CORRECTION OF NERVE-CONDUCTION AND ENDONEURIAL BLOOD-FLOW DEFICITS BYTHE ALDOSE REDUCTASE INHIBITOR, TOLRESTAT, IN DIABETIC RATS

Increased activation of the first half of the polyol pathway, the conv ersion of glucose to sorbitol by aldose reductase, has been implicated in aldose reductase inhibitor-preventable neurochemical changes that may contribute to the aetiology of diabetic neuropathy. Tolrestat has been used as a standard aldose reductase inhibitor to dissect out poly ol pathway-dependent mechanisms in many experimental studies; however, doubt has been cast upon its ability to prevent nerve conduction velo city deficits in diabetic rats. Nerve dysfunction has also been linked to abnormal endoneurial blood flow and oxygenation via increased vasa nervorum polyol pathway flux. The aim of this study was to test wheth er tolrestat could correct sciatic conduction velocity and perfusion d efects in diabetic rats. Sciatic motor conduction velocity, 21% reduce d by 1 month of streptozotocin-induced diabetes; was corrected by 23% and 84% with 1 month of tolrestat treatment at doses of 7 and 35 mg/ k g/day respectively. Endoneurial blood flow, 44-52% reduced by untreate d diabetes, was within the nondiabetic range with high-dose tolrestat treatment and the flow deficit was 39% corrected by the low dose. Scia tic sorbitol and fructose concentrations were similar to 13-fold and s imilar to 4-fold elevated by untreated diabetes. This was 32-50% atten uated by low-dose tolrestat and sorbitol and fructose content was supp ressed below the nondiabetic level by high dose treatment. A 58% nerve myo-inositol deficit was partially (32%) corrected by high-dose tolre stat treatment. We conclude that tolrestat restores defective conducti on and blood flow in diabetic rats and is a good pharmacological tool for studies on polyol pathway effects in peripheral nerve.