Polyol pathway hyperactivity is closely related to carnitine deficiency inthe pathogenesis of diabetic neuropathy of streptozotocin-diabetic rats

To investigate the relationship between polyol pathway hyperactivity and al tered carnitine metabolism in the pathogenesis of diabetic neuropathy, the effects of an aldose reductase inhibitor, [5-(3-thienyl) tetrazol-1-yl]acet ic acid (TAT), and a carnitine analog, acetyl-L-carnitine (ALC), on neural functions and biochemistry and hemodynamic factors were compared in strepto zotocin-diabetic rats. Significantly delayed motor nerve conduction velocit y, decreased R-R interval variation, reduced sciatic nerve blood flow and d ecreased erythrocyte 2,3-diphosphoglycerate concentrations in diabetic rats were all ameliorated by treatment with TAT (administered with rat chow con taining 0.05% TAT, similar to 50 mg/kg/day) or ALC (by gavage, 300 mg/kg/da y) for 4 weeks. Platelet hyperaggregation activity in diabetic rats was dim inished by TAT but not by ALC. TAT decreased sorbitol accumulation and prev ented not only myoinositol depletion but also free-carnitine deficiency in diabetic nerves. On the other hand, ALG also increased the myo-inositol as well as the free-carnitine content without affecting the sorbitol content. These observations suggest that there is a close relationship between incre ased polyol pathway activity and carnitine deficiency in the development of diabetic neuropathy and that an aldose reductase inhibitor, TAT, and a car nitine analog, ALC, have therapeutic potential for the treatment of diabeti c neuropathy.