Nerve conduction and aldose reductase inhibition during 5 years of diabetes or galactosaemia in dogs

Abstract

To evaluate the role of excessive polyol pathway activity in the pathogenesis of nerve disorders in diabetes mellitus, nerve conduction velocity was measured in motor nerves of diabetic dogs given an aldose reductase inhibitor (Sorbinil) or placebo, and also in non-diabetic dogs made experimentally galactosaemic. The nerve conduction velocity slowly declined in the diabetic placebo group, becoming significantly less than normal by the fifth year of the study, and the decline was prevented by administration of the aldose reductase inhibitor. Non-diabetic dogs made galactosaemic by consuming a 30% galactose diet developed erythrocyte and nerve polyol concentrations many times greater than that of diabetic or normal animals, but the nerve conduction velocity remained normal throughout 5 years of study. These results in dogs suggest that aldose reductase inhibitors may prevent defective nerve conduction in long-term diabetes, and raise the possibility that excessive accumulation of polyol itself is not sufficient to produce the nerve defect in the absence of excessive polyol utilization.

Aldose Reductase Inhibitors as Potential Therapeutic Drugs of Diabetic Complications

“…For example, a long-term AR inhibition in diabetic dogs prevented sorbitol accumulation in erythrocytes and even diabetic neuropathy, but showed no beneficial effect on renal structure or albuminuria. It failed to prevent retinopathy or thickening of the capillary basement membrane in the retina, kidney and muscle [121,122]. The similar results were observed in a transgenic rat model with human AR cDNA.…”

Comparison of the effects of inhibitors of aldose reductase and sorbitol dehydrogenase on neurovascular function, nerve conduction and tissue polyol pathway metabolites in streptozotocin-diabetic rats

“…In diabetic models, inhibitors of the first enzyme in the pathway, aldose reductase, prevent or correct nerve conduction velocity (NCV) and regeneration deficits [2][3][4][5][6][7][8][9][10][11][12][13]. Clinical trials of aldose reductase inhibitors (ARIs) have shown modest improvements in neurological symptoms, NCV, sensory measures, and an increase in nerve fibre regeneration [14-17] despite a less effective polyol pathway blockade than was found necessary for functional effects in animal studies [6,10,18].…”

Association of Advanced Glycation End Products (AGEs) with Diabetic Nephropathy and Alcohol Consumption

“…There are four major hypotheses about hyperglycemia induced diabetes complications which are (i) accelerated glucose flux through polyol pathway [3]; (ii) activation of protein kinase C (PKC) isoforms through de novo synthesis of the lipid second messenger diacylglycerol induced by hyperglycemia [4]; (iii) formation of Advanced Glycation End Products (AGEs) [5] and (iv) increased oxidative stress [6].…”