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.
Hirata
Y
Y
Central Research Laboratories, Kyorin Pharmaceutical Co, Ltd, Tochigi, Japan.
Fujimori
S
S
Okada
K
K
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D005947:Glucose / Q000032:analysis; D007093:Imidazoles / Q000494:pharmacology; D048289:Imidazolidines; D007294:Inositol / Q000032:analysis; D008297:Male; D009046:Motor Neurons / Q000187:drug effects* / Q000502:physiology; D009431:Neural Conduction / Q000187:drug effects*; D010078:Oxazines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012584:Sciatic Nerve / Q000032:analysis; D000254:Sodium-Potassium-Exchanging ATPase / Q000032:analysis; D013012:Sorbitol / Q000032:analysis; D013401:Sugar Alcohol Dehydrogenases / Q000037:antagonists & inhibitors*
D007093:Imidazoles; D048289:Imidazolidines; D010078:Oxazines; D011758:Pyrroles; D007294:Inositol; D013012:Sorbitol; C054644:ADN 138; D013401:Sugar Alcohol Dehydrogenases; D000449:Aldehyde Reductase; D000254:Sodium-Potassium-Exchanging ATPase; C026411:sorbinil; D005947:Glucose