scholarly journals Diosgenin, a Novel Aldose Reductase Inhibitor, Attenuates the Galactosemic Cataract in Rats

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Lixia Ji ◽  
Lixia Cheng ◽  
Zhihong Yang
Keyword(s):  
Aldose Reductase ◽  
Reductase Inhibitor ◽  
Biological Activities ◽  
Aldose Reductase Inhibitor ◽  
Synthetic Compounds ◽  
Natural Extracts ◽  
Reductase Inhibitors ◽  
Sugar Cataract

Objective. To seek efficient aldose reductase inhibitors (ARIs) with excellent in vitro and in vivo biological activities against rat galactosemic cataract. Methods. The method was firstly optimized to screen strong ARIs from nonoriented synthetic compounds and natural extracts. Then, diosgenin was assessed on osmotic expansion of primarily cultured lens epithelial cells (LECs) induced by galactose (50 mM). Diosgenin was administered to galactosemic rats by oral (100 and 200 mg/kg) or direct drinking (0.1%) to evaluate its anticataract effects. Results. Diosgenin was found as the strongest ARI with IC50 of 4.59 × 10−6 mol/L. Diosgenin (10 μM) evidently inhibited the formation of tiny vacuoles and upregulation of AR mRNA in LECs. In vivo, diosgenin delayed lens opacification, inhibited the increase of ratio of lens weight to body weight, and decreased AR activity, galactitol level, and AR mRNA expression, especially in the diosgenin drinking (0.1%) group. Conclusions. Diosgenin was an efficient ARI, which not only significantly decreased the LECs’ osmotic expansion in vitro but also markedly delayed progression of rat galactosemic cataract in vivo. Thus, diosgenin rich food can be recommended to diabetic subjects as dietary management to postpone the occurrence of sugar cataract, and diosgenin deserves further investigation for chronic diabetic complications.

scholarly journals Purified rat lens aldose reductase. Polyol production in vitro and its inhibition by aldose reductase inhibitors

1986 ◽  
Vol 240 (1) ◽  
pp. 233-237 ◽  
Author(s):  
P F Kador ◽  
J H Kinoshita ◽  
D R Brittain ◽  
D J Mirrlees ◽  
C M Sennitt ◽  
...  
Keyword(s):  
Aldose Reductase ◽  
Reductase Inhibitor ◽  
Aldose Reductase Inhibitor ◽  
Free Radical Scavenger ◽  
Radical Scavenger ◽  
Kinetic Measurements ◽  
Rat Lens Aldose Reductase ◽  
Aldose Reductase Inhibitors ◽  
Reductase Inhibitors

The production of polyols in vitro by highly purified aldose reductase (EC 1.1.1.21) was monitored by g.l.c. In the presence of NADPH aldose reductase reduced glucose, galactose and xylose to the respective polyols sorbitol, galactitol and xylitol. The rates of formation of these polyols closely mirrored the Km values for the substrates obtained from kinetic measurements that monitored the rate of disappearance of NADPH. No polyol production occurred in the absence of purified aldose of purified aldose reductase, and analysis by g.l.c. revealed only the presence of unchanged monosaccharides. Addition of the aldose reductase inhibitor sorbinil to purified rat lens aldose reductase incubated with xylose in the presence of NADPH resulted in decreased xylitol production. However, aldose reductase inhibitors produced no effect in altering the rate of Nitro Blue Tetrazolium formation from either glucose or xylose, indicating that the observed inhibition in vitro does not result from a free-radical-scavenger effect.

scholarly journals Development of Novel Indole-Based Bifunctional Aldose Reductase Inhibitors/Antioxidants as Promising Drugs for the Treatment of Diabetic Complications

Molecules ◽  
2021 ◽  
Vol 26 (10) ◽  
pp. 2867
Author(s):  
Lucia Kovacikova ◽  
Marta Soltesova Prnova ◽  
Magdalena Majekova ◽  
Andrej Bohac ◽  
Cimen Karasu ◽  
...  
Keyword(s):  
Aldose Reductase ◽  
Diabetic Complications ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Biological Activities ◽  
In Vivo Models ◽  
Aldose Reductase Inhibitors ◽  
Reductase Inhibitors ◽  
Promising Therapeutic Approach

Aldose reductase (AR, ALR2), the first enzyme of the polyol pathway, is implicated in the pathophysiology of diabetic complications. Aldose reductase inhibitors (ARIs) thus present a promising therapeutic approach to treat a wide array of diabetic complications. Moreover, a therapeutic potential of ARIs in the treatment of chronic inflammation-related pathologies and several genetic metabolic disorders has been recently indicated. Substituted indoles are an interesting group of compounds with a plethora of biological activities. This article reviews a series of indole-based bifunctional aldose reductase inhibitors/antioxidants (ARIs/AOs) developed during recent years. Experimental results obtained in in vitro, ex vivo, and in vivo models of diabetic complications are presented. Structure–activity relationships with respect to carboxymethyl pharmacophore regioisomerization and core scaffold modification are discussed along with the criteria of ‘drug-likeness”. Novel promising structures of putative multifunctional ARIs/AOs are designed.

Spirohydantoin derivatives of thiopyrano[2,3-b]pyridin-4(4H)-one as potent in vitro and in vivo aldose reductase inhibitors

2005 ◽  
Vol 13 (2) ◽  
pp. 491-499 ◽  
Author(s):  
Federico Da Settimo ◽  
Giampaolo Primofiore ◽  
Concettina La Motta ◽  
Silvia Salerno ◽  
Ettore Novellino ◽  
...  
Keyword(s):  
Aldose Reductase ◽  
Aldose Reductase Inhibitors ◽  
Reductase Inhibitors ◽  
Derivatives Of

Aldose Reductase Inhibitors: An Update

1993 ◽  
Vol 27 (6) ◽  
pp. 751-754 ◽  
Author(s):  
Sandra C. Tsai ◽  
Thomas G. Burnakis
Keyword(s):  
Clinical Trials ◽  
Aldose Reductase ◽  
Reductase Inhibitor ◽  
Aldose Reductase Inhibitor ◽  
Data Synthesis ◽  
Medline Search ◽  
Reductase Inhibitors ◽  
Pharmaceutical Manufacturers ◽  
Study Selection ◽  
Pain Symptoms

OBJECTIVE: To update readers on research being conducted with the aldose reductase inhibitor (ARI) tolrestat in treating complications of diabetes mellitus. The article briefly describes early investigations with other ARIs and reviews the more recent studies of tolrestat. In addition, the article gives readers a simplified overview of the biochemical background pertinent to the use of these agents. DATA SOURCES: A MEDLINE search was performed to identify articles relating to the clinical use of, and research involving, the following ARIs: sorbinil, alrestatin, ponalrestat, and tolrestat. In addition, pharmaceutical manufacturers were contacted in an attempt to obtain data relating to ongoing investigations. STUDY SELECTION: Review articles and clinical trials of sorbinil, alrestatin, and ponalrestat were included. Articles dealing with clinical trials of tolrestat were selected from the MEDLINE search. As there were only a few trials, all studies identified were included. No additional written data were available from the manufacturers. DATA SYNTHESIS: ARIs, which when first introduced were proclaimed to be major advances in treating diabetic complications, have never produced the expected results. Problems with efficacy and toxicity relegated most of this class of agents to historical interest. One compound, tolrestat, has continued to be tested and has potential clinical application. To date, the extent of benefit that has been realized in tolrestat-treated patients is small to moderate. Improvements have occurred in paresthesia and neuropathy, but unfortunately, not in pain symptoms. Adverse effects have been minor and are primarily confined to elevations of hepatic alanine aminotransferase. Additional clinical trials are being conducted with this agent. CONCLUSIONS: Tolrestat is the only one of the original ARIs still undergoing clinical trials. Results so far have been encouraging, but by no means definitive, for improvement in some aspects of diabetic neuropathy. Information from ongoing investigations is necessary before the true usefulness of tolrestat therapy can be determined.

Permeability changes at blood-retinal barrier in diabetes and effect of aldose reductase inhibition

1990 ◽  
Vol 259 (3) ◽  
pp. R601-R605
Author(s):  
S. Lightman ◽  
G. Pinter ◽  
L. Yuen ◽  
M. Bradbury
Keyword(s):  
Aldose Reductase ◽  
Reductase Inhibitor ◽  
Concomitant Administration ◽  
Aldose Reductase Inhibitor ◽  
Normal Diet ◽  
Diabetic Rat ◽  
Blood Retinal Barrier ◽  
Time Points ◽  
Permeability Changes

Sensitive quantitative in vivo techniques were used to assess the permeability at the blood-retinal barrier (BRB) to [14C]sucrose in the anesthetized streptozocin-diabetic rat at various time points (3 wk, 6 mo, 13 mo) after induction of diabetes. The effects of concomitant administration of an aldose reductase inhibitor (ARI) on sorbitol levels in the retina and on BRB permeability were also measured. No increase in BRB permeability was found in rats diabetic for 3 wk or 6 mo, but after 13 mo of hyperglycemia there was an increase in permeability of 240%. No effect on permeability was seen in diabetic animals given the ARI despite the retinal sorbitol levels being decreased in the treated compared with the untreated diabetic group fed a normal diet. This study suggests that the accumulation of sorbitol within the cells of the BRB is not responsible for the breakdown of BRB permeability seen after 7-13 mo of hyperglycemia and that the enzyme aldose reductase is not involved in its pathogenesis.

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