Neuropathology and blood flow of nerve, spinal roots and dorsal root ganglia in longstanding diabetic rats

Abstract Vascular perfusion and neuropathologic evaluation of the lumbar spinal roots and dorsal root ganglia (DRG) were studied in rats with longstanding (duration 12–15 months) streptozotocin-induced diabetes and age- and sex-matched control rats. We also undertook nerve conduction studies including F-wave recordings and measured blood flow in sciatic nerve, DRG, and superior cervical ganglion (SCG). Light microscopically, changes of the myelin sheath in the dorsal and ventral roots and vacuolated cells in the DRG were the major findings, being significantly higher in diabetic rats than in control rats. The effects of the diabetic state on myelin splitting were greater in the dorsal than ventral roots. Electron microscopic studies revealed a gradation of changes in myelin from mild separation to severe ballooning of myelin with relative axonal sparing. DRG cells showed vacuoles of all sizes with cristae-like residues, suggestive of mitochondria. These findings suggest that diabetes mellitus has a dual effect; it accelerates the normal age-related degenerative changes in the spinal roots and DRG, and it also has a selective effect on the sensory neuron. Nerve conduction studies showed markedly reduced conduction velocities in the distal nerve segments and prolonged F-wave latency and proximal conduction time despite the shorter conduction pathway in diabetic rats. Blood flow, which was measured using iodo[14C]antipyrine autoradiography, was significantly reduced in the sciatic nerves, DRG, and SCG of diabetic rats. We suggest that the combination of hyperglycemia and ischemia results in oxidative stress and a predominantly sensory neuropathy.

[1]  R. Myers,et al.  Reduced Nerve Blood Flow in Hexachlorophene Neuropathy: Relationship to Elevated Endoneurial Fluid Pressure , 1982, Journal of neuropathology and experimental neurology.

[2]  P. Lampert,et al.  Mechanism of demyelination in tellurium neuropathy. Electron microscopic observations. , 1971, Laboratory investigation; a journal of technical methods and pathology.

[3]  T. Lagerlund,et al.  Analysis of H2 clearance curves used to measure blood flow in rat sciatic nerve. , 1989, The Journal of physiology.

[4]  H. Tritschler,et al.  Lipoic Acid Improves Nerve Blood Flow, Reduces Oxidative Stress, and Improves Distal Nerve Conduction in Experimental Diabetic Neuropathy , 1995, Diabetes Care.

[5]  K. Mitsumori,et al.  An Ultrastructural Study of Spinal Nerve Roots and Dorsal Root Ganglia in Aging Rats with Spontaneous Radiculoneuropathy , 1981, Veterinary pathology.

[6]  P. Wilson,et al.  The effect of age on mitochondrial ultrastructure and enzymes. , 1975, Advances in experimental medicine and biology.

[7]  J. Jakobsen,et al.  Reduced Perikaryal Volume of Lower Motor and Primary Sensory Neurons in Early Experimental Diabetes , 1980, Diabetes.

[8]  J. Perez-polo,et al.  Effects of nerve growth factor on catalase and glutathione peroxidase in a hydrogen peroxide-resistant pheochromocytoma subclone , 1994, Brain Research.

[9]  S. A. Gilmore Spinal nerve root degeneration in aging laboratory rats: A light microscopic study , 1972, The Anatomical record.

[10]  J. Greenberg,et al.  Regional perfusion in normal and ischemic rat sciatic nerves , 1985, Annals of neurology.

[11]  P. Low,et al.  Adrenergic control of nerve blood flow , 1990, Experimental Neurology.

[12]  A. Tappel,et al.  Peroxidation of Subcellular Organelles: Formation of Lipofuscinlike Fluorescent Pigments , 1969, Science.

[13]  P. Low,et al.  The influence of dose of microspheres on nerve blood flow, electrophysiology, and fiber degeneration of rat peripheral nerve , 1993, Muscle & nerve.

[14]  B. Ames,et al.  Oxidative damage and mitochondrial decay in aging. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[15]  P. Lampert,et al.  Demyelination and remyelination in lead neuropathy. Electron microscopic studies. , 1968, Journal of neuropathology and experimental neurology.

[16]  H. Wiśniewski,et al.  Lipopigment in the aging brain. , 1988, American journal of medical genetics. Supplement.

[17]  P. Low,et al.  Aminoguanidine effects on nerve blood flow, vascular permeability, electrophysiology, and oxygen free radicals. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[18]  S. Brimijoin,et al.  Ischemic conduction failure and energy metabolism in experimental diabetic neuropathy. , 1985, The American journal of physiology.

[19]  G. Nisticó,et al.  NGF restores decrease in catalase activity and increases superoxide dismutase and glutathione peroxidase activity in the brain of aged rats. , 1992, Free radical biology & medicine.

[20]  P. Low,et al.  Oxygen Free Radical Effects in Sciatic Nerve in Experimental Diabetes , 1991, Diabetes.

[21]  B. Chance,et al.  Oxygen toxicity in the perfused rat liver and lung under hyperbaric conditions. , 1976, The Biochemical journal.

[22]  J. A. Bastron,et al.  Diabetic polyradiculopathy: clinical and electromyographic findings in 105 patients. , 1981, Mayo Clinic proceedings.

[23]  P. Low,et al.  Dynamic peripheral nerve metabolic and vascular responses to exsanguination. , 1987, The American journal of physiology.

[24]  N. Gonatas,et al.  Hexachlorophene neuropathy in rats. , 1973, Laboratory investigation; a journal of technical methods and pathology.

[25]  E. Kokmen,et al.  Morphometric Alteration of Rat Myelinated Fibers with Aging , 1989, Journal of neuropathology and experimental neurology.

[26]  J. Turrens,et al.  Generation of superoxide anion by the NADH dehydrogenase of bovine heart mitochondria. , 1980, The Biochemical journal.

[27]  H. Wiśniewski,et al.  An ultrastructural study of experimental demyelination and remyelination. I. Acute experimental allergic encephalomyelitis in the peripheral nervous system. , 1969, Laboratory investigation; a journal of technical methods and pathology.

[28]  P. Low,et al.  Endoneurial blood flow and oxygen tension in the sciatic nerves of rats with experimental diabetic neuropathy. , 1984, Brain : a journal of neurology.

[29]  J I Hoffman,et al.  Blood flow measurements with radionuclide-labeled particles. , 1977, Progress in cardiovascular diseases.

[30]  B. Berg,et al.  Degenerative lesions of spinal roots and peripheral nerves in aging rats. , 1962, Gerontologia.

[31]  R. King,et al.  Influence of age on the late retrograde effects of sciatic nerve section in the rat. , 1995, Journal of anatomy.

[32]  G. Parry,et al.  Severe radicular pathology in rats with longstanding diabetes , 1994, Journal of the Neurological Sciences.

[33]  J. Jacobs,et al.  Vascular leakage in the dorsal root ganglia of the rat, studied with horseradish peroxidase , 1976, Journal of the Neurological Sciences.

[34]  R. Keyes Nerve conduction studies and electromyography. , 1990, Canadian family physician Medecin de famille canadien.

[35]  P. Low,et al.  Effect of α-tocopherol deficiency on indices of oxidative stress in normal and diabetic peripheral nerve , 1994, Journal of the Neurological Sciences.

[36]  U. Brunk,et al.  Electron microscopical studies on rat brain neurons. Localization of acid phosphatase and mode of formation of lipofuscin bodies. , 1972, Journal of ultrastructure research.

[37]  R. Crichton,et al.  Ultrastructural changes in brain parenchyma during normal aging and in animal models of aging. , 1994, Journal of neural transmission. Supplementum.

[38]  J. Halsey,et al.  Use of Hydrogen for Measurement of Regional Cerebral Blood Flow Problem of Intercompartmental Diffusion , 1977, Stroke.

[39]  Jun Kimura,et al.  Distal slowing of motor nerve conduction velocity in diabetic polyneuropathy , 1979, Journal of the Neurological Sciences.

[40]  B. Ames,et al.  Normal oxidative damage to mitochondrial and nuclear DNA is extensive. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[41]  S. Herold,et al.  Hydrogen Clearance Method for Determining Local Cerebral Blood Flow. I. Spatial Resolution , 1986, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[42]  D. Zochodne,et al.  Unique microvascular characteristics of the dorsal root ganglion in the rat , 1991, Brain Research.

[43]  D. Greene,et al.  Distal neuropathy in experimental diabetes mellitus , 1980, Annals of neurology.

[44]  R. Myers,et al.  Perineurial Window: Demyelination in Nonherniated Endoneurium with Reduced Nerve Blood Flow , 1992, Journal of neuropathology and experimental neurology.

[45]  J. Crapo,et al.  Biology of disease: free radicals and tissue injury. , 1982, Laboratory investigation; a journal of technical methods and pathology.

[46]  A. Sima,et al.  Proximal Motor Neuropathy in the BB-Wistar Rat , 1982, Diabetes.

[47]  R. Hellweg,et al.  Endogenous levels of nerve growth factor (NGF) are altered in experimental diabetes mellitus: A possible role for NGF in the pathogenesis of diabetic neuropathy , 1990, Journal of neuroscience research.

[48]  Louis Sokoloff,et al.  Measurement of local cerebral blood flow with Indo (14C) antipyrine. [/sup 131/I, rats, cats] , 1978 .

[49]  R. Myers,et al.  Schwann cell changes and demyelination in chronic galactose neuropathy , 1983, Muscle & nerve.

[50]  S. Yagihashi,et al.  Axo-glial dysjunction. A novel structural lesion that accounts for poorly reversible slowing of nerve conduction in the spontaneously diabetic bio-breeding rat. , 1986, The Journal of clinical investigation.

[51]  J. Koistinaho,et al.  Light and electron microscopic features of peripheral ganglion cells cultured from young and aged Wistar rats , 1991, Mechanisms of Ageing and Development.

[52]  P. Low,et al.  Effects of changes of blood pressure, respiratory acidosis and hypoxia on blood flow in the sciatic nerve of the rat. , 1984, The Journal of physiology.

[53]  E. Cadenas,et al.  Role of ubiquinone in the mitochondrial generation of hydrogen peroxide. , 1976, The Biochemical journal.

[54]  A. J. van der Kogel,et al.  Degenerative Myelopathy in Three Strains of Aging Rats , 1976, Veterinary pathology.