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The British Journal of Diabetes & Vascular Disease
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The aetiology of neuropathy in experimental diabetes

Norman E Cameron

Department of Biomedical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, Scotland, UK, n.e.Cameron{at}abdn.ac.uk

Most information on the aetiology of experimental diabetic neuropathy comes from studies on rodent models, particularly the streptozotocin-diabetic rat. The major factor that impairs small and large nerve fibre function is a decrease in nerve and ganglion perfusion. This leads to reduced conduction velocity, increased resistance to ischaemic conduction failure, blunted regenerative capacity, painful neuropathy, and autonomic nerve dysfunction. Hyperglycaemia, altered lipid metabolism and reduced insulin action combine to cause adverse metabolic effects on vasa nervorum, vascular endothelium being a notable target. The resultant reduced vasodilation and increased vasoconstriction causes endoneurial hypoxia. Oxidative stress is of primary importance, due to increased production of reactive oxygen species from a plethora of intra- and extracellular sources. Advanced glycation and carbonyl stress play a supporting role, as does essential fatty acid dysmetabolism. These mechanisms are associated with alterations in cell signalling mediated by protein kinases, nuclear factor Kappa B and poly (ADP-ribose) polymerase.

Key Words: neuropathy • vasa nervorum • blood flow • vasodilators • oxidative stress • advanced glycation • protein kinase • nuclear factor kappa B • poly (ADP-ribose) polymerase.

References

  • Cameron NE, Eaton SEM, Cotter MA, Tesfaye S. Vascular factors and metabolic interactions in the pathogenesis of diabetic neuropathy. Diabetologia 2001;44:1973-88.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Sima AAF, Sugimoto K. Experimental diabetic neuropathy: an update. Diabetologia 1999;42:773-88.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Hotta N., Koh N., Sakakibara F. et al. Effect of proprionyl-L-carnitine on motor nerve conduction, autonomic cardiac function, and nerve blood flow in rats with streptozotocin-induced diabetes: Comparison with an aldose reductase inhibitor. J Pharmacol Exp Ther 1996;276:49-55.[Abstract/Free Full Text]
  • Schmidt RE, Plurad SB Ultrastructural and biochemical characterisation of autonomic neuropathy in rats with chronic streptozotocin diabetes. J Neuropathol Exp Neurol 1986;45:525-44.[Web of Science][Medline] [Order article via Infotrieve]
  • Sasaki H., Schmelzer JD, Zollman PJ, Low PA Neuropathology and blood flow of nerve, spinal roots and dorsal root ganglia in longstanding diabetic rats. Acta Neuropathologica 1997;93:118-28.[CrossRef][Medline] [Order article via Infotrieve]
  • Coppey LJ, Gellett JS, Davidson EP, Dunlap JA, Yorek MA Changes in endoneurial blood flow, motor nerve conduction velocity and vascular relaxation of epineurial arterioles of the sciatic nerve in ZDF-obese diabetic rats. Diabetes/Metab Res Rev 2002;18:49-56.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Cameron NE, Cotter MA, Low PA Nerve blood flow in early experimental diabetes in rats: relation to conduction deficits. Am J Physiol 1991; 261:E1-E8.[Web of Science][Medline] [Order article via Infotrieve]
  • Cameron NE, Cotter MA Diabetes causes an early reduction in autonomic ganglion blood flow in rats. J Diabetes Complications 2001; 15:198-202.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Low PA, Nickander KK Oxygen free radical effects in sciatic nerve in experimental diabetes. Diabetes 1991;40:873-7.[Abstract]
  • Vinik AI, Newlon PG, Lauterio TJ et al. Nerve survival and regeneration in diabetes. Diabetes Rev 1995;3:139-57.
  • Cameron NE, Cotter MA Effects of a non-peptide endothelin-1 ETA antagonist on neurovascular function in diabetic rats: Interaction with the renin-angiotensin system. J Pharmacol Exp Ther 1996;278:1262-8.[Abstract/Free Full Text]
  • Tuck RR, Schmelzer JD, Low PA Endoneurial blood flow and oxygen tension in the sciatic nerves of rats with experimental diabetic neuropathy. Brain 1984;107:935-50.[Abstract/Free Full Text]
  • Cameron NE, Cotter MA 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;10:189-224.[Web of Science][Medline] [Order article via Infotrieve]
  • Ritchie JM A note on the mechanism of resistance to anoxia and ischaemia in the pathophysiological mammalian myelinated nerve. J Neurol Neurosurg Psychiatry 1985;48:274-7.[Abstract/Free Full Text]
  • Cotter MA, Gibson TM, Inkster ME, Cameron NE Effects of angiotensin converting enzyme inhibition on nerve function, neural tissue perfusion and vascular endothelium in diabetic rats. Diabetes 2002;51(suppl 2):A78.
  • Maxfield EK, Love A., Cotter MA, Cameron NE Nerve function and regeneration in diabetic rats: effects of ZD7155, an AT1 receptor antagonist. Am J Physiol 1995;269:E530-E537.[Web of Science][Medline] [Order article via Infotrieve]
  • Malik RA, Williamson S., Abbott C. et al. Effect of the angiotensin converting enzyme inhibitor trandalopril on human diabetic neuropathy: a randomised controlled trial. Lancet 1998;352:1978-81.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Nicolucci A., Carinci F., Graepel JG, Hohman TC, Ferris F., Lachin JM The efficacy of tolrestat in the treatment of diabetic peripheral neuropathy. A meta-analysis of individual patient data. Diabetes Care 1996;19:1091-6.[Abstract]
  • Litchy W., Dyck P., Tesfaye S., Zhang D., Bastyr E. Diabetic peripheral neuropathy (DPN) assessed by neurological examination (NE) and composite scores (CS) is improved with LY333531 treatment. Diabetes 2002;51 (suppl 2):800.
  • Brownlee M. Biochemistry and molecular biology of diabetic complications. Nature 2001;414:813-20.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Cameron NE, Cotter MA Effects of antioxidants on nerve and vascular dysfunction in experimental diabetes. Diabetes Res Clin Prac 1999;45: 137-46.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Desco MC, Asensi M., Marquez R. et al. Xanthine oxidase is involved in free radical production in type 1 diabetes: protection by allopurinol. Diabetes 2002;51:1118-24.[Abstract/Free Full Text]
  • Baynes JW, Thorpe SR Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes 1999;48:1-9.[Abstract]
  • Wolff SP Diabetes mellitus and free radicals. Br Med Bull 1993;49:642-52.[Abstract/Free Full Text]
  • Yu PH Deamination of methylamine and angiopathy: toxicity of formaldehyde, oxidative stress and relevance of protein glycoxidation in diabetes. J Neural Trans 1998;52(suppl):201-16.
  • Ishii N., Patel KP, Lane PH et al. Nitric oxide synthesis and oxidative stress in the renal cortex of rats with diabetes mellitus. J Am Soc Nephrol 2001; 12:1630-9.[Abstract/Free Full Text]
  • Keegan A., Cotter MA, Cameron NE Effects of diabetes and treatment with the antioxidant, alpha-lipoic acid, on endothelial and neurogenic functions of corpus cavernosum in rats. Diabetologia 1999;42:343-50.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Cameron NE, Jack AM, Cotter MA Effect of alpha-lipoic acid on vascular responses and nociception in diabetic rats. Free Radic Biol Med 2001;31: 125-35.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Coppey LJ, Gellett JS, Davidson EP et al. Effect of M40403 treatment of diabetic rats on endoneurial blood flow, motor conduction velocity and vascular function of epineurial arterioles of the sciatic nerve. Br J Pharmacol 2001;134:21-9.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Cameron NE, Tuck Z., McCabe L., Cotter MA Effects of the hydroxyl radical scavenger, dimethylthiourea, on peripheral nerve tissue perfusion and function in experimental diabetes. Diabetologia 2001;44:1161-9.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Keegan A., Cotter MA, Cameron NE Effects of chelator treatment on aorta and corpus cavernosum from diabetic rats. Free Radic Biol Med 1999;27:536-43.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Cameron NE, Cotter MA Effects of an extracellular transition metal chelator, hydroxyethyl starch-deferoxamine, on neurovascular function in diabetic rats. Diabetologia 2001;44:621-8.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Wada R., Nishizawa Y., Yagihashi N. et al. Effects of OPB-9165, anti-glycation agent, on experimental diabetic neuropathy. Eur J Clin Invest 2001; 31:513-20.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Mohamed AK, Bierhaus A., Schiekofer S., Tritschler H., Ziegler R., Nawroth PP The role of oxidative stress and NF-kappaB activation in late diabetic complications. Biofactors 1999;10:157-67.[Web of Science][Medline] [Order article via Infotrieve]
  • Cameron NE, Cotter MA, Dines KC, Maxfield EK, Carey F., Mirrlees D. Aldose reductase inhibition, nerve perfusion, oxygenation and function in streptozotocin-diabetic rats: dose-response considerations and independence from a myo-inositol mechanism. Diabetologia 1994;37:651-63.[Web of Science][Medline] [Order article via Infotrieve]
  • Keegan A., Jack AM, Cameron NE, Cotter MA Effects of aldose reductase inhibition on responses of the corpus cavernosum and mesenteric vascular bed of diabetic rats. J Cardiovasc Pharmacol 2000;35:606-13.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Ford I., Cotter MA, Cameron NE, Greaves M. The effects of alpha-lipoic acid or evening primrose oil treatment on vascular risk factors, blood flow and peripheral nerve conduction in the streptozotocin-diabetic rat. Metabolism 2001;50:868-75.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Horrobin DF The roles of essential fatty acids in the development of diabetic neuropathy and other complications of diabetes mellitus. Prostaglandins Leukot Essent Fatty Acids 1988;31:181-97.[Web of Science][Medline] [Order article via Infotrieve]
  • Jack AM, Keegan A., Cotter MA, Cameron NE Effects of diabetes and chronic evening primrose oil treatment on responses of aorta, corpus cavernosum and mesenteric vasculature in rats. Life Sci 2002;71:1863-77.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Koya D., King GL Protein kinase C activation and the development of diabetic complications. Diabetes 1998;47:859-66.[Abstract]
  • Cameron NE, Cotter MA, Jack AM, Basso MD, Hohman TC Protein kinase C effects on nerve function, perfusion and Na+,K+-ATPase activity and glutathione content in diabetic rats. Diabetologia 1999;42:1120-30.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Cotter MA, Jack AM, Cameron NE Effects of the protein kinase C β-isoform inhibitor, LY333531, on neural and vascular function in streptozotocin-diabetic rats. Clin Sci 2002;103:311-21.[Web of Science][Medline] [Order article via Infotrieve]
  • Purves T., Middlemas A., Agthong S. et al. A role for mitogen-activated protein kinases in the etiology of diabetic neuropathy. FASEB J 2001; 15:2508-14.[Abstract/Free Full Text]
  • Soriano FG, Pacher P., Mabley J., Liaudet L., Szabo C. Rapid reversal of the diabetic endothelial dysfunction by pharmacological inhibition of poly (ADP-ribose) polymerase. Circ Res 2001;89:684-91.[Abstract/Free Full Text]
  • Obrosova IG, Abatan OI, Li F. Poly (ADP-ribosyl)ation inhibitors correct conduction velocity deficits and energy metabolism in experimental diabetic neuropathy (EDN). Diabetes 2001;50(suppl 2):A188-9.[CrossRef]
  • Mizisin AP, Steinhardt RC, O'Brien JS, Calcutt NA TX14(A), a prosaposinderived peptide, reverses established nerve disorders in streptozotocin-diabetic rats and prevents them in galactose-fed rats. J Neuropathol Exp Neurol 2001;60:953-60.[Web of Science][Medline] [Order article via Infotrieve]

The British Journal of Diabetes & Vascular Disease, Vol. 3, No. 2, 98-105 (2003)
DOI: 10.1177/14746514030030020401
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This Article
Right arrow Abstract Freely available
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What's this?