Diabetes complications and their potential prevention: Aldose reductase inhibition and other approaches

Costantino, Luca; Rastelli, Giulio; Vianello, Paola; Cignarella, Giorgio; Barlocco, Daniela

doi:10.1002/(sici)1098-1128(199901)19:1<3::aid-med2>3.3.co;2-z

Cited by 57 publications

(89 citation statements)

References 37 publications

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“…Depletion of NADPH due to AR activity reduces intracellular glutathione (GSH), an endogenous antioxidant, thereby inducing oxidative stress, which is implicated in diabetic complications including retinopathy, nephropathy, neuropathy, and cataract formation (Costantino et al, 1999). The inhibition of AR pathway with chronic oral administration of AR inhibitors (ARIs) has ameliorated diabetic complications in animal models and human subjects (Oates and Mylari, 1999).…”

Section: Introductionmentioning

confidence: 99%

Inhibitory effects of chlorogenic acid on aldose reductase activity in vitro and cataractogenesis in galactose-fed rats

Kim

Lee

et al. 2011

Arch. Pharm. Res.

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Chlorogenic acid (5-O-caffeoylquinic acid, CA), a phenolic compound found ubiquitously in plants, has antidiabetic effect in diabetic animal models. In this study, we investigated the inhibitory effect of CA on diabetic cataractogenesis. We evaluated the aldose reductase (AR) activity during cataract development in 50% galactose-fed rats, an animal model of sugar cataract. Galactose-fed rats were treated orally with CA (10 and 50 mg/kg body weight) once a day for 2 weeks. In vehicle-treated galactose-fed rats, lens opacity was increased, and lens fiber swelling and membrane rupture were observed. In addition, AR protein was highly expressed in lens epithelial cells and lens cortical fibers of galactose-fed rats. However, CA inhibited the rat AR activity in vitro, and the administration of CA prevented the development of sugar cataract through the inhibition of AR activity. These observations suggest that CA is useful for the treatment of sugar cataract.

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Section: Introductionmentioning

confidence: 99%

Inhibitory effects of chlorogenic acid on aldose reductase activity in vitro and cataractogenesis in galactose-fed rats

Kim

Lee

et al. 2011

Arch. Pharm. Res.

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“…Hence it has been considered as a promising therapeutic target and its inhibition has gained attention in past few years (Alexiou et al, 2009). Various aldose reductase inhibitors (ALR2 inhibitors) were found to be implicated in the etiology of the long term diabetic complications, such as retinopathy, nephropathy, and neuropathy (Costantino et al, 1999). Although several aldose reductase inhibitors have progressed to the clinical level, but till date only one drug, epalrestat is currently in the market.…”

Section: Introductionmentioning

confidence: 99%

Induced fit binding of aldose reductase inhibitors to AKR1B10

et al. 2011

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AKR1B10 is a recently identified NADP? dependent aldo-keto reductase. It is strongly over expressed in lung and hepatic carcinomas as well as in colorectal and uterine cancers. AKR1B10 has 71% sequence identity with aldose reductase, the latter plays an important role in diabetic complications. The enzyme also exhibits substratespecificity and inhibitor-sensitivity similar to aldose reductase. Various aldose reductase inhibitors show induced fit phenomenon in aldose reductase. It is reported that the selective ALR2 inhibitor, zopolrestat, also inhibits wild type AKR1B10. In this study, we have performed the induced fit docking of a few aldose reductase inhibitors in crystal structure of AKR1B10 (i.e., 1ZUA). This study elucidates the binding mode of various aldose reductase inhibitors in AKR1B10 and provides insights for the design of more selective and specific inhibitors.

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“…Moreover, from the pioneering studies on sorbinil and alrestatin to recent investigation on zopolrestat and zenarestat, several compounds in clinical trials or on the market for the treatment of the diabetic complications have been developed but were subsequently withdrawn, suggesting that no universally potent inhibitor currently exists. This demands the development of potent inhibitors (Costantino et al, 1999;Miyamoto, 2002;Soni and Kaskhedikar, 2006;Amic et al, 1997;Stefanic-Petek et al, 2002;Prabhakar et al, 2006). To gain insight into the structural and molecular requirements influencing the aldose reductase inhibitor activity, we herein describe QSAR analysis of 5-arylidene-2,4-thiazolidinediones (Maccari et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

QSAR study of 5-arylidene-2,4-thiazolidinediones as aldose reductase inhibitors

Soni¹,

Gupta²,

Kaskhedikar³

2007

Med Chem Res

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The shortage of drugs currently available for the treatment of diabetic complications has aroused our interest for the search of new aldose reductase inhibitors (ARIs) endowed with more favorable biological properties. In response, quantitative structure-activity relationship (QSAR) study has been performed on a series of 5-arylidene-2,4-thiazolidinediones using the Fujita-Ban and the classical Hansch approach and molecular modeling studies employing AM1 calculations to gain structural insight into the binding mode of these molecules to the aldose reductase enzyme. The QSAR models were generated using 18 compounds. The predictive ability of the resulting QSAR models was evaluated employing the leaveone-out method of cross validation. Remarkably, the results obtained from the Fujita-Ban and Hansch approaches were in agreement with the molecular modeling studies. The QSAR analysis reported herein confirms that the presence of the carboxylic anionic head of the N-3 acetic chain is an important, albeit not essential, structural requisite to produce high levels of enzyme inhibition. Furthermore, the hydrophobic substitutions are conducive to this activity.

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Diabetes complications and their potential prevention: Aldose reductase inhibition and other approaches

Cited by 57 publications

References 37 publications

Inhibitory effects of chlorogenic acid on aldose reductase activity in vitro and cataractogenesis in galactose-fed rats

Inhibitory effects of chlorogenic acid on aldose reductase activity in vitro and cataractogenesis in galactose-fed rats

Induced fit binding of aldose reductase inhibitors to AKR1B10

QSAR study of 5-arylidene-2,4-thiazolidinediones as aldose reductase inhibitors

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