Inhibition of sorbitol dehydrogenase exacerbates autonomic neuropathy in rats with streptozotocin-induced diabetes

We have developed an animal model of diabetic autonomic neuropathy that is characterized by neuroaxonal dystrophy (NAD) involving ileal mesenteric ner ves and prevertebral sympathetic superior mesenteric ganglia (SMG) in chron ic streptozotocin (STZ)-diabetic rats. Studies with the sorbitol dehydrogen ase inhibitor SDI-158, which interrupts the conversion of sorbitol to fruct ose (and reactions dependent on the second step of the sorbitol pathway), h ave shown a dramatically increased frequency of NAD in ileal mesenteric ner ves and SMG of SDI-treated versus untreated diabetics. Although lesions dev eloped prematurely and in greater numbers in SDI-treated diabetics, their d istinctive ultrastructural appearance was identical to that previously repo rted in long-term untreated diabetics. An SDI effect was first demonstrated in the SMG of rats that were diabetic for as little as 5 wk and was mainta ined for at least 7.5 months. As in untreated diabetic rats, rats treated w ith SDI i) showed involvement of lengthy ileal, but not shorter, jejunal me senteric nerves; ii) demonstrated NAD in paravascular mesenteric nerves dis tributed to myenteric gan.-Iia while sparing adjacent perivascular axons ra mifying within the vascular adventitia; and, iii) failed to develop NAD in the superior cervical ganglia (SCG). After only 2 months of SDI-treatment, tyrosine hydroxylase immunolocalization demonstrated marked dilatation of p ostganglionic noradrenergic axons in paravascular ileal mesenteric nerves a nd within the gut wall versus those innervating extramural mesenteric vascu lature. The effect of SDI on diabetic NAD in SMG was completely prevented b y concomitant administration of the aldose reductase inhibitor Sorbinil. Tr eatment of diabetic rats with Sorbinil also prevented NAD in diabetic rats not treated with SDI. These findings indicate that sorbitol pathway-linked metabolic imbalances play a critical role in the development of NAD in this model of diabetic sympathetic autonomic neuropathy.