Aldose reductase [ALR2; EC 1.1.1.21], a key enzyme of polyol pathway, catalyzes NADPH-dependent reduction of glucose to sorbitol (Sorbitol pathway), and an excessive accumulation of intracellular sorbitol found in various tissues of diabetic animals and in cells cultured under high glucose conditions has been proposed to be an important factor for the pathogenesis of diabetic complications. The only strategy shown to be consistently beneficial in the treatment of diabetic complications is meticulous control of blood glucose. However, aldose reductase (AR) enzyme inhibition is becoming one of the therapeutic strategies that have been proposed to prevent or ameliorate long-term diabetic complications. Therefore, AR inhibitors (ARIs) hold promise for reducing metabolic nerve injury, but further study is needed. On the other hand, there is strong evidence to show that diabetes is associated with increased oxidative stress. However, the source of this oxidative stress remains unclear. This relationship between diabetic complications and free radical production was also under investigation. The studies suggest that hydroxyl radical is indirectly inhibited by ARIs resulting from decreasing polyol levels and hydroxyl radical formation is related to the early stages of diabetic complications, possibly via the Fenton reaction involving H(2)O(2) produced from the activated polyol pathway. Therefore, it is proposed that hydroxyl radical may accelerate damage to the cell membranes resulting from polyol accumulation. The search for specific inhibitors of AR enzyme has still become a major pharmaceutic challenge, though a number of AR inhibitors have so far been assessed for diabetic complications.

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