Inhibition of aldose reductase

Chethan, S., Dharmesh, S. M., and Malleshi, N. G. (2008a). Inhibition of aldose reductase from cataracted eye lenses by finger millet (Eleusine coracana) polyphenols. Bioorg. Med. Chem. 16,10085-10090. 

The structure of (60) and other inhibitors Tound to porcine aldose reductase (136) provided a rich lode of information on the requirements for potent and selective inhibition of aldose reductase. This was mined by scientists at the Institute for Diabetes Discovery, in a project that began in 1996. The Institute for Diabetes Discovery filed an IND application for (61) (lidorestat, IDD 676), a potent aldose... 

The overall accumulation of sorbitol in the retina of diabetic rats seems to be of little significance, but the distribution of the polyols in the different cellular locations could produce osmotic force. In alloxan-diabetic animals the above-mentioned triad of myo-inositol depletion, reduced Na/K-ATPase activity and activation of PKC following accumulation of sorbitol is seen and can be prevented by inhibition of aldose reductase (MacGregor and Matschinsky, 1985), although the impact of this system on the generation of diabetic retinopathy remains to be established. 

The presence of aldose reductase in many tissues, which may not be involved in diabetic complications, makes unwanted effects likely, although isozymic differences in the enzyme in different tissues may be possible. Since aldose reductase inhibitors are not yet regularly used and since the effects of long-term inhibition of aldose reductase are not yet known, knowledge on possible unwanted effects is scarce. Information on side effects is therefore based only on individual reports. 

Stefanic-Petek, A., Krbavcic, A. and Solmajer, T. (2002) QSAR of flavonoids. 4. Differential inhibition of aldose reductase and p56 protein tyrosine kinase. Croat. Chem. Acta, 75, 517-529. 

Okuda J, Miwa I, InagaM K et al (1984) Inhibition of aldose reductase by 3, 4 -dihydroxy-flavones. Chem Pharm Bull 32 767-772... 

Okuda J, Miwa I, Inagaki K et al (1982) Inhibition of aldose reductases from rat and bovine lenses by flavonoids. Biochem Pharmacol 31 3807-3822... 

Morales J, Dunbar JC, Ram JL (2002) Effect of aldose reductase inhibition on interleukin-ip-induced nitric oxide (NO) synthesis in vascular tissue. Int J Exp Diabetes Res 3(1) 11-20 Muthenna P, Suryanarayana P, Gunda SK, Petrash JM, Reddy GB (2009) Inhibition of aldose reductase by dietary antioxidant curcumin mechanism of inhibition, specificity and significance. EEBS Eett 583(22) 3637-3642... 

Shoeb M, Yadav UC, Srivastava SK, Ramana KV (2011) Inhibition of aldose reductase prevents endotoxin-induced inflammation by regulating the arachidonic acid pathway in murine macrophages. Free Radic Biol Med 51(9) 1686-1696... 

Tarralin, an ethanolic extract of A. dracunculus, administered to genetically diabetic mice by oral gavage resulted in a significant anti-hyperglycemic effect in comparison to trogli-tazone and metformin. The effect was attributed to the inhibition of aldose reductase by the four compounds mentioned above, which was comparable to that produced by quercitrin as a reference control. 

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