Interactions between sorbitol pathway of glucose metabolism and 12/15‐lipoxygenase activation in diabetic peripheral neuropathy

Abstract

Both sorbitol pathway of glucose metabolism and, recently, 12/15‐lipoxygenase (12/15‐LO) activation have been implicated in the pathogenesis of diabetic peripheral neuropathy (DPN). Activation of the key enzyme of the sorbitol pathway, aldose reductase, is known to lead to NF‐κB activation and accumulation of cytosolic Ca++ i.e., two events implicated in 12/15‐LO overexpression and activation. We, therefore, evaluated the relationship between the two mechanisms using a pharmacological approach. Male C57Bl6/J mice were made diabetic with streptozotocin, after which non‐diabetic and diabetic mice were treated with the aldose reductase inhibitor fidarestat, at 16 mgkg−1d−1, in the drinking water, for 12 weeks. Diabetic mice displayed accumulation of glucose, sorbitol pathway intermediates, as well as 12/15‐LO overexpression and 12(S)‐HETE accumulation (a sign of increased 12/15‐LO activity) in two tissue‐targets for DPN, sciatic nerve and spinal cord. Fidarestat treatment did not affect diabetes‐induced glucose accumulation and completely corrected sorbitol and fructose accumulation in both tissues. It did not affect sciatic nerve or spinal cord 12/15‐LO overexpression; however, 12(S)‐HETE concentrations were either completely (sciatic nerve) or partially (spinal cord) corrected. In conclusion, increased sorbitol pathway activity is responsible for activation, but not overexpression, of 12/15‐LO in the pathogenesis of DPN. Studies in dorsal root ganglia are in progress.