Effects of an extracellular metal chelator on neurovascular function in diabetic rats.

Abstract

Increased oxidative stress has been causally linked to diabetic neurovascular complications, which are attenuated by antioxidants. There are several possible sources of reactive oxygen species in diabetes. Our aim was to assess the contribution of free radicals, produced by transition metal catalysed reactions, to early neuropathic changes. To this end, we examined, firstly, the effects of an extracellular high molecular weight chelator, hydroxyethyl starch-deferoxamine, which is expected to be confined to vascular space, on nerve perfusion and conduction deficits in diabetic rats and, secondly, the action of a single chelator dose. Diabetes was induced by streptozotocin. In vivo measurements comprised sciatic nerve motor conduction velocity and endoneurial perfusion, monitored by hydrogen clearance microelectrode polarography. We found that 8 weeks of diabetes reduced sciatic blood flow and conduction velocity by 48.3 % and 19.9% respectively. Two weeks of intravenous treatment corrected these deficits. Starch vehicle was ineffective. The time-course of action of a single hydroxyethyl starch-deferoxamine injection was examined in diabetic rats. There was a rapid increase in nerve blood flow on day 1, which remained within the non-diabetic range for 9 days before declining to the diabetic level at day 27. In contrast, conduction velocity changes were slower, reaching the non-diabetic range at day 6 and declining to the diabetic level at day 27. Extracellular transition metal catalysed reactions play a major role in the neurovascular deficits of experimental diabetes. Given the long-lasting effect of a single treatment, extracellular metal chelator therapy could be suitable for further assessment in clinical trials.