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Microangiopathy, Diabetes, and the Peripheral Nervous System

  • Chapter
Diabetic Neuropathy

Part of the book series: Clinical Diabetes ((CLD))

Abstract

This chapter reviews how disease of small nerve and ganglia microvessels, or microangiopathy, relates to the development of diabetic peripheral neuropathy. Microangiopathy involving vessels of the nerve trunk and those of dorsal root ganglia (that house sensory neuron cell bodies), does develop in parallel with neuropathy and is likely to eventually contribute to it. It is debatable whether early polyneuropathy in models or in humans can be exclusively linked to reductions in the blood supply of nerves. More likely, diabetes targets neural structures and vessels concurrently. There might be chronic ganglion ischemia altering neuronal function such that terminal branches of the nerve can no longer be properly supported. Downregulation, in turn, of critical structural and survival proteins in the sensory (or autonomic) neuron tree might account for early sensory dysfunction and pain (or autonomic abnormalities). There might also be exquisite sensitivity of vessels to vasoconstriction as an early functional abnormality. Rises in local endothelin levels, for example, might trigger acute nerve trunk and ganglion ischemia, and damage. Finally, failed upregulation of blood flow to injured nerves after acute injury might impair their ability to regenerate. Future therapy of diabetic polyneuropathy will require attention toward both direct neuronal degeneration and superimposed microangiopathy.

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References

  1. Toth C, Brussee V, Cheng C, Zochodne DW. Diabetes mellitus and the sensory neuron. J Neuropathol Exp Neurol 2004;63:561–573.

    PubMed  CAS  Google Scholar 

  2. Zochodne DW. Nerve and ganglion blood flow in diabetes: an appraisal, in Neurobiology of diabetic neuropathy (Tomlinson D, eds.), Academic Press, San Diego, 2002, pp. 161–202.

    Google Scholar 

  3. McManis PG, Low PA. Factors affecting the relative viability of centrifascicular and subperineurial axons in acute peripheral nerve ischemia. Exp Neurol 988;99:84–95.

    Google Scholar 

  4. Dyck PJ, Karnes J, O’Brien P, Nukada H, Lais A, Low P. Spatial pattern of nerve fiber abnormality indicative of pathologic mechanism. Am J Pathol 1984;117:225–238.

    PubMed  CAS  Google Scholar 

  5. Zochodne DW, Cheng C. Diabetic peripheral nerves are susceptible to multifocal ischemic damage from endothelin. Brain Res 1999;838:11–17.

    PubMed  CAS  Google Scholar 

  6. Lagerlund TD, Low PA. Mathematical modeling of hydrogen clearance blood flow measurements in peripheral nerve. Comput Biol Med 1994;24:77–89.

    PubMed  CAS  Google Scholar 

  7. Adams WE. The blood supply of nerves. I. Historical review. J Anat 1942;76:323–341.

    PubMed  CAS  Google Scholar 

  8. Bell MA, Weddell AG. A morphometric study of intrafascicular vessels of mammalian sciatic nerve. Muscle Nerve 1984;7:524–534.

    PubMed  CAS  Google Scholar 

  9. Appenzeller O, Dhital KK, Cowen T, Burnstock G. The nerves to blood vessels supplying blood to nerves: the innervation of vasa nervorum. Brain Res 1984;304:383–386.

    PubMed  CAS  Google Scholar 

  10. Dhital KK, Appenzeller O. Innervation of Vasa Nervorum, in Nonadrenergic innervation of blood vessels (Burnstock G, Griffith SG, eds.), CRC Press, Boca Raton, FL, 1988, pp. 191–211.

    Google Scholar 

  11. Brain SD, Williams TJ, Tippins JR, Morris HR, MacIntyre I. Calcitonin gene-related peptide is a potent vasodilator. Nature 1985;313:54–56.

    PubMed  CAS  Google Scholar 

  12. Quayle JM, Bonev AD, Brayden JE, Nelson MT. Calcitonin gene-related peptide activated ATP-sensitive K+ currents in rabbit arterial smooth muscle via protein kinase A. J Physiol 1994;475(1):9–13.

    PubMed  CAS  Google Scholar 

  13. Rechthand E, Hervonen A, Sato S, Rapoport SI. Distribution of adrenergic innervation of blood vessels in peripheral nerve. Brain Res 1986;374:185–189.

    PubMed  CAS  Google Scholar 

  14. Zochodne DW, Low PA. Adrenergic control of nerve blood flow. Exp Neurol 1990; 109:300–307.

    PubMed  CAS  Google Scholar 

  15. Zochodne DW, Huang ZX, Ward KK, Low PA. Guanethidine-induced adrenergic sympathectomy augments endoneurial perfusion and lowers endoneurial microvascular resistance. Brain Res 1990;519:112–117.

    PubMed  CAS  Google Scholar 

  16. Zochodne DW, Ho LT. Vasa nervorum constriction from substance P and calcitonin generelated peptide antagonists: sensitivity to phentolamine and nimodipine. Regul Pept 1993;47:285–290.

    PubMed  CAS  Google Scholar 

  17. Rechthand E, Sato S, Oberg PA, Rapoport SI. Sciatic nerve blood flow response to carbon dioxide. Brain Res 1988;446:61–66.

    PubMed  CAS  Google Scholar 

  18. Low PA, Tuck RR. Effects of changes of blood pressure, respiratory acidosis and hypoxia on blood flow in the sciatic nerve of the rat. J Physiol 1984;347:513–524.

    PubMed  CAS  Google Scholar 

  19. Rundquist I, Smith QR, Michel ME, Ask P, Oberg PA, Rapoport SI. Sciatic nerve blood flow measured by laser Doppler flowmetry and [14C]iodoantipyrine. Am J Physiol 1985; 248:H311–H317.

    PubMed  CAS  Google Scholar 

  20. Zochodne DW, Ho LT. Unique microvascular characteristics of the dorsal root ganglion in the rat. Brain Res 1991;559:89–93.

    PubMed  CAS  Google Scholar 

  21. McManis PG, Schmelzer JD, Zollman PJ, Low PA. Blood flow and autoregulation in somatic and autonomic ganglia. Comparison with sciatic nerve. Brain 1997;120(Pt 3):445–449.

    PubMed  Google Scholar 

  22. Tuck RR, Schmelzer JD, Low PA. Endoneurial blood flow and oxygen tension in the sciatic nerves of rats with experimental diabetic neuropathy. Brain 1984; 107:935–950.

    PubMed  Google Scholar 

  23. Zochodne DW, Ho LT. Normal blood flow but lower oxygen tension in diabetes of young rats: microenvironment and the influence of sympathectomy. Can J Physiol Pharmacol 1992;70:651–659.

    PubMed  CAS  Google Scholar 

  24. Zochodne DW, Sun H, Li XQ. Evidence that nitric oxide and opioid containing interneurons innerate vessels in the dorsal horn of the spinal cord of rats. J Physiol 2001;532:749–758.

    PubMed  CAS  Google Scholar 

  25. Zochodne DW, Ho LT. Neonatal guanethidine treatment alters endoneurial but not dorsal root ganglion perfusion in the rat. Brain Res 1994;649:147–150.

    PubMed  CAS  Google Scholar 

  26. Low PA, Lagerlund TD, McManis PG. Nerve blood flow and oxygen delivery in normal, diabetic, and ischemic neuropathy. Int Rev Neurobiol 1989;31:355–438.

    PubMed  CAS  Google Scholar 

  27. Sugimoto K, Yagihashi S. Effects of aminoguanidine on structural alterations of microvessels in peripheral nerve of streptozotocin diabetic rats. Microvasc Res 1997; 53:105–112.

    PubMed  CAS  Google Scholar 

  28. Zochodne DW, Nguyen C. Increased peripheral nerve microvessels in early experimental diabetic neuropathy: quantitative studies of nerve and dorsal root ganglia. J Neurol Sci 1999;166:40–46.

    PubMed  CAS  Google Scholar 

  29. Tesfaye S, Harris N, Jakubowski JJ, et al. Impaired blood flow and arterior-venous shunting in human diabetic neuropathy: a novel technique of nerve photography and fluorescein angiography. Diabetologia 1993;36:1266–1274.

    PubMed  CAS  Google Scholar 

  30. Hotta N, Koh N, Sakakibara F, et al. Effects of beraprost sodium and insulin on the electroretinogram, nerve conduction, and nerve blood flow in rats with streptozotocin-induced diabetes. Diabetes 1996;45:361–366.

    PubMed  CAS  Google Scholar 

  31. Hotta N, Koh N, Sakakibara F, et al. Effect of propionyl-L-carnitine on motor nerve conduction, autonomic cardiac function, and nerve blood flow in rats with streptozotocininduced diabetes: comparison with an aldose reductase inhibitor. J Pharmacol Exp Ther 1996;276:49–55.

    PubMed  CAS  Google Scholar 

  32. Hotta N, Koh N, Sakakibara F, et al. Prevention of abnormalities in motor nerve conduction and nerve blood-flow by a prostacyclin analog, beraprost sodium, in streptozotocininduced diabetic rats. Prostaglandins 1995;49:339–349.

    PubMed  CAS  Google Scholar 

  33. Obrosova IG, Van Huysen C, Fathallah L, Cao X, Stevens MJ, Greene DA. Evaluation of alpha(1)-adrenoceptor antagonist on diabetes-induced changes in peripheral nerve function, metabolism, and antioxidative defense. FASEB J 2000;14:1548–1558.

    PubMed  CAS  Google Scholar 

  34. Stevens MJ, Obrosova I, Cao X, Van Huysen C, Greene DA. Effects of DL-alpha-lipoic acid on peripheral nerve conduction, blood flow, energy metabolism, and oxidative stress in experimental diabetic neuropathy. Diabetes 2000;49:1006–1015.

    PubMed  CAS  Google Scholar 

  35. Kalichman MW, Lalonde AW. Experimental nerve ischemia and injury produced by cocaine and procaine. Brain Res 1991;565:34–41.

    PubMed  CAS  Google Scholar 

  36. Pugliese G, Tilton RG, Speedy A, et al. Effects of very mild versus overt diabetes on vascular haemodynamics and barrier function in rats. Diabetologia 1989;32:845–857.

    PubMed  CAS  Google Scholar 

  37. Tilton RG, Chang K, Nyengaard JR, Van Den Enden M, Ido Y, Williamson JR. Inhibition of sorbitol dehydrogenase. Effects on vascular and neural dysfunction in streptozocininduced diabetic rats. Diabetes 1995;44:234–242.

    PubMed  CAS  Google Scholar 

  38. Sutera SP, Chang K, Marvel J, Williamson JR. Concurrent increases in regional hematocrit and blood flow in diabetic rats: prevention by sorbinil. Am J Physiol 1992;263:H945–H950.

    PubMed  CAS  Google Scholar 

  39. Sugimoto H, Monafo WW, Eliasson SG. Regional sciatic nerve and muscle blood flow in conscious and anesthetized rats. Am J Physiol 1986;251:H1211–H1216.

    PubMed  CAS  Google Scholar 

  40. Chang K, Ido Y, LeJeune W, Williamson JR, Tilton RG. Increased sciatic nerve blood flow in diabetic rats: assessment by “molecular” vs. particulate microspheres. Am J Physiol 1997;273:E164–E173.

    PubMed  CAS  Google Scholar 

  41. Korthals JK, Korthals MA. Distribution of nerve lesions in serotonin-induced acute ischemic neuropathy. Acta Neuropathol 1990;81:20–24.

    PubMed  CAS  Google Scholar 

  42. Korthals JK, Korthals MA, Wisniewski HM. Peripheral nerve ischemia: Part 2. Accumulation of organelles. Ann Neurol 1978;4:487–498.

    PubMed  CAS  Google Scholar 

  43. Korthals JK, Maki T, Gieron MA. Nerve and muscle vulnerability to ischemia. J Neurol Sci 1985;71:283–290.

    PubMed  CAS  Google Scholar 

  44. Korthals JK, Maki T, Korthals MA, Prockop LD. Nerve and muscle damage after experimental thrombosis of large artery. Electrophysiology and morphology. J Neurol Sci 1996; 136:24–30.

    PubMed  CAS  Google Scholar 

  45. Korthals JK, Wisniewski HM. Peripheral nerve ischemia. Part 1. Experimental model. J Neurol Sci 1975;24:65–76.

    PubMed  CAS  Google Scholar 

  46. Parry GJ, Brown MJ. Arachidonate-induced experimental nerve infarction. J Neurol Sci 1981;50:123–133.

    PubMed  CAS  Google Scholar 

  47. Kihara M, Zollman PJ, Schmelzer JD, Low PA. The influence of dose of microspheres on nerve blood flow, electrophysiology and fiber degeneration of rat peripheral nerve. Muscle Nerve 1993;16:1383–1389.

    PubMed  CAS  Google Scholar 

  48. Kihara M, McManis PG, Schmelzer JD, Kihara Y, Low PA. Experimental ischemic neuropathy: salvage with hyperbaric oxygenation. Ann Neurol 1995;37:89–94.

    PubMed  CAS  Google Scholar 

  49. Day TJ, Schmelzer JD, Low PA. Aortic occlusion and reperfusion and conduction, blood flow and the blood-nerve barrier of rat sciatic nerve. Exp Neurol 1989; 103:173–178.

    PubMed  CAS  Google Scholar 

  50. Schmelzer JD, Zochodne DW, Low PA. Ischemic and reperfusion injury of rat peripheral nerve. Proc Natl Acad Sci USA 1989;86:1639–1642.

    PubMed  CAS  Google Scholar 

  51. Bennett GJ, Xie YK. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 1988;33:87–107.

    PubMed  CAS  Google Scholar 

  52. Sommer C, Myers RR. Vascular pathology in CCI neuropathy: a quantitative temporal study. Exp Neurol 1996; 141:113–119.

    PubMed  CAS  Google Scholar 

  53. Zochodne DW, Ho LT. Endoneurial microenvironment and acute nerve crush injury in the rat sciatic nerve. Brain Res 1990;535:43–48.

    PubMed  CAS  Google Scholar 

  54. Zochodne DW, Ho LT. Hyperemia of injured peripheral nerve: sensitivity to CGRP antagonism. Brain Res 1992;598:59–66.

    PubMed  CAS  Google Scholar 

  55. Raff MC, Sangalang V, Asbury AK. Ischemic mononeuropathy multiplex associated with diabetes mellitus. Arch Neurol 1968;18:487–499.

    PubMed  CAS  Google Scholar 

  56. Dyck PJ, Norell JE. Microvasculitis and ischemia in diabetic lumbosacral radiculoplexus neuropathy. Neurology 1999;53:2113–2121.

    PubMed  CAS  Google Scholar 

  57. Nukada H. Increased susceptibility to ischemic damage in steptozocin diabetic nerve. Diabetes 1986;35:1058–1061.

    PubMed  CAS  Google Scholar 

  58. Nukada H. Mild Ischemia Causes Severe Pathological Changes in Experimental Diabetic Nerve. Muscle Nerve 1992;15(10):1116–1122.

    PubMed  CAS  Google Scholar 

  59. Zochodne DW, Cheng C, Sun H. Diabetes increases sciatic nerve susceptibility to endothelininduced ischemia. Diabetes 1996;45:627–632.

    PubMed  CAS  Google Scholar 

  60. Takahashi K, Ghatei MA, Lam H-C, O’Halloran DJ, Bloom SR. Elevated plasma endothelin in patients with diabetes mellitus. Diabetologia 1990;33:306–310.

    PubMed  CAS  Google Scholar 

  61. Ak G, Buyukberber S, Sevinc A, et al. The relation between plasma endothelin-1 levels and metabolic control, risk factors, treatment modalities, and diabetic microangiopathy in patients with Type 2 diabetes mellitus. J Diab Comp 2001;15:150–157.

    CAS  Google Scholar 

  62. Bertello P, Veglio F, Pinna G, et al. Plasma endothelin in NIDDM patients with and without complications. Diabetes Care 1994; 17:574–577.

    PubMed  CAS  Google Scholar 

  63. Xu Q-G, Cheng C, Sun H, Thomsen K, Zochodne DW. Local sensory ganglion ischemia induced by endothelin vasoconstriction. Neuroscience 2003; 122:897–905.

    PubMed  CAS  Google Scholar 

  64. Cameron NE, Cotter MA. Comparison of the effects of ascorbyl gamma-linolenic acid and gamma-linolenic acid in the correction of neurovascular deficits in diabetic rats. Diabetologia 1996;39:1047–1054.

    PubMed  CAS  Google Scholar 

  65. Cameron NE, Cotter MA. Diabetes causes an early reduction in autonomic ganglion blood flow in rats. J Diab Comp 2001;15:198–202.

    CAS  Google Scholar 

  66. Cameron NE, Cotter MA. Effects of a nonpeptide endothelin-1 ETA antagonist on neurovascular function in diabetic rats: interaction with the renin-angiotensin system. J Pharmacol Exp Ther 1996;278:1262–1268.

    PubMed  CAS  Google Scholar 

  67. Cameron NE, Cotter MA. Effects of an extracellular metal chelator on neurovascular function in diabetic rats. Diabetologia 2001;44:621–628.

    PubMed  CAS  Google Scholar 

  68. Cameron NE, Cotter MA. Effects of chronic treatment with a nitric oxide donor on nerve conduction abnormalities and endoneurial blood flow in streptozotocin-diabetic rats. Eur J Clin Invest 1995;25:19–24.

    PubMed  CAS  Google Scholar 

  69. Cameron NE, Cotter MA. Effects of evening primrose oil treatment on sciatic nerve blood flow and endoneurial oxygen tension in streptozotocin-diabetic rats. Acta Diabetol 1994;31:220–225.

    PubMed  CAS  Google Scholar 

  70. Cameron NE, Cotter MA. Impaired contraction and relaxation in aorta from streptozotocindiabetic rats: role of polyol pathway. Diabetologia 1992;35:1011–1019.

    PubMed  CAS  Google Scholar 

  71. Cameron NE, Cotter MA. Interaction between oxidative stress and gamma-linolenic acid in impaired neurovascular function of diabetic rats. Am J Physiol 1996;271: E471–E476.

    PubMed  CAS  Google Scholar 

  72. Cameron NE, Cotter MA. Potential therapeutic approaches to the treatment or prevention of diabetic neuropathy: evidence from experimental studies. Diabet Med 1993;10: 593–605.

    PubMed  CAS  Google Scholar 

  73. Cameron NE, Cotter MA. Rapid reversal by aminoguanidine of the neurovascular effects of diabetes in rats: modulation by nitric oxide synthase inhibition. Metabolism 1996;45: 1147–1152.

    PubMed  CAS  Google Scholar 

  74. Cameron NE, Cotter MA, Archibald V, Dines KC, Maxfield EK. Anti-oxidant and pro-oxidant effects on nerve conduction velocity, endoneurial blood flow and oxygen tension in nondiabetic and streptozotocin-diabetic rats. Diabetologia 1994;37:449–459.

    PubMed  CAS  Google Scholar 

  75. Cameron NE, Cotter MA, Basso M, Hohman TC. Comparison of the effects of inhibitors of aldose reductase and sorbitol dehydrogenase on neurovascular function, nerve conduction and tissue polyol pathway metabolites in streptozotocin-diabetic rats. Diabetologia 1997;40:271–281.

    PubMed  CAS  Google Scholar 

  76. Cameron NE, Cotter MA, Dines K, Love A. Effects of aminoguanidine on peripheral nerve function and polyol pathway metabolites in streptozotocin-diabetic rats. Diabetologia 1992;35:946–950.

    PubMed  CAS  Google Scholar 

  77. Cameron NE, Cotter MA, Dines KC, Maxfield EK. Pharmacological manipulation of vascular endothelium function in non-diabetic and streptozotocin-diabetic rats: effects on nerve conduction, hypoxic resistance and endoneurial capillarization. Diabetologia 1993;36:516–522.

    PubMed  CAS  Google Scholar 

  78. Cameron NE, Cotter MA, Dines KC, Maxfield EK, Carey F, Mirrlees DJ. Aldose reductase inhibition, nerve perfusion, oxygenation and function in streptozotocin-diabetic rats: dose-response considerations and independence from a myo-inositol mechanism. Diabetologia 1994;37:651–663.

    PubMed  CAS  Google Scholar 

  79. Cameron NE, Cotter MA, Dines KC, Robertson S, Cox D. The effects of evening primrose oil on nerve function and capillarization in streptozotocin-diabetic rats: modulation by the cyclo-oxygenase inhibitor flurbiprofen. Br J Pharmacol 1993;109:972–979.

    PubMed  CAS  Google Scholar 

  80. Cameron NE, Cotter MA, Ferguson K, Robertson S, Radcliffe MA. Effects of chronic alpha-adrenergic receptor blockade on peripheral nerve conduction, hypoxic resistance, polyols, Na+-k+-ATPase activity, and vascular supply in STZ-D rats. Diabetes 1991;40: 1652–1658.

    PubMed  CAS  Google Scholar 

  81. Cameron NE, Cotter MA, Hohman TC. Interactions between essential fatty acid, prostanoid, polyol pathway and nitric oxide mechanisms in the neurovascular deficit of diabetic rats. Diabetologia 1996;39:172–182.

    PubMed  CAS  Google Scholar 

  82. Cameron NE, Cotter MA, Horrobin DH, Tritschler HJ. Effects of alpha-lipoic acid on neurovascular function in diabetic rats: interaction with essential fatty acids. Diabetologia 1998;41:390–399.

    PubMed  CAS  Google Scholar 

  83. Cameron NE, Cotter MA, Jack AM, Basso MD, Hohman TC. Protein kinase C effects on nerve function, perfusion, Na(+), K(+)-ATPase activity and glutathione content in diabetic rats. Diabetologia 1999;42:1120–1130.

    PubMed  CAS  Google Scholar 

  84. 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.

    PubMed  CAS  Google Scholar 

  85. Cameron NE, Cotter MA, Maxfield EK. Anti-oxidant treatment prevents the development of peripheral nerve dysfunction in streptozotocin-diabetic rats. Diabetologia 1993;36: 299–304.

    PubMed  CAS  Google Scholar 

  86. Cameron NE, Cotter MA, Robertson S. Chronic low frequency electrical activation for one week corrects nerve conduction velocity deficits in rats with diabetes of three months duration. Diabetologia 1989;32:759–761.

    PubMed  CAS  Google Scholar 

  87. Cameron NE, Cotter MA, Robertson S. Rapid reversal of a motor nerve conduction deficit in streptozotocin-diabetic rats by the angiotensin converting enzyme inhibitor lisinopril. Acta Diabetol 1993;30:46–48.

    PubMed  CAS  Google Scholar 

  88. Cameron NE, Cotter MA, Robertson S. The effect of aldose reductase inhibition on the pattern of nerve conduction deficits in diabetic rats. Q J Exp Physiol 1989;74:917–926.

    PubMed  CAS  Google Scholar 

  89. Cameron NE, Cotter MA, Robertson S, Maxfield EK. Nerve function in experimental diabetes in rats: effects of electrical stimulation. Am J Physiol 1993;264:E161–E166.

    PubMed  CAS  Google Scholar 

  90. Cameron NE, Dines KC, Cotter MA. The potential contribution of endothelin-1 to neurovascular abnormalities in streptozotocin-diabetic rats. Diabetologia 1994;37:1209–1215.

    PubMed  CAS  Google Scholar 

  91. Cotter MA, Cameron NE. Correction of neurovascular deficits in diabetic rats by beta2-adrenoceptor agonist and alpha1-adrenoceptor antagonist treatment: interactions with the nitric oxide system. Eur J Pharmacol 1998;343:217–223.

    PubMed  CAS  Google Scholar 

  92. Cotter MA, Cameron NE. Neuroprotective effects of carvedilol in diabetic rats: prevention of defective peripheral nerve perfusion and conduction velocity. Naunyn Schmiedebergs Arch Pharmacol 1995;351:630–635.

    PubMed  CAS  Google Scholar 

  93. Cotter MA, Cameron NE, Hohman TC. Correction of nerve conduction and endoneurial blood flow deficits by the aldose reductase inhibitor, tolrestat, in diabetic rats. J Peripher Nerv Syst 1998;3:217–223.

    PubMed  CAS  Google Scholar 

  94. Cotter MA, Love A, Watt MJ, Cameron NE, Dines KC. Effects of natural free radical scavengers on peripheral nerve and neurovascular function in diabetic rats. Diabetologia 1995;38:1285–1294.

    PubMed  CAS  Google Scholar 

  95. Obrosova IG, Van Huysen C, Fathallah L, Cao XC, Greene DA, Stevens MJ. An aldose reductase inhibitor reverses early diabetes-induced changes in peripheral nerve function, metabolism, and antioxidative defense. FASEB J 2002;16:123–125.

    PubMed  CAS  Google Scholar 

  96. Hotta N, Koh N, Sakakibara F, et al. Nerve function and blood flow in Otsuka Long-Evans Tokushima Fatty rats with sucrose feeding: effect of an anticoagulant. Eur J Pharmacol 1996;313:201–209.

    PubMed  CAS  Google Scholar 

  97. Kihara M, Schmelzer JD, Low PA. Effect of cilostazol on experimental diabetic neuropathy in the rat. Diabetologia 1995;38:914–918.

    PubMed  CAS  Google Scholar 

  98. Singhal A, Cheng C, Sun H, Zochodne DW. Near nerve local insulin prevents conduction slowing in experimental diabetes. Brain Res 1997;763:209–214.

    PubMed  CAS  Google Scholar 

  99. Brussee V, Cunningham FA, Zochodne DW. Direct insulin signaling of neurons reverses diabetic neuropathy. Diabetes 2004;53:1824–1830.

    PubMed  CAS  Google Scholar 

  100. Zochodne DW, Sun H-S, Cheng C, Eyer J. Accelerated diabetic neuropathy in axons without neurofilaments. Brain 2004;127:2193–2200.

    PubMed  Google Scholar 

  101. Zochodne DW, Ho LT. The influence of indomethacin and guanethidine on experimental streptozotocin diabetic neuropathy. Can J Neurol Sci 1992;19:433–441.

    PubMed  CAS  Google Scholar 

  102. Zochodne DW, Ho LT. The influence of sulindac on experimental streptozotocin-induced diabetic neuropathy. Can J Neurol Sci 1994;21:194–202.

    PubMed  CAS  Google Scholar 

  103. Zochodne DW, Ho LT, Allison JA. Dorsal root ganglia microenvironment of female BB Wistar diabetic rats with mild neuropathy. J Neurol Sci 1994;127:36–42.

    PubMed  CAS  Google Scholar 

  104. Chang K, Ido Y, LeJeune W, Williamson JR, Tilton RG. Increased sciatic nerve blood flow in diabetic rats: assessment by “molecular” vs. particulate microspheres. Am J Physiol 1997;273:E164–E173.

    PubMed  CAS  Google Scholar 

  105. Yasuda H, Dyck PJ. Abnormalities of endoneurial microvessels and sural nerve pathology in diabetic neuropathy. Neurology 1987;37:20–28.

    PubMed  CAS  Google Scholar 

  106. Schratzberger P, Walter DH, Rittig K, et al. Reversal of experimental diabetic neuropathy by VEGF gene transfer. J Clin Invest 2001;107:1083–1092.

    PubMed  CAS  Google Scholar 

  107. 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 Neuropathol 1997;93:118–128.

    PubMed  CAS  Google Scholar 

  108. Calver A, Collier J, Vallance P. Inhibition and stimulation of nitric oxide synthesis in the human forearm arterial bed of patients with insulin-dependent diabetes. J Clin Invest 1992;90:2548–2554.

    PubMed  CAS  Google Scholar 

  109. Elliott TG, Cockcroft JR, Groop PH, Viberti GC, Ritter JM. Inhibition of nitric oxide synthesis in forearm vasculature of insulin-dependent diabetic patients: blunted vasoconstriction in patients with microalbuminuria. Clin Sci 1993;85:687–693.

    PubMed  CAS  Google Scholar 

  110. Durante W, Sen AK, Sunahara FA. Impairment of endothelium-dependent relaxation in aortae from spontaneously diabetic rats. Br J Pharmacol 1988;94:463–468.

    PubMed  CAS  Google Scholar 

  111. Kihara M, Low PA. Impaired vasoreactivity to nitric oxide in experimental diabetic neuropathy. Exp Neurol 1995;132:180–185.

    PubMed  CAS  Google Scholar 

  112. Lawrence E, Brain SD. Altered microvascular reactivity to endothelin-1, endothelin-3 and NG-nitro-L-arginine methyl ester in streptozotocin-induced diabetes mellitus. Br J Pharmacol 1992;106:1035–1040.

    PubMed  CAS  Google Scholar 

  113. Tolins JP, Schultz PJ, Raij L, Brown DM, Mauer SM. Abnormal renal hemodynamic response to reduced renal perfusion pressure in diabetic rats: role of NO. Am J Physiol 1993;265:F886–F895.

    PubMed  CAS  Google Scholar 

  114. Bucala R, Tracey KJ, Cerami A. Advanced glycosylation products quench nitric oxide and mediate defective endothelium-dependent vasodilatation in experimental diabetes. J Clin Invest 1991;87:432–438.

    PubMed  CAS  Google Scholar 

  115. Diederich D, Skopec J, Diederich A, Dai FX. Endothelial dysfunction in mesenteric resistance arteries of diabetic rats: role of free radicals. Am J Physiol 1994;266: H1153–H1161.

    PubMed  CAS  Google Scholar 

  116. Hill MA, Meininger GA, Larkins RG. Alterations in microvascular reactivity in experimental diabetes mellitus: contribution of the endothelium?, in Endothelial cell function in diabetic microangiopathy: problems in methodology and clinical aspects (Molinatti GM, Bar RS, Belfiore F, Porta M, eds.), Karger, Basel, 1990, pp. 118–126.

    Google Scholar 

  117. Zochodne DW, Verge VM, Cheng C, et al. Nitric oxide synthase activity and expression in experimental diabetic neuropathy. J Neuropathol Exp Neurol 2000;59:798–807.

    PubMed  CAS  Google Scholar 

  118. Zochodne DW, Ho LT. Diabetes mellitus prevents capsaicin from inducing hyperaemia in the rat sciatic nerve. Diabetologia 1993;36:493–496.

    PubMed  CAS  Google Scholar 

  119. Willars GB, Calcutt NA, Compton AM, Tomlinson DR, Keen P. Substance P levels in peripheral nerve, skin, atrial myocardium and gastrointestinal tract of rats with long-term diabetes mellitus. Effects of aldose reductase inhibition. J Neurol Sci 1989;91:153–164.

    PubMed  CAS  Google Scholar 

  120. Kihara M, Mitsui MK, Mitsui Y, et al. Altered vasoreactivity to angiotension II in experimental diabetic neuropathy: role of nitric oxide. Muscle Nerve 1999;22:920–925.

    PubMed  CAS  Google Scholar 

  121. White RE, Carrier GO. Enhanced vascular alpha-adrenergic neuroeffector system in diabetes: importance of calcium. Am J Physiol 1988;255:H1036–H1042.

    PubMed  CAS  Google Scholar 

  122. Ward KK, Low PA, Schmelzer JD, Zochodne DW. Prostacyclin and noradrenaline in peripheral nerve of chronic experimental diabetes in rats. Brain 1989; 112:197–208.

    PubMed  Google Scholar 

  123. Parry GJ, Kohzu H. Studies of resistance to ischemic nerve conduction failure in normal and diabetic rats. J Neurol Sci 1989;93:61–67.

    PubMed  CAS  Google Scholar 

  124. Kennedy JM, Zochodne D. Impaired peripheral nerve regeneration in diabetes mellitus. J Peripher Nerv Syst 2005; 10(2): 144–157.

    PubMed  CAS  Google Scholar 

  125. Kennedy JM, Zochodne DW. The regenerative deficit of peripheral nerves in experimental diabetes: its extent, timing and possible mechanisms. Brain 2000;123:2118–2129.

    PubMed  Google Scholar 

  126. Nukada H. Post-traumatic endoneurial neovascularization and nerve regeneration: a morphometric study. Brain Res 1988;449:89–96.

    PubMed  CAS  Google Scholar 

  127. Zochodne DW, Levy D, Zwiers H, et al. Evidence for nitric oxide and nitric oxide synthase activity in proximal stumps of transected peripheral nerves. Neuroscience 1999;91: 1515–1527.

    PubMed  CAS  Google Scholar 

  128. Zochodne DW, Allison JA, Ho W, Ho LT, Hargreaves K, Sharkey KA. Evidence for CGRP accumulation and activity in experimental neuromas. Am J Physiol 1995;268:H584–H590.

    PubMed  CAS  Google Scholar 

  129. Hoke A, Sun H, Gordon T, Zochodne DW. Do denevated peripheral nerve trunks become ischomic? Exp Neurol 2001;172(2):398–406.

    PubMed  CAS  Google Scholar 

  130. Zochodne DW, Nguyen C. Angiogenesis at the site of neuroma formation in transected peripheral nerve. J Anat 1997;191:23–30.

    PubMed  Google Scholar 

  131. Hoke A, Gordon T, Zochodne DW, Sulaiman OA. A decline in glial cell-line-derived neurotrophic factor expression is associated with impaired regeneration after long-term Schwann cell denervation. Exp Neurol 2002;173:77–85.

    PubMed  CAS  Google Scholar 

  132. Roytta M, Salonen V. Long-term endoneurial changes after nerve transection. Acta Neuropathol 1988;76:35–45.

    PubMed  CAS  Google Scholar 

  133. Siironen J, Vuorinen V, Taskinen HS, Roytta M. Axonal regeneration into chronically denervated distal stump. 2. Active expression of type I collagen mRNA in epineurium. Acta Neuropathol 1995;89:219–226.

    PubMed  CAS  Google Scholar 

  134. Kennedy JM, Zochodne DW. Influence of experimental diabetes on the microcirculation of injured peripheral nerve. Functional and morphological aspects. Diabetes 2002;51: 2233–2240.

    PubMed  CAS  Google Scholar 

  135. Kennedy JM, Rubin I, Lauritzen M, Zochodne DW. Injury-induced nitric oxide synthase activity in regenerating diabetic peripheral nerves. Soc Neurosci Abs 2002;31:449(Abstract).

    Google Scholar 

  136. Levy D, Kubes P, Zochodne DW. Delayed peripheral nerve degeneration, regeneration, and pain in mice lacking inducible nitric oxide synthase. J Neuropathol Exp Neurol 2001;60:411–421.

    PubMed  CAS  Google Scholar 

  137. Dyck PJ, Giannini C. Pathologic alterations in the diabetic neuropathies of humans: a review. J Neuropathol Exp Neurol 1996;55:1181–1193.

    PubMed  CAS  Google Scholar 

  138. Dyck PJ, Hansen S, Karnes J, et al. Capillary number and percentage closed in human diabetic sural nerve. Proc Natl Acad Sci USA 1985;82:2513–2517.

    PubMed  CAS  Google Scholar 

  139. Korthals JK, Gieron MA, Dyck PJ. Intima of epineurial arterioles is increased in diabetic polyneuropathy. Neurology 1988;38:1582–1586.

    PubMed  CAS  Google Scholar 

  140. Dyck PJ, Karnes JL, O’Brien P, Okazaki H, Lais A, Engelstad J. The spatial distribution of fiber loss in diabetic polyneuropathy suggests ischemia. Ann Neurol 1986; 19:440–449.

    PubMed  CAS  Google Scholar 

  141. Dyck PJ, Lais A, Karnes JL, O’Brien P, Rizza R. Fiber loss is primary and multifocal in sural nerves in diabetic polyneuropathy. Ann Neurol 1986;19:425–439.

    PubMed  CAS  Google Scholar 

  142. Dyck PJ. Hypoxic neuropathy: Does hypoxia play a role in diabetic neuropathy? The 1988 Robert Wartenberg lecture. Neurology 1989;39:111–118.

    PubMed  CAS  Google Scholar 

  143. Malik RA. The pathology of human diabetic neuropathy. Diabetes 1997;46:S50–S53.

    PubMed  CAS  Google Scholar 

  144. Malik RA, Newrick PG, Sharma AK, et al. Microangiopathy in human diabetic neuropathy: relationship between capillary abnormalities and the severity of neuropathy. Diabetologia 1989;32:92–102.

    PubMed  CAS  Google Scholar 

  145. Malik RA, Tesfaye S, Thompson SD, et al. Endoneurial localisation of microvascular damage in human diabetic neuropathy. Diabetologia 1993;36:454–459.

    PubMed  CAS  Google Scholar 

  146. Malik RA, Veves A, Masson EA, et al. Endoneurial capillary abnormalities in mild human diabetic neuropathy. J Neurol Neurosurg Psychiatry 1992;55:557–561.

    PubMed  CAS  Google Scholar 

  147. Johnson PC, Doll SC, Cromey DW. Pathogenesis of diabetic neuropathy. Ann Neurol 1986; 19:450–457.

    PubMed  CAS  Google Scholar 

  148. Thrainsdottir S, Malik RA, Dahlin LB, et al. Endoneurial capillary abnormalities presage deterioration of glucose tolerance and accompany peripheral neuropathy in man. Diabetes 2003;52:2615–2622.

    PubMed  CAS  Google Scholar 

  149. Tesfaye S, Chaturvedi N, Eaton SE, et al. Vascular risk factors and diabetic neuropathy. N Engl J Med 2005;352:341–350.

    PubMed  CAS  Google Scholar 

  150. Ibrahim S, Harris ND, Radatz M, et al. A new minimally invasive technique to show nerve ischaemia in diabetic neuropathy. Diabetologia 1999;42:737–742.

    PubMed  CAS  Google Scholar 

  151. Newrick PG, Wilson AJ, Jakubowski J, Boulton AJ, Ward JD. Sural nerve oxygen tension in diabetes. Br Med J 1986;293:1053–1054.

    CAS  Google Scholar 

  152. Theriault M, Dort J, Sutherland G, Zochodne DW. Local human sural nerve blood flow in diabetic and other polyneuropathies. Brain 1997;120:1131–1138.

    PubMed  Google Scholar 

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Zochodne, D.W. (2007). Microangiopathy, Diabetes, and the Peripheral Nervous System. In: Veves, A., Malik, R.A. (eds) Diabetic Neuropathy. Clinical Diabetes. Humana Press. https://doi.org/10.1007/978-1-59745-311-0_12

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