METABOLIC AND VASCULAR FACTORS IN THE PATHOGENESIS OF DIABETIC NEUROPATHY

Reduced nerve perfusion is an important factor in the etiology of diab etic neuropathy. Studies in streptozotocin-induced diabetic rats show that nerve conduction velocity (NCV) and blood flow deficits are corre cted by treatment with vasodilator drugs, with angiotensin II and endo thelin-l antagonists being particularly important. The AT(1) antagonis t ZD7155 also prevents diabetic deficits in regeneration following ner ve damage, indicating that hypoperfusion is an important limitation fo r nerve repair. Metabolic changes include high polyol pathway flux, in creased advanced glycosylation, elevated oxidative stress, and impaire d omega-6 essential fatty acid metabolism. Aldose reductase inhibitors (ARIs) restore NCV via their effects on perfusion. ARI action probabl y depends on blocking the conversion of glucose to sorbitol, thus prev enting depletion of vasa nervorum glutathione, an important endogenous free radical scavenger. Free radicals cause vascular endothelium dama ge and reduced nitric oxide vasodilation. Inhibition of advanced glyco sylation and autoxidation (autoxidative glycosylation), major sources of free radicals, by aminoguanidine or transition metal chelators, cor rects neurovascular dysfunction. Evening primrose oil supplies gamma-l inolenic acid (GLA) to improve vasodilator eicosanoid synthesis in dia betes, correcting nerve blood flow and NCV deficits. Interactions betw een some of these mechanisms have therapeutic implications. Thus, comb ined ARI and evening primrose oil treatment produced a 10-fold amplifi cation of NCV and blood flow responses. Similarly, GLA effects are mar kedly enhanced when given in combination with ascorbate as ascorbyl-GL A. Thus, metabolic abnormalities combine to produce deleterious change s in nerve perfusion that make a major contribution to the etiology of diabetic neuropathy. The potential importance of multi-action therapy is stressed.