Characterization of a novel aldose reductase inhibitor, TAT, and its effects on streptozotocin-induced diabetic neuropathy in rats.
TAT ([5-(3-thienyl)tetrazol-1-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 x 10(-8) M), rabbit lens (IC50 = 2.3 x 10(-8) M) and human placenta (IC50 = 2.8 x 10(-8) M). On the other hand, TAT had a weak inhibitory activity against mouse liver aldehyde reductase (ALR) (IC50 = 2.4 x 10(-6) M) and poor inhibitory activity against several adenine nucleotide-requiring enzymes. Against rat lens AR, TAT exhibited an uncompetitive inhibition at a concentration of 1.0 x 10(-8) M and a mixed type inhibition at higher concentrations. TAT inhibited sorbitol accumulation in the isolated rat sciatic nerve (IC50 = 1.0 x 10(-6) M), rat lens (IC50 = 5.7 x 10(-6) M), human erythrocytes (IC50 = 2.5 x 10(-7) M), and rabbit erythrocytes (IC50 = 2.1 x 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.
Inukai
S
S
Research Department, Wakamoto Pharmaceutical Co., Ltd., Kanagawa, Japan.
Agata
M
M
Sato
M
M
Naitou
A
A
Matsukawa
H
H
Goto
M
M
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D003929:Diabetic Neuropathies / Q000188:drug therapy*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009431:Neural Conduction / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000187:drug effects / Q000378:metabolism; D013012:Sorbitol / Q000378:metabolism; D013402:Sugar Alcohols / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D013876:Thiophenes / Q000494:pharmacology / Q000627:therapeutic use*
D013402:Sugar Alcohols; D013777:Tetrazoles; D013876:Thiophenes; C080974:(5-(3-thienyl)tetrazol-1-yl)acetic acid; D013012:Sorbitol; D000449:Aldehyde Reductase