Only limited effects of aminoguanidine treatment on peripheral nerve function, (Na + ,K + )-ATPase activity and thrombomodulin expression in streptozotocin-induced diabetic rats

Abstract

Inhibition of glycation by use of anti-glycation agents like aminoguanidine is now regarded as a promising new way for the prevention and treatment of vascular and neuropathic complications in diabetes [1,2]. Several laboratories have reported beneficial effects of aminoguanidine on peripheral nerve function in experimental models of diabetic neuropathy [3±5]. In these studies, the aminoguanidine effects were accompanied by an improvement in nerve blood flow [3,4] and reduction of advanced glycation end product (AGE) formation in nerve tissues [5]. It has also been shown that aminoguanidine treatment can prevent the structural changes of endoneurial microvessels in long-term diabetic rats [6]. The mechanisms for these effects of aminoguanidine and the relation between endothelial cell injury and peripheral nerve dysfunction, however, are not clearly understood.Thrombomodulin, a high-affinity receptor for thrombin, is a membrane glycoprotein found on the surface of endothelial cells [7,8]. Increased plasma Diabetologia (1999) Abstract Aims/hypothesis. Aminoguanidine, a potent anti-glycation reagent, is known to be beneficial in experimental diabetic neuropathy. In this study, we explored the mechanisms of how aminoguanidine inhibits neuropathic changes in diabetes and compared its effects with those of insulin treatment. Methods. Wistar rats, aged 8 weeks, were made diabetic by streptozotocin and given aminoguanidine dissolved in drinking water (1 g/l) for 8 weeks. Effects of daily insulin (protamine-zinc) treatment were also examined for comparison. At the end of the 8 weeks, we examined the peripheral nerve function and (Na + ,K + )-ATPase activity and their relation to serum thrombomodulin concentrations that are considered as a marker of endothelial injury. Results. Aminoguanidine treatment reduced the diabetes-induced decrease in tibial nerve conduction velocity by 47 % (p < 0.05 vs untreated diabetic rats) and inhibited the loss of sciatic nerve (Na + ,K + )-ATPase activity by 54 % (p < 0.05 vs untreated diabetic rats). Insulin-treatment of diabetic rats restored these variables by 83 % and 75 %, respectively (both, p < 0.01 vs untreated diabetic rats). Thrombomodulin concentrations were increased (p < 0.01) in diabetic rats compared with those in non-diabetic controls and unaffected by aminoguanidine treatment. In contrast, the concentrations remained within the normal range in the insulin-treated group. Conclusion/interpretation. Although aminoguanidine treatment improved nerve conduction velocity and (Na + ,K + )-ATPase activity, its effects were considerably less than those of insulin and were not apparent in some measures of endothelial cell injury. [Diabetologia (1999) 42: 743±747]

Thrombomodulin Deficiency in Human Diabetic Nerve Microvasculature

“…Hence, this animal model does not establish whether diabetes or its treatment is related to altered TM expression in nerve microvasculature (33). These findings must be interpreted with caution because streptozoticin-induced diabetes may differ from human diabetic neuropathy in its time course and biological mechanisms.…”

Functional and structural abnormalities in the nerves of Type I diabetic baboons: aminoguanidine treatment does not improve nerve function

“…Its effects on nerve morphometry have not been assessed at this stage because aminoguanidine treated animals have not reached the duration of diabetes for nerve biopsies electrophysiological results lead us, however, to believe that aminoguanidine will have little it any effect on structural changes. The inability of aminoguanidine to restore nerve function in baboons differs from some of the studies in rats that showed treatment to be beneficial although the results are conflicting [18,19,22,41,42]. One study found that diabetic rats given 50 mg/kg aminoguanidine in the drinking water for 16 weeks had NCV restored although doses of 10 and 25 mg/ kg were ineffective [19].…”

New insights into the metabolic and molecular basis for diabetic neuropathy

“…1). Short-term treatment with aminoguanidine ameliorates the NCV and the Na + /K + -ATPase defects, but not endothelial damage as reflected by systemic thrombomodulin concentrations [111]. On the other hand, long-term aminoguanidine treatment has beneficial effects on the structural alterations of endoneurial microvessels in the STZ rat [112].…”