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. 1995 Aug;96(2):1159–1163. doi: 10.1172/JCI118104

Neurovascular dysfunction in diabetic rats. Potential contribution of autoxidation and free radicals examined using transition metal chelating agents.

N E Cameron 1, M A Cotter 1
PMCID: PMC185307  PMID: 7635953

Abstract

Oxygen free radical activity is elevated in diabetes mellitus and has been implicated in the etiology of vascular complications. Recent studies have shown that impaired perfusion of nerve endoneurium is a major cause of nerve fiber dysfunction in experimental diabetes. Free radical scavenger treatment prevents the development of nerve conduction abnormalities in diabetic rats. In vitro experiments suggest that autoxidation reactions of glucose, catalyzed by free transition metal ions, are a potential source of free radicals in diabetes. We investigated whether chronic treatment with deferoxamine and trientine, transition metal chelating agents which can prevent autoxidation, could correct nerve conduction and blood flow changes in streptozotocin-diabetic rats. A 20% reduction in sciatic nerve motor conduction velocity after 2 mo diabetes was 90% ameliorated by 2 wk of treatment with deferoxamine or trientine. Sciatic endoneurial nutritive blood flow was 45% reduced by diabetes, but was completely corrected by treatment. In contrast, transition metal chelation had no effect on blood flow or conduction velocity in nondiabetic rats. Thus, the data support the hypothesis that increased free radical activity by glucose autoxidation as a result of impaired transition metal handling is a major cause of early neurovascular deficits in diabetes.

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Selected References

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  1. Baynes J. W. Role of oxidative stress in development of complications in diabetes. Diabetes. 1991 Apr;40(4):405–412. doi: 10.2337/diab.40.4.405. [DOI] [PubMed] [Google Scholar]
  2. Bravenboer B., Kappelle A. C., Hamers F. P., van Buren T., Erkelens D. W., Gispen W. H. Potential use of glutathione for the prevention and treatment of diabetic neuropathy in the streptozotocin-induced diabetic rat. Diabetologia. 1992 Sep;35(9):813–817. doi: 10.1007/BF00399926. [DOI] [PubMed] [Google Scholar]
  3. Brownlee M. Glycation products and the pathogenesis of diabetic complications. Diabetes Care. 1992 Dec;15(12):1835–1843. doi: 10.2337/diacare.15.12.1835. [DOI] [PubMed] [Google Scholar]
  4. Bucala R., Tracey K. J., Cerami A. Advanced glycosylation products quench nitric oxide and mediate defective endothelium-dependent vasodilatation in experimental diabetes. J Clin Invest. 1991 Feb;87(2):432–438. doi: 10.1172/JCI115014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Calcutt N. A., Mizisin A. P., Kalichman M. W. Aldose reductase inhibition, Doppler flux and conduction in diabetic rat nerve. Eur J Pharmacol. 1994 Jan 4;251(1):27–33. doi: 10.1016/0014-2999(94)90439-1. [DOI] [PubMed] [Google Scholar]
  6. Cameron N. E., Cotter M. A., Archibald V., Dines K. C., Maxfield E. K. Anti-oxidant and pro-oxidant effects on nerve conduction velocity, endoneurial blood flow and oxygen tension in non-diabetic and streptozotocin-diabetic rats. Diabetologia. 1994 May;37(5):449–459. doi: 10.1007/s001250050131. [DOI] [PubMed] [Google Scholar]
  7. Cameron N. E., Cotter M. A., Dines K. C., Maxfield E. K., Carey F., Mirrlees D. J. Aldose reductase inhibition, nerve perfusion, oxygenation and function in streptozotocin-diabetic rats: dose-response considerations and independence from a myo-inositol mechanism. Diabetologia. 1994 Jul;37(7):651–663. doi: 10.1007/BF00417688. [DOI] [PubMed] [Google Scholar]
  8. Cameron N. E., Cotter M. A., Dines K. C., Maxfield E. K. Pharmacological manipulation of vascular endothelium function in non-diabetic and streptozotocin-diabetic rats: effects on nerve conduction, hypoxic resistance and endoneurial capillarization. Diabetologia. 1993 Jun;36(6):516–522. doi: 10.1007/BF02743267. [DOI] [PubMed] [Google Scholar]
  9. Cameron N. E., Cotter M. A., Dines K., Love A. Effects of aminoguanidine on peripheral nerve function and polyol pathway metabolites in streptozotocin-diabetic rats. Diabetologia. 1992 Oct;35(10):946–950. doi: 10.1007/BF00401423. [DOI] [PubMed] [Google Scholar]
  10. Cameron N. E., Cotter M. A. Impaired contraction and relaxation in aorta from streptozotocin-diabetic rats: role of polyol pathway. Diabetologia. 1992 Nov;35(11):1011–1019. doi: 10.1007/BF02221675. [DOI] [PubMed] [Google Scholar]
  11. Cameron N. E., Cotter M. A., Low P. A. Nerve blood flow in early experimental diabetes in rats: relation to conduction deficits. Am J Physiol. 1991 Jul;261(1 Pt 1):E1–E8. doi: 10.1152/ajpendo.1991.261.1.E1. [DOI] [PubMed] [Google Scholar]
  12. Cameron N. E., Cotter M. A., Maxfield E. K. Anti-oxidant treatment prevents the development of peripheral nerve dysfunction in streptozotocin-diabetic rats. Diabetologia. 1993 Apr;36(4):299–304. doi: 10.1007/BF00400231. [DOI] [PubMed] [Google Scholar]
  13. Cameron N. E., Cotter M. A., Robertson S. The effect of aldose reductase inhibition on the pattern of nerve conduction deficits in diabetic rats. Q J Exp Physiol. 1989 Nov;74(6):917–926. doi: 10.1113/expphysiol.1989.sp003362. [DOI] [PubMed] [Google Scholar]
  14. Cameron N. E., Cotter M. A. The relationship of vascular changes to metabolic factors in diabetes mellitus and their role in the development of peripheral nerve complications. Diabetes Metab Rev. 1994 Oct;10(3):189–224. doi: 10.1002/dmr.5610100302. [DOI] [PubMed] [Google Scholar]
  15. Cameron N. E., Dines K. C., Cotter M. A. The potential contribution of endothelin-1 to neurovascular abnormalities in streptozotocin-diabetic rats. Diabetologia. 1994 Dec;37(12):1209–1215. doi: 10.1007/BF00399794. [DOI] [PubMed] [Google Scholar]
  16. Cutler P. Deferoxamine therapy in high-ferritin diabetes. Diabetes. 1989 Oct;38(10):1207–1210. doi: 10.2337/diab.38.10.1207. [DOI] [PubMed] [Google Scholar]
  17. Day T. J., Lagerlund T. D., Low P. A. Analysis of H2 clearance curves used to measure blood flow in rat sciatic nerve. J Physiol. 1989 Jul;414:35–54. doi: 10.1113/jphysiol.1989.sp017675. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Jiang Z. Y., Woollard A. C., Wolff S. P. Hydrogen peroxide production during experimental protein glycation. FEBS Lett. 1990 Jul 30;268(1):69–71. doi: 10.1016/0014-5793(90)80974-n. [DOI] [PubMed] [Google Scholar]
  19. Kappelle A. C., Biessels G., Bravenboer B., van Buren T., Traber J., de Wildt D. J., Gispen W. H. Beneficial effect of the Ca2+ antagonist, nimodipine, on existing diabetic neuropathy in the BB/Wor rat. Br J Pharmacol. 1994 Mar;111(3):887–893. doi: 10.1111/j.1476-5381.1994.tb14821.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kashiwagi A., Asahina T., Ikebuchi M., Tanaka Y., Takagi Y., Nishio Y., Kikkawa R., Shigeta Y. Abnormal glutathione metabolism and increased cytotoxicity caused by H2O2 in human umbilical vein endothelial cells cultured in high glucose medium. Diabetologia. 1994 Mar;37(3):264–269. doi: 10.1007/BF00398053. [DOI] [PubMed] [Google Scholar]
  21. Kihara M., Schmelzer J. D., Poduslo J. F., Curran G. L., Nickander K. K., Low P. A. Aminoguanidine effects on nerve blood flow, vascular permeability, electrophysiology, and oxygen free radicals. Proc Natl Acad Sci U S A. 1991 Jul 15;88(14):6107–6111. doi: 10.1073/pnas.88.14.6107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kihara M., Zollman P. J., Smithson I. L., Lagerlund T. D., Low P. A. Hypoxic effect of exogenous insulin on normal and diabetic peripheral nerve. Am J Physiol. 1994 Jun;266(6 Pt 1):E980–E985. doi: 10.1152/ajpendo.1994.266.6.E980. [DOI] [PubMed] [Google Scholar]
  23. Langenstroer P., Pieper G. M. Regulation of spontaneous EDRF release in diabetic rat aorta by oxygen free radicals. Am J Physiol. 1992 Jul;263(1 Pt 2):H257–H265. doi: 10.1152/ajpheart.1992.263.1.H257. [DOI] [PubMed] [Google Scholar]
  24. Loven D., Schedl H., Wilson H., Daabees T. T., Stegink L. D., Diekus M., Oberley L. Effect of insulin and oral glutathione on glutathione levels and superoxide dismutase activities in organs of rats with streptozocin-induced diabetes. Diabetes. 1986 May;35(5):503–507. doi: 10.2337/diab.35.5.503. [DOI] [PubMed] [Google Scholar]
  25. Low P. A., Nickander K. K. Oxygen free radical effects in sciatic nerve in experimental diabetes. Diabetes. 1991 Jul;40(7):873–877. doi: 10.2337/diab.40.7.873. [DOI] [PubMed] [Google Scholar]
  26. Low P. A. Recent advances in the pathogenesis of diabetic neuropathy. Muscle Nerve. 1987 Feb;10(2):121–128. doi: 10.1002/mus.880100204. [DOI] [PubMed] [Google Scholar]
  27. Lyons T. J. Oxidized low density lipoproteins: a role in the pathogenesis of atherosclerosis in diabetes? Diabet Med. 1991 Jun;8(5):411–419. doi: 10.1111/j.1464-5491.1991.tb01624.x. [DOI] [PubMed] [Google Scholar]
  28. Maxfield E. K., Cameron N. E., Cotter M. A., Dines K. C. Angiotensin II receptor blockade improves nerve function, modulates nerve blood flow and stimulates endoneurial angiogenesis in streptozotocin-diabetic rats and nerve function. Diabetologia. 1993 Dec;36(12):1230–1237. doi: 10.1007/BF00400799. [DOI] [PubMed] [Google Scholar]
  29. McCord J. M. Oxygen-derived free radicals in postischemic tissue injury. N Engl J Med. 1985 Jan 17;312(3):159–163. doi: 10.1056/NEJM198501173120305. [DOI] [PubMed] [Google Scholar]
  30. Monafo W. W., Eliasson S. G., Shimazaki S., Sugimoto H. Regional blood flow in resting and stimulated sciatic nerve of diabetic rats. Exp Neurol. 1988 Mar;99(3):607–614. doi: 10.1016/0014-4886(88)90177-x. [DOI] [PubMed] [Google Scholar]
  31. Moncada S., Gryglewski R. J., Bunting S., Vane J. R. A lipid peroxide inhibits the enzyme in blood vessel microsomes that generates from prostaglandin endoperoxides the substance (prostaglandin X) which prevents platelet aggregation. Prostaglandins. 1976 Nov;12(5):715–737. doi: 10.1016/0090-6980(76)90048-4. [DOI] [PubMed] [Google Scholar]
  32. Picard S., Parthasarathy S., Fruebis J., Witztum J. L. Aminoguanidine inhibits oxidative modification of low density lipoprotein protein and the subsequent increase in uptake by macrophage scavenger receptors. Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):6876–6880. doi: 10.1073/pnas.89.15.6876. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Rubanyi G. M., Polokoff M. A. Endothelins: molecular biology, biochemistry, pharmacology, physiology, and pathophysiology. Pharmacol Rev. 1994 Sep;46(3):325–415. [PubMed] [Google Scholar]
  34. Stevens M. J., Dananberg J., Feldman E. L., Lattimer S. A., Kamijo M., Thomas T. P., Shindo H., Sima A. A., Greene D. A. The linked roles of nitric oxide, aldose reductase and, (Na+,K+)-ATPase in the slowing of nerve conduction in the streptozotocin diabetic rat. J Clin Invest. 1994 Aug;94(2):853–859. doi: 10.1172/JCI117406. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Tesfaye S., Malik R., Ward J. D. Vascular factors in diabetic neuropathy. Diabetologia. 1994 Sep;37(9):847–854. doi: 10.1007/BF00400938. [DOI] [PubMed] [Google Scholar]
  36. Tilton R. G., Chang K., Hasan K. S., Smith S. R., Petrash J. M., Misko T. P., Moore W. M., Currie M. G., Corbett J. A., McDaniel M. L. Prevention of diabetic vascular dysfunction by guanidines. Inhibition of nitric oxide synthase versus advanced glycation end-product formation. Diabetes. 1993 Feb;42(2):221–232. doi: 10.2337/diab.42.2.221. [DOI] [PubMed] [Google Scholar]
  37. Tuck R. R., Schmelzer J. D., Low P. A. Endoneurial blood flow and oxygen tension in the sciatic nerves of rats with experimental diabetic neuropathy. Brain. 1984 Sep;107(Pt 3):935–950. doi: 10.1093/brain/107.3.935. [DOI] [PubMed] [Google Scholar]
  38. Ward K. K., Low P. A., Schmelzer J. D., Zochodne D. W. Prostacyclin and noradrenaline in peripheral nerve of chronic experimental diabetes in rats. Brain. 1989 Feb;112(Pt 1):197–208. doi: 10.1093/brain/112.1.197. [DOI] [PubMed] [Google Scholar]
  39. Young I. S., Torney J. J., Trimble E. R. The effect of ascorbate supplementation on oxidative stress in the streptozotocin diabetic rat. Free Radic Biol Med. 1992;13(1):41–46. doi: 10.1016/0891-5849(92)90164-c. [DOI] [PubMed] [Google Scholar]

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