Aminoguanidine and diabetic neuropathy

Abstract

In this issue, Miyauchi and colleagues (1) present a study in which they have administered aminoguanidine orally for 16 weeks to young rats with streptozotocininduced diabetes. Whereas motor nerve conduction velocity (MNCV) kept increasing with time in the nondiabetic control rats and reached a plateau at 16 weeks, initially no such increase was noted in diabetic rats on aminoguanidine. However, after 2 months of treatment a dose-dependent progressive increase in MNCV was noted, which, at the dose of 50 mg/kg body weight, reached almost normal levels at 16 weeks. Morphometric analysis of the sciatic nerve revealed no significant differences between diabetic animals receiving aminoguanidine and controls. The improvement in MNCV did not appear to relate to glycemic status or amelioration in body weight, both of which were unchanged at 16 weeks compared to what they were at study onset. Somewhat surprising is the fact that Na+, K+-ATPase activity in sciatic nerve was not ameliorated by aminoguanidine therapy. In effect, mean levels of both ouabain-sensitive and -insensitive forms were below those of untreated controls. This is surprising because the activity of this enzyme was found impaired in several independent studies of diabetic neuropathy in the rat and ameliorated by treatment with, for example, myoinositol or aldose reducíase inhibitor (2). Thus, one has to assume that aminoguanidine corrected the defect in MNCV by a mechanism independent of Na+, K+-ATPase.This study joins a growing number of studies showing that aminoguanidine in diabetic rodents is effective at improving diabetic neuropathy (MNCV, myelinated fiber size, nerve blood flow) as well as a host of other abnormalities, including albuminuria, mesangial expansion, formation of fluorescent products in kidney cortex, basement membrane, arterial wall and skin (3, 4), retinopathy-like changes consisting of acellular capillaries and microaneurysms (5), vascular permeability, increase in granulation tissue, retina and nerve and collagen cross-linking (3, 6, 7). Thus, aminoguanidine emerges as a drug with the potential to prevent a broad range of diabetes-induced dysfunctions that are thought to lead eventually to full-blown complications.Aminoguanidine was initially investigated for its potential activity as an inhibitor of the advanced Maillard-glycation reaction, which is though to play an important role in the pathogenesis of diabetic complications (8,9). Indeed, when proteins modified by advanced glycation endproducts (AGEs) in vitro or in vivo were applied to certain culture systems or injected into animals, a number of diabetes-like changes could be reproduced, including increases in protein trapping, low-density lipoprotein oxidation, permeability of endothelium and vasculature, basement membrane thickening and mesangial matrix production, procoagulant effects and thrombotic events (9). Some of these changes may be in part related to AGE receptormediated effects, such as the release of cytokines and growth factors, and are preventable by aminoguan...

Effect of Treating Streptozotocin‐Induced Diabetic Rats With Sorbinil, Myo‐Inositol or Aminoguanidine on Endoneurial Blood Flow, Motor Nerve Conduction Velocity and Vascular Function of Epineurial Arterioles of the Sciatic Nerve

“…As has been previously reported, we demonstrate that treating streptozotocin-induced diabetic rats with sorbinil or aminoguanidine significantly improves the reduction in EBF and slowing of MNCV [3][4][5][6][7][8][9][10][11][12][24][25][26][27][28]. In sorbinil treated diabetic rats EBF and MNCV remained suppressed by 15 and 18%, respectively compared to controls, whereas in aminoguanidine treated rats EBF and MNCV, compared to controls, was decreased by 6 and 16%, respectively.…”

“…We have previously shown that endothelialdependent vascular relaxation of arterioles that provide circulation to the region of the sciatic nerve is impaired by diabetes [35,36]. In the present study we sought to determine the effect treatment of diabetic rats with sorbinil, an aldose reductase inhibitor, aminoguanidine, an inhibitor of nonenzymatic glycation, or myoinositol supplementation has on EBF, MNCV as well as vascular relaxation of arterioles that provide circulation to the region of the sciatic nerve.As has been previously reported, we demonstrate that treating streptozotocin-induced diabetic rats with sorbinil or aminoguanidine significantly improves the reduction in EBF and slowing of MNCV [3][4][5][6][7][8][9][10][11][12][24][25][26][27][28]. In sorbinil treated diabetic rats EBF and MNCV remained suppressed by 15 and 18%, respectively compared to controls, whereas in aminoguanidine treated rats EBF and MNCV, compared to controls, was decreased by 6 and 16%, respectively.…”

“…Based on these studies pharmacological compounds, like aldose reductase inhibitors and anti-glycation agents, have been developed for the treatment of diabetic neuropathy [59]. In diabetic animal models these agents have been shown to improve nerve function and endoneurial blood flow [3][4][5][6][7][8][9][10][11][12][24][25][26][27][28]. However, studies on the effect these agents may have on vascular function of vessels that provide circulation to nerves have been limited.…”

“…Treatment of diabetic rats with aminoguanidine, an inhibitor of the formation of advanced glycosylation end products [23], ameliorates the slowing of motor nerve conduction velocity and reduction of endoneurial blood flow [24][25][26][27][28]. This suggests that the formation of advanced glycation end products in the nerve or vascular tissue perturbs neural function [29][30][31][32].…”

Diabetic neuropathies: components of etiology

“…Functional and structural assessment of the impact of glycation on nerve has been hampered by the lack of molecules, analogous to ARIs, which specifically inhibit glycation reactions. In this context, aminoguanidine has been used, but it clearly has several other pharmacological properties ( Monnier, 1996 ) , and its use as an investigative tool is flawed. New glycation inhibitors, such as pyridoxamine, might offer new insight into the effects of macromolecule glycation in nerve dysfunction ( Metz et al, 2003 ) .…”