Characterization of a Novel Aldose Reductase Inhibitor, TAT, and Its Effects on Streptozotocin-Induced Diabetic Neuropathy in Ra

Abstract

TAT {[5-(3-thienyl)tetrazol-l-yl]acetic acid} is a novel aldose reductase (AR) inhibitor. It exhibited highly potent inhibition of partially purified AR from rat lens (IC50=2.1 × 10-8 M), rabbit lens (IC50 = 2.3 × 10-8 M) and human placenta (IC50=2.8 × 10-8 M). On the other hand, TAT had a weak inhibitory activity against mouse liver aldehyde reductase (ALR) (IC50=2.4x 10“6M) and poor inhibitory activity against several adeninenucleotide-requiring enzymes. Against rat lens AR, TAT exhibited an uncompetitive inhibition at a concentration of l. Ox 10-8M and a mixed type inhibition at higher concentrations. TAT inhibited sorbitol accumulation in the isolated rat sciatic nerve (IC50= l. Ox 10-6 M), rat lens (IC50=5.7x 10-6 M), human erythrocytes (IC50=2.5 × 10-7 M), and rabbit erythrocytes (IC50=2.1 × 10-7 M) incubated with high glucose concentrations. The oral administration of TAT (5-100 mg/kg/day) to streptozotocin (STZ)-induced diabetic rats during a 5-day treatment period decreased the sorbitol content in the sciatic nerve, dose-dependently (ED50: 8.8 mg/kg/day for the prevention and 9.0 mg/kg/day for the reversal). Moreover, TAT (2.5-40 mg/kg/day) improved the decreased motor nerve conduction velocity (MNCV) after a 14-day treatment period. There was a significant correlation between MNCV and sciatic nerve sorbitol content. From these results, TAT is expected to be useful for the clinical treatment of diabetic complications. © 1993, The Japanese Pharmacological Society. All rights reserved.