Characterization of a novel aldose reductase inhibitor, FR74366, and its effects on diabetic cataract and neuropathy in the rat

Ao, Shizuo; Shingu, Yasuhiko; Kikuchi, Chie; Takano, Yuko; Nomura, Kazutoshi; Fujiwara, Tatsujiro; Ohkubo, Y.; Notsu, Yoshitada; Yamaguchi, Isamu

doi:10.1016/0026-0495(91)90196-4

Cited by 76 publications

(48 citation statements)

References 43 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: 92%

“…Opacities in both lenses were examined with a slit lamp according to the method of Ao et al (18) after dilating the pupils with Mydrin P (0.5% tropicamide and 0.5% phenylephrine; Santen Pharmaceutical, Osaka). The degree of lens opacity was given a score as follows: 0 = clear normal lens, 1 = slight opacity in the superficial cortical layers, and 2 = diffuse central opacity.…”

Section: Cataract Evaluationmentioning

confidence: 99%

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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: 92%

Section: Cataract Evaluationmentioning

confidence: 99%

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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“…A number of AR inhibitors (ARIs) such as epalrestat (14), tolrestat (15), zenaresat (16), and SNK 860 (18) exhibit some beneficial effects in streptozotocin (STZ)-induced diabetic rats and some are now in clinical trials. The effects of these compounds on cataract forma tion is inadequate in spite of their potent ameliorating effect on the decreased motor nerve conduction velocity (MCV) in diabetic animals.…”

Section: Abstract-gp-1447mentioning

confidence: 99%

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.

Ashizawa¹,

Yoshida²,

Sugiyama³

et al. 1997

Jpn.J.Pharmacol

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“…AR inhibitors can reduce the elevated tissue sor bitol contents through the inhibition of AR, the rate-limit ing enzyme of the polyol pathway. To date, a number of AR inhibitors (12,13) such as epalrestat (Ono Pharm., Osaka) (14,15), tolrestat (Ayerst, Princeton, NJ, USA) (16,17), zenarestat (FK-366; Fujisawa Pharma., Osaka) (18), zopolrestat (Pfizer, Groton, CT, USA) (19) and sor binil (Pfizer) (20)(21)(22) have been found to improve some dia betic complications in animal experiments and have been developed in clinical stages of evaluation. Although these compounds are effective in the nerves, few compounds are effective in other tissues, such as the lens and retina, which are vulnerable to hyperglycemia in the diabetic state.…”

mentioning

confidence: 99%

Pharmacological Profiles of a Novel Aldose Reductase Inhibitor, SPR-210, and Its Effects on Streptozotocin-Induced Diabetic Rats

Matsui

Nakamura

Ishikawa

et al. 1994

Japanese Journal of Pharmacology

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ABSTRACT-SPR-210{2-[4-(4,5,7-trifluorobenzothiazol-2-yl)methyl-3-oxo-3,4-dihydro-2H-1,4-benzo thiazin-2-yl] acetic acid}, a novel aldose reductase (AR) inhibitor, exhibited highly potent inhibition of partially purified AR from porcine lens (IC50=9.5 x 10-9 M) and human placenta (IC50=1.0 x 10-'M). On the other hand, very weak inhibition by SPR-210 was observed against human placenta aldehyde reductase, which is the most closely related enzyme to AR, and against several adeninenucleotide-requiring enzymes. SPR-210 showed a noncompetitive mechanism with respect to DL-glyceraldehyde against porcine lens AR. Sorbitol accumulation in isolated human erythrocytes was effectively inhibited by SPR-210 during incuba tion with 50 mM glucose (IC50=1.6 x 10-'M). Oral administration of SPR-210 (1 30 mg/kg/day for 5 days) to streptozotocin-induced diabetic rats decreased the sorbitol contents in the sciatic nerve and lens (ED50= 1.9 and 6.8 mg/kg/day, respectively). SPR-210 had higher potency in the lens than other AR in hibitors. Moreover, the deterioration in motor nerve conduction velocity in diabetic rats was ameliorated by treatment with SPR-210 (1-30mg/kg/day) accompanying the reduction in sorbitol content in the sciatic nerve. SPR-210 induced the recovery of the delayed peak latency of oscillatory potentials (O, 04) in the electroretinogram in diabetic rats (10 mg/kg/day). These results suggest that the specific AR inhibitor SPR 210 will be a useful therapeutic agent for preventing and improving some diabetic complications, especially diabetic neuropathy and retinopathy, and therefore, can be discriminated from other AR inhibitors.

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Characterization of a novel aldose reductase inhibitor, FR74366, and its effects on diabetic cataract and neuropathy in the rat

Cited by 76 publications

References 43 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

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.

Pharmacological Profiles of a Novel Aldose Reductase Inhibitor, SPR-210, and Its Effects on Streptozotocin-Induced Diabetic Rats

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