We have developed an animal model of diabetic sympathetic autonomic neuropathy which is characterized by
neuroaxonal dystrophy (
NAD), an ultrastructurally distinctive axonopathy, in chronic
streptozotocin (STZ)-diabetic rats. Diabetes-induced alterations in the
sorbitol pathway occur in sympathetic ganglia and therapeutic agents which inhibit
aldose reductase or
sorbitol dehydrogenase improve or exacerbate, respectively, diabetes-induced
NAD. The
sorbitol dehydrogenase inhibitor SDI-711 (CP-470711, Pfizer) is approximately 50-fold more potent than the structurally related compound
SDI-158 (CP 166,572) used in our earlier studies. Treatment with SDI-711 (5 mg/kg/day) for 3 months increased ganglionic
sorbitol (26-40 fold) and decreased
fructose content (20-75%) in control and diabetic rats compared to untreated animals. SDI-711 treatment of diabetic rats produced a 2.5- and 4-5-fold increase in
NAD in the SMG and ileal mesenteric nerves, respectively, in comparison to untreated diabetics. Although SDI-711 treatment of non-diabetic control rat ganglia increased ganglionic
sorbitol 40-fold (a value 8-fold higher than untreated diabetics), the frequency of
NAD remained at control levels. Levels of ganglionic
sorbitol pathway intermediates in STZ-treated rats (a model of
type 1 diabetes) and Zucker Diabetic Fatty rats (ZDF, a genetic model of
type 2 diabetes) were comparable, although STZ-diabetic rats develop
NAD and ZDF-diabetic rats do not. SDI failed to increase diabetes-related ganglionic
NGF above levels seen in untreated diabetics. Initiation of
Sorbinil treatment for the last 4 months of a 9 month course of diabetes, substantially reversed the frequency of established
NAD in the diabetic rat SMG without affecting the metabolic severity of diabetes. These findings indicate that
sorbitol pathway-linked metabolic alterations play an important role in the development of
NAD, but
sorbitol pathway activity, not absolute levels of
sorbitol or
fructose per se, may be most critical to its pathogenesis.