

References 32 publications

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“…STZ-diabetic rats have been reported to show sciatic nerve and lens functional and biochemical changes similar to those that occur in patients with diabetes (17,18,20,21), although the histopathological changes in STZ-induced diabetic rats are milder than functional and biochemical abnormalities (19). In addition, neuropathological lesions characterized by reduced axonal area (atrophy) of the peripheral meylinated nerve fibers have been reported in STZ-diabetic rats (14,22,23).…”

Section: Discussionmentioning

confidence: 94%

Long-Term Treatment With Ranirestat (AS-3201), a Potent Aldose Reductase Inhibitor, Suppresses Diabetic Neuropathy and Cataract Formation in Rats

et al. 2008

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Abstract. We investigated the chronic functional and histopathological changes in the sciatic nerve and lens of streptozotocin (STZ)-diabetic rats and evaluated the preventive effects of ranirestat (AS-3201), a potent aldose reductase inhibitor, on these changes. Sorbitol levels in the sciatic nerve and lens, motor nerve conduction velocity (MNCV), and development of cataracts were measured in STZ-diabetic rats given a ranirestat-admixed diet (0.0005%) for 35 weeks. Ranirestat reduced sorbitol accumulation in the sciatic nerve and improved the decrease in MNCV of STZ-diabetic rats. Morphological and morphometric examination of changes in sural nerve revealed that treatment with ranirestat prevented both the deformity of myelinated fibers and the decrease in their axonal and myelin areas (atrophy). Ranirestat also averted the changes in the size frequency histogram of myelinated fibers. Finally, STZ-diabetic rats developed early lens opacities 8 weeks after STZ injection and had cataract by the end of the experimental period. However, in the ranirestat-treated diabetic rats, no lens opacity was observed in any rat throughout the entire experimental period. This study suggests that the polyol pathway plays an important role in the progress of diabetic neuropathy and cataract formation in STZ-diabetic rats. Ranirestat should be a promising agent for the treatment of complications associated with diabetes, especially neuropathy.

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Section: Discussionmentioning

confidence: 94%

Long-Term Treatment With Ranirestat (AS-3201), a Potent Aldose Reductase Inhibitor, Suppresses Diabetic Neuropathy and Cataract Formation in Rats

et al. 2008

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“…It has been demonstrated that such drugs are actually e¡ective in suppressing cataract formation in lens [13]. A generally accepted mechanism by which the drug exerts its e¡ect is through suppression of the formation of sorbitol, a sugar alcohol which penetrates the cell membrane with di¤culty and, therefore, contributes to the elevation of osmolarity within cells.…”

Section: Discussionmentioning

confidence: 99%

“…The sorbitol content of rat lens was determined using a method described previously [13], by measuring the enzymatic formation of NADH from NAD with sorbitol dehydrogenase.…”

Section: Measuring Sorbitol Content In Rat Lensesmentioning

confidence: 99%

Specific detections of the early process of the glycation reaction by fructose and glucose in diabetic rat lens

et al. 1998

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The glycation reaction by fructose, as well as that by glucose, in control and diabetic rat lens was analyzed by using antibodies which specifically recognize adducts of lysine with fructose and with glucose. Levels of fructose adducts in diabetic rat lens were 2.5 times that of the control, and correlated with sorbitol levels. This was mainly due to enhanced glycation of L Land Q Q-crystallins by fructose under diabetic conditions. These data suggest that glycation by fructose may also play a role in cataract formation under conditions of diabetes and aging.z 1998 Federation of European Biochemical Societies.

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“…inhibitor GP-1447, which has been reported to prevent completely the diabetic cataract (20), in order to determine whether the drug can inhibit cataract formation even under our severe experimental conditions. Seven diabetic rats were fed on chow containing 0.01% w /w GP-1447 for 9 weeks from the third day of streptozo- tocin injection.…”

Section: Drug Treatmentmentioning

confidence: 99%

“…Seven diabetic rats were fed on chow containing 0.01% w /w GP-1447 for 9 weeks from the third day of streptozo- tocin injection. The concentration was chosen on the basis of the previous report (20).…”

Section: Drug Treatmentmentioning

confidence: 99%

A Novel High Resolution In Vivo Digital Imaging System for the Evaluation of Experimental Cataract in Diabetic Rats

et al. 2008

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Abstract. The purpose of this study was to establish a novel imaging system for evaluation of cataract in small animals. Diabetic cataract was induced in male Wistar rats by a combination of a bolus injection of streptozotocin (65 mg/kg, i.v.) and 5% D-glucose given as drinking water. To assess cataract development, we designed a digital camera system equipped with a nonreflecting illuminator for capturing clear high-resolution full lens images in the horizontal plane. Cataract was evaluated from the resulting images using both an observer-based scoring system and quantitative digital image-analysis techniques. The onset of cataract was detected in the peripheral section of the lens in 57% of cases 2 weeks after induction of hyperglycemia. Central opacities were visible following 3 weeks in hyperglycemic conditions. The cataract increased in severity with time, so that by week 9 in hyperglycemic conditions, mature cataracts were developed in over 90% of lenses. Treatment of diabetic rats with GP-1447, an aldose reductase inhibitor, completely prevented the formation of diabetic cataracts. These results indicate that the digital imaging system established in the present study permits an assessment of all stages of cataract development and it is helpful for accurately evaluating the effects of therapeutic drugs on cataracts.

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Effects of a Novel Potent Aldose Reductase Inhibitor, GP-1447, on Aldose Reductase Activity In Vitro and on Diabetic Neuropathy and Cataract Formation in Rats.

Cited by 31 publications

References 32 publications

Long-Term Treatment With Ranirestat (AS-3201), a Potent Aldose Reductase Inhibitor, Suppresses Diabetic Neuropathy and Cataract Formation in Rats

Long-Term Treatment With Ranirestat (AS-3201), a Potent Aldose Reductase Inhibitor, Suppresses Diabetic Neuropathy and Cataract Formation in Rats

Specific detections of the early process of the glycation reaction by fructose and glucose in diabetic rat lens

A Novel High Resolution In Vivo Digital Imaging System for the Evaluation of Experimental Cataract in Diabetic Rats

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