The
polyol pathway and its dependent biochemical pathways are thought to play 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 superior mesenteric ganglia (SMG) in chronic
streptozocin-diabetic rats. Our previous studies have shown a salutary effect of
aldose reductase inhibitors on experimental autonomic neuropathy, suggesting a role for the
polyol pathway in its pathogenesis. In the current studies we have examined the effect of the
sorbitol dehydrogenase inhibitor (SDI)
CP-166,572, which interrupts the conversion of
sorbitol to
fructose (and reactions dependent on the second 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 to that previously reported in long-term untreated diabetics.
CP-166,572 treatment 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 for 14 weeks with the
aldose reductase inhibitor
zopolrestat resulted in a significant decrease in the frequency of
neuroaxonal dystrophy compared with untreated diabetics.