Enzyme specificity and tissue distribution of zenarestat, an aldose reductase inhibitor, and its relevance in the use of zenarestat as a therapeutic agent against diabetic neuropathy

The enzyme specificity and tissue distribution of zenarestat, an aldose red uctase inhibitor, was investigated in diabetic rats. Zenarestat inhibited b oth rat sciatic nerve aldose reductase (AR) activity and recombinant human AR with IC50 values of 7.5 and 44 nM, respectively. However, the IC50 value for rat aldehyde reductase of zenarestat was 2.4 muM and the compound did not inhibit any other enzymes tested, e.g., enzymes in the glycolytic pathw ay, NADPH-dependent enzymes such as nitric oxide synthase and glutathione r eductase, at a concentration of 0.1 mM. Two weeks of treatment with zenares tat in diabetic rats reduced sorbitol concentration in sciatic nerve, lens, retina, and renal cortex with ED50 values of 6.9, 41.0, 37.6, and greater than 100 mg/kg, respectively. The tissue distribution of zenarestat was hig her in the sciatic nerve as compared with lens and retina. Zenarestat also reduced sorbitol concentration in dorsal root ganglia and spinal cord in di abetic rats. These data indicate the relevance of zenarestat as a therapeut ic agent for the treatment of diabetic peripheral polyneuropathy. (C) 2001 Wiley-Liss, Inc.