Effects of Aldose Reductase Inhibitor Sorbinil on Neuroaxonal Dystrophy and Levels of myo-inositol and Sorbitol in Sympathetic Autonomic Ganglia of Streptozocin-Induced Diabetic Rats

Abstract

Biochemical and ultrastructural effects of the aldose reductase inhibitor sorbinil were examined in two experimental rat models of chronic diabetic neuropathy: rats with streptozocin-induced diabetes (STZ-D) and rats fed a galactose-enriched diet. The frequency of neuroaxonal dystrophy in the superior mesenteric sympathetic ganglia of rats with untreated 8-mo STZ-D increased sevenfold compared with that in age-matched controls. Animals chronically maintained on a diet containing 50% galactose, however, did not develop neuroaxonal dystrophy in excess of that found in untreated age-matched control rats. Institution of sorbinil therapy at the time of induction of STZ-D decreased, but did not completely normalize, the frequency of neuroaxonal dystrophy without altering the severity of diabetes; this finding is based on measurements of plasma glucose, body weight, food consumption, 24-h urine volume, and levels of glycosylated hemoglobin. Sorbitol levels in the superior cervical sympathetic ganglia (SCG) of untreated 8-mo-diabetic animals increased three- to fourfold compared with levels in controls. The increase in sorbitol content of diabetic SCG was completely prevented by early institution of dietary sorbinil therapy. The myo-inositol content of 8-mo-diabetic SCG was modestly decreased compared with controls. Sorbinil administration improved but did not completely normalize diabetic SCG myo-inositol. The sorbitol content of the SCG, superior mesenteric and celiac sympathetic ganglia, and a major trunk of the superior mesenteric nerve of short-term (2.5-mo)-diabetic rats increased comparably, but only the diabetic SCG showed a decrease in myo-inositol.

Tyrosine Hydroxylase Activity in Sympathetic Nervous System of Rats With Streptozocin-Induced Diabetes

“…Yip, and R.G. Tilton, unpublished observations) or ultrastructural features of neuroaxonal dystrophy (14) in the sympathetic ganglia of galactosemic rats compared to animals with chronic diabetes. Recently, other studies have demonstrated a number of differences between galactosemic and diabetic rats (55).…”

“…Aldose reductase inhibitors have been found to prevent and, in some cases, reverse abnormalities in sciatic nerve Na + -K + -ATPase activity, axonal transport, and nerve conduction velocity in experimental diabetes (27)(28)(29)(30). Although most of these studies have concentrated on somatic myelinated nerves, a few studies have suggested that there is an effect on biochemical (45), pathophysiological, and structural histopathology (14) involving the autonomic nervous system as well. In our TOH experiments, only a small effect of sorbinil, if any, was detectable.…”

“…Institution of aldose reductase therapy with sorbinil within a day of onset of diabetes did not significantly alter the severity of diabetes as monitored by glycosylated hemoglobin values and plasma glucose ( Table 6). In this experiment, CG were assayed for TOH activity, and the SMG were used for ultrastructural studies that are reported elsewhere (14). Sorbinil treatment diminished but did not prevent elevation of TOH activity in the diabetic CG (Table 6).…”

Effects of Sorbinil, Dietary myo-Inositol Supplementation, and Insulin on Resolution of Neuroaxonal Dystrophy in Mesenteric Nerves of Streptozocin-Induced Diabetic Rats

“…In one study, we showed that biochemical and ultrastructural alterations in the sympathetic ganglia of chronically diabetic rats were substantially improved, but not normalized, by initiation of sorbinil treatment at the time of induction of diabetes (30). However, it would be more clinically relevant to examine the ability of aldose reductase therapy to reverse established ultrastructural lesions in experimental diabetic animals.…”

“…However, the accumulation of sorbitol and variable decrease in myo-inositol, which have been described in sympathetic ganglia in STZ-D rats (29,30), suggested a role for aldose reductase inhibitors in the treatment of autonomic neuropathy. Several clinical (31)(32)(33) and experimental animal (29,34,35) studies have demonstrated improvement of selected biochemical and physiological parameters of autonomic nervous system function in response to aldose reductase inhibitors.…”