Effect of a new aldose reductase inhibitor, 8'-chloro-2',3'-dihydrospiro [pyrrolidine-3,6'(5'H)-pyrrolo[1,2,3-de] [1,4]benzoxazine]-2,5,5'- trione (ADN-138), on delayed motor nerve conduction velocity in streptozotocin-diabetic rats

The effects of a chemically new type of aldose reductase inhibitor, ADN-138, on delayed motor nerve conduction velocity (MNCV) and sciatic nerve sorbitol, fructose and myo-inositol levels were studied in streptozotocin-diabetic rats. MNCV in rats was significantly delayed after 3 weeks of diabetes and ADN-138 treatment was started at this point. Treatment of diabetics with ADN-138 at 5 and 20 but not 1 mg/kg/d for 3 weeks resulted in a significant increase in MNCV and reduced sorbitol levels to or below those of nondiabetic controls. However, fructose, though decreased in a dose-dependent manner, was not normalized. The reference drug, Sorbinil, showed similar effects on them. After the 3 weeks of ADN-138(20 mg/kg/d) treatment, diabetics were left on ADN-138 or continued further to be treated with it for 3 weeks. The withdrawal of ADN-138 prevented a further increase in MNCV and restored sorbitol and fructose to nontreated diabetic levels, and myo-inositol levels declined. In contrast, the ADN-138-continued group kept improving its MNCV and normalized sorbitol and myo-inositol. These results suggest that polyol accumulation is responsible for delayed MNCV and that the action of ADN-138 on MNCV reflected reversibility of metabolic function in diabetics.