Effect of M40403 treatment of diabetic rats on endoneurial blood flow, motor nerve conduction velocity and vascular function of epineurial arterioles of the sciatic nerve

Abstract

1 To further explore the e ect of antioxidants in preventing diabetes-induced vascular and neural dysfunction we treated streptozotocin-induced diabetic rats daily with subcutaneous injections of 10 mg kg 71 of M40403 (n=11) and compared the results obtained from 17 control rats and 14 untreated diabetic rats. M40403 is a manganese(II) complex with a bis(cyclo-hexylpyridine)-substituted macrocyclic ligand that was designed to be a selective functional mimetic of superoxide dismutase. Thus, M40403 provides a useful tool to evaluate the roles of superoxide in disease states. 2 Treatment with M40403 signi®cantly improved diabetes-induced decrease in endoneurial blood ow, acetylcholine-mediated vascular relaxation in arterioles that provide circulation to the region of the sciatic nerve, and motor nerve conduction velocity (P50.05). M40403 treatment also reduced the appearance of superoxide in the aorta and epineurial vessels and peroxynitrite in epineurial vessels. Treating diabetic rats with M40403 reduced the diabetes-induced increase in thiobarbituric acid reactive substances in serum but did not prevent the decrease in lens glutathione level. Treating diabetic rats with M40403 did not improve sciatic nerve Na + /K + ATPase activity or the sorbitol, fructose or myo-inositol content of the sciatic nerve. 3 These studies provide additional evidence that diabetes-induced oxidative stress and the generation of superoxide and perhaps peroxynitrite may be partially responsible for the development of diabetic vascular and neural complications.

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

“…The present study demonstrated that treatment of streptozotocin-induced diabetic rats with sorbinil prevented the metabolic derangements in the sciatic nerve as well as the reduction of glutathione in the lens. These defects were not uniformly corrected by treatment with antioxidants [52,57]. Thus, treatment protocols utilizing the combination of antioxidants and aldose reductase inhibitors may be an effective approach in preventing diabetic vascular and neural disease.…”

“…Previously we have demonstrated that treating diabetic rats with two different antioxidants, α-lipoic acid or M40403, prevented the reduction in EBF, MNCV and impairment of vascular relaxation of epineurial vessels [52,57]. Treatment with these antioxidants prevented the generation of superoxide and peroxynitrite in epineurial vessels and the aorta and the increase in serum TBARS but did not correct the metabolic derangements of the sciatic nerve.…”

“…Data in Figure 1 demonstrate that treating streptozotocin-induced diabetic rats with sorbinil, myo-inositol or aminoguanidine did not prevent the diabetes-induced increase in the level of superoxide in epineurial vessels as measured by hydroethidine fluorescence compared to paired analysis of untreated diabetic rats. The apparent small improvement in superoxide level in epineurial vessels from diabetic rats treated with sorbinil or aminoguanidine was vividly less than observed following treatment with antioxidants [52,57]. …”

SOD2 protects neurons from injury in cell culture and animal models of diabetic neuropathy

“…The reasons for this failure are likely multiple, and include the absence of genetic susceptibility genes and a short life-span (Breyer et al, 2005). Since SOD mimetics can both decrease rodent nerve conduction deficits (Coppey et al, 2001) and restore blood flow (Schnackenberg and Wilcox, 2001) in diabetes, we hypothesized that decreased expression of SOD would accelerate oxidative injury in hyperglycemia and magnify DN. To address this question, we first altered the level of SOD2 in an in vitro model of DN, primary dorsal root ganglion (DRG) neurons.…”

Treatment of Streptozotocin-Induced Diabetic Rats With AVE7688, a Vasopeptidase Inhibitor

“…tudies performed in our laboratory with streptozotocin-induced diabetic rats have provided evidence that the generation of oxidative stress through the production of superoxide and peroxynitrite impairs vascular function of epineurial arterioles of the sciatic nerve, and this precedes slowing of motor nerve conduction velocity (MNCV) (1)(2)(3). These studies imply that hyperglycemia-induced oxidative stress may be responsible for diabetes-induced vascular and neural dysfunction that occurs during diabetic neuropathy.…”