A novel carboxymethylated mercaptotriazinoindole inhibitor of aldose reductase interferes with the polyol pathway in streptozotocin-induced diabetic rats.

Abstract

The aim of the present work was to study the effect of 3-mercapto-5H-1,2,4-triazino[5,6-b]indole-5-acetic acid (CMTI), an efficient aldose reductase inhibitor, on sorbitol accumulation in selected organs of streptozotocin-induced diabetic rats in vivo. In addition, the effect of CMTI on aldose reductase back reaction and on sorbitol dehydrogenase was determined. The model of experimental diabetes in male Wistar rats induced by streptozotocin was used. Experimental diabetes was induced by triple intraperitoneal doses of streptozotocin on three consecutive days. In diabetic rats, significant elevation of sorbitol concentration in the sciatic nerve and eye lenses was recorded. CMTI administered intragastrically (50 mg/kg/day) for five consecutive days significantly inhibited sorbitol accumulation in the sciatic nerve, yet it was without effect in eye lenses of diabetic animals. For aldose reductase back reaction, the substrate affinity of glycerol to aldose reductase was one order lower than that of glyceraldehyde in forward reaction. In addition, the back reaction was much slower, characterized by V(max) value of about 30 times lower than that of the forward reaction. Inhibition of aldose reductase by CMTI was characterized by closely related IC(50) values in submicromolar range for both forward and back reactions. No significant inhibition of the second enzyme of the polyol pathway, sorbitol dehydrogenase, by 100 microM CMTI was recorded (I=0.9+/-2.7 %, n=3). To conclude, the presented results showed the ability of CMTI to affect the polyol pathway in diabetic rats in vivo and represent thus a further step in a complex preclinical evaluation of CMTI as a potential agent for treatment of chronic diabetic complications.