Effect of sorbitol dehydrogenase inhibition on experimental diabetic autonomic neuropathy

The polyol pathway and its dependent biochemical pathways are thought to pl ay a role in the pathogenesis of diabetic neuropathy. We have developed an animal model of diabetic autonomic neuropathy characterized by neuroaxonal dystrophy involving ileal mesenteric nerves and prevertebral sympathetic su perior mesenteric ganglia (SMG) in chronic streptozocin-diabetic rats. Our previous studies have shown a salutary effect of aldose reductase inhibitor s on experimental autonomic neuropathy, suggesting a role for the polyol pa thway in its pathogenesis. In the current studies we have examined the effe ct of the sorbitol dehydrogenase inhibitor (SDI) CP-166,572, which interrup ts the conversion of sorbitol to fructose (and reactions dependent on the s econd step of the polyol pathway) resulting in markedly increased levels of sorbitol in peripheral nerve. Fourteen weeks of treatment with CP-166,572 resulted in a dramatically increased frequency of neuroaxonal dystrophy in ileal mesenteric nerves and SMG. Although lesions developed prematurely and in greater numbers in SDI-treated diabetics than untreated diabetics did, their anatomic distribution and ultrastructural appearance were identical t o that previously reported in long-term untreated diabetics. CP-166,572 tre atment did not produce neuroaxonal dystrophy in control animals despite the fact that sciatic nerve sorbitol levels were markedly increased, reaching the same levels as untreated diabetic animals. Treatment of diabetic rats f or 14 weeks with the aldose reductase inhibitor zopolrestat resulted in a s ignificant decrease in the frequency of neuroaxonal dystrophy compared with untreated diabetics.