An aldose reductase inhibitor reverses early diabetes-induced changes in peripheral nerve function, metabolism, and antioxidative defense

Aldose reductase inhibitors (ARIs) prevent peripheral nerve dysfunction and morphological abnormalities in diabetic animal models. However, some exper imental intervention studies and clinical trials of ARIs on diabetic neurop athy appeared disappointing because of either 1) their inadequate design an d, in particular, insufficient correction of the sorbitol pathway activity or 2) the inability to reverse established functional and metabolic deficit s of diabetic neuropathy by AR inhibition in general. We evaluated whether diabetes-induced changes in nerve function, metabolism, and antioxidative d efense are corrected by the dose of ARI (sorbinil, 65 mg/kg/d in the diet), resulting in complete inhibition of increased sorbitol pathway activity. T he groups included control rats and streptozotocin-diabetic rats treated wi th/without ARI for 2 weeks after 4 weeks of untreated diabetes. ARI treatme nt corrected diabetes-induced nerve functional changes; that is, decrease i n endoneurial nutritive blood flow, motor and sensory nerve conduction velo cities, and metabolic abnormalities (i.e., mitochondrial and cytosolic NAD( +)/NADH redox imbalances and energy deficiency). ARI restored nerve concent rations of two major non-enzymatic antioxidants, reduced glutathione (GSH) and ascorbate, and completely arrested diabetes-induced lipid peroxidation. In conclusion, treatment with adequate doses of ARIs (that is, doses that completely inhibit increased sorbitol pathway activity) is an effective app roach for reversal of, at least, early diabetic neuropathy.