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The effects of Ginkgo biloba extract (GBe) on axonal transport microvasculature and morphology of sciatic nerve in streptozotocin-induced diabetic rats

Abstract

To evaluate the protective effects ofGinkgo biloba extract (GBe) which has antioxidant activity against peripheral neuropathy due to diabetes mellitus, slow axonal transport and morphology of sciatic nerve including endoneurial microvessels were examined in 12 rats with diabetes mellitus induced by streptozotocin (STZ, 60mg/kg, b.w., i.p.). Six of the diabetic rats were treated with 0.1 % of GBe for 6 weeks from one week after the STZ injection. Serum glucose and lipid peroxide levels in GBe-treated diabetic rats were significantly lower than those in untreated diabetic rats (p<0.01, respectively), though the serum glucose level was higher than that in the control rats. L-[35S] methionine pulse radiolabeling with subsequent gel fluorography demonstrated that mean velocities (Vmean) of actin and β-tubulin, i.e. slow component b (SCb) transport in untreated diabetic rats were significantly lower than those in control rats (p<0.05, respectively); mean diameter of axons in the former rats was significantly smaller than that in the latter (p<0.01). Vmean of actin transport in GBe-treated diabetic rats was significantly faster than that in untreated diabetic rats (p<0.05). Vmean of slow axonal transport was significantly correlated with mean diameter of axons in the three groups of rats combined (p<0.01). On electron microscopy, severe altered endoneurial microvessels decreasing in luminal area together with endothelial cell degeneration or hypertrophy, pericyte debris and basement membrane thickening were observed in untreated diabetic rats; on the other hand these findings were less prominent in the diabetic rats treated with GBe. It is suggested that GBe treatment may protect disturbed slow axonal transport and pathological alterations of peripheral nerve with abnormal endoneurial microvasculature from diabetes mellitus by antioxidant activity.

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References

  1. Tomlinson DR, Filliatreau G, Figliomeni B, Hassig R, Giamberardino LD, Willars GB. Proteins of slow axonal transport in sciatic motorneurones of rats with streptozotocin-induced diabetes or galactosamia. Diabet Res Clin Prac 1990; 9: 15–21.

    Article  CAS  Google Scholar 

  2. Figliomeni B, Bacci B, Panozzo C, Fogarolo F, Triban C, Fiori MG. Experimental diabetic neuropathy. Effect of ganglioside treatment on axonal transport of cytoskeletal proteins. Diabetes 1992; 41: 866–71.

    PubMed  Article  CAS  Google Scholar 

  3. Medori R, Jenich H, Autilio-Gambetti L, Gambetti P. Experimental diabetic neuropathy: similar changes of slow axonal transport and axonal size in different animal models. J Neurosci 1988; 8: 1814–21.

    PubMed  CAS  Google Scholar 

  4. Larsen JR, Sidenius P. Slow axonal transport of structural polypeptides in rat, early changes in streptozotocin diabetes, and effect of insulin treatment. J Neurochem 1989; 52: 390–401.

    PubMed  Article  CAS  Google Scholar 

  5. Lasek RJ, Garner JA, Brady ST. Axonal transport of the cytoplasmic matrix. J Cell Biol 1984; 99: 212s-21s.

    PubMed  Article  CAS  Google Scholar 

  6. Jakobsen J, Sidenius P, Braendgaard H. A proposal for a classification of neuropathies according to their axonal transport abnormalities. J Neurol Neurosurg Psychiat 1986; 49: 986–90.

    PubMed  CAS  Google Scholar 

  7. Hanaoka Y, Ohi T, Furukawa S, Furukawa Y, Hayashi K, Matsukura S. The therapeutic effects of 4-methylcatechol, a stimulator of endogenous nerve growth factor synthesis, on experimental diabetic neuropathy in rats. J Neurol Sci 1994; 122:28–32.

    PubMed  Article  CAS  Google Scholar 

  8. Weis J, Dimpfel W, Schroder JM. Nerve conduction changes and fine structural alterations of extra- and intrafusal muscle and nerve fibers in streptozotcin diabetic rats. Muscle & Nerve 1995; 18: 175–84.

    Article  CAS  Google Scholar 

  9. Yagihashi S, Kamijo M, Watanabe K. Reduced myelinated fiber size correlates with loss of axonal neurofilaments inperipheral nerve of chronically streptozotcin diabetic rats. Am J Pathol 1990; 136: 1365–73.

    PubMed  CAS  Google Scholar 

  10. Powell HC, Rosoff J, Myers RR. Microangiopathy in human diabetic neuropathy. Acta Neuropathol 1985; 68: 295–305.

    PubMed  Article  CAS  Google Scholar 

  11. Sidenius P. The axonopathy of diabetic neuropathy. Diabetes 1982; 31: 356–63.

    PubMed  CAS  Google Scholar 

  12. Stevens MJ, Feldman EL, Greene DA. The aetiology of diabetic neuropathy: the combined roles of metabolic and vascular defects. Diabet Med 1995; 12: 566–79.

    PubMed  CAS  Google Scholar 

  13. Horowitz SH. Diabetic neuropathy. Clin Orthopaed Res 1993; 296: 78–85.

    Google Scholar 

  14. Ward JD. Abnormal microvasculature in diabetic neuropathy. Eye 1993; 7: 223–6.

    PubMed  Google Scholar 

  15. Tesfaye S, Malik R, Ward JD. Vascular factors in diabetic neuropathy. Diabetologia 1994; 37: 847–54.

    PubMed  Article  CAS  Google Scholar 

  16. Tuck RR Schmelzer JD, Low PA. Endoneurial blood flow and oxygen tension in the sciatic nerves in the rats in experimental diabetic neuropathy. Brain 1984; 107: 935–50.

    PubMed  Article  Google Scholar 

  17. Newrick PG, Willson AJ, Jakubowski J, Boulton AJ, Ward JD. Sural nerve oxygen tension in diabetes. Brit Med J 1986; 293: 1053–4.

    CAS  Google Scholar 

  18. Cameron NE, Cotter MA, Archibald V, Dines KC, Maxfied EK. Anti-oxidant and pro-oxidant effects on nerve conduction velocity, endoneurial blood flow and oxygen tenson in non-diabetic and streptozotocin-diabetic rats. Diabetologia 1994; 37: 449–59.

    PubMed  Article  CAS  Google Scholar 

  19. Cameron NE, Cotter MA, Dines KC, Maxfield EK. Pharmacological manipulation of vascular endothelium in non-diabetic and streptozotocin-diabetic rats: effects on nerve conduction, hypoxic resistance and endoneurial capillarization. Diabetologia 1993; 36: 516–22.

    PubMed  Article  CAS  Google Scholar 

  20. Yasuda H, Hisanaga T, Maeda K, et al. An animal model of chronic ischemic neuropathy with proliferative changes of nerve microvessel wall. J Neurol Sci 1993; 120: 64–70.

    PubMed  Article  CAS  Google Scholar 

  21. Nickander KK, McPhee BR, Low PA, Tritchler HJ. Alphalipoic acid: antioxidant potency against lipid peroxidation of neural tissues in vitro and implications for diabetic neuropathy. Free Radic Biol Med 1996; 21: 631–9.

    PubMed  Article  CAS  Google Scholar 

  22. Cameron NE, Cotter MA. Interaction between oxidative stress and r-linolenic acid in impaired neurovascular function of diabetic rats. Am J Physiol 1996; 271: E471–6.

    PubMed  CAS  Google Scholar 

  23. Armstrong AM, Chestnutt JE, Gormley MJ, Young IS. The effects of diatary treatment on lipid peroxidation and antioxidant status in newly diagnosed noninsulin dependent diabetes. Free Radic Biol Med 1996; 21: 719–26.

    PubMed  Article  CAS  Google Scholar 

  24. Jamal GA. The use of gamma linolenic acid in the prevention and treatment of diabetic neuropathy. Diabet Med 1994; 11: 145–9.

    PubMed  CAS  Google Scholar 

  25. Low PA. Recent advances in the pathogenesis of diabetic neuropathy. Muscle & Nerve 1987; 10: 121–8.

    Article  CAS  Google Scholar 

  26. Nakata H, Brimijoin S, Low PA, Schmelzer JD. Slow axonal transport in experimental hypoxia and in neuropathy induced by p-bromophenylacetylurea. Brain Res 1987; 422: 319–26

    Article  Google Scholar 

  27. Kleijnen J, Knipschild P. Gikgo biloba. Lancet 1992; 340: 1136–9.

    PubMed  Article  CAS  Google Scholar 

  28. Rong Y, Geng Z, Lau PH. Ginkgo biloba attenuates oxidative stress in macrophages and endothelial cells. Free Radic Biol Med 1996; 20: 121–7.

    PubMed  Article  CAS  Google Scholar 

  29. Welt K, Fitzl G, Schaffranietz L. Myocardium-protective effects of Ginkgo biloba extract (Egb 761) in old rats against acute isobaric hypoxia. An electron microscopic morphometric study. II. Protection of microvascular endothelium. Exp Toxicol Pathol 1996; 48: 81–6.

    PubMed  CAS  Google Scholar 

  30. Jassens D, Michiels C, Eliaers E, Drieu K, Remacle J. Protection of hypoxia-induced ATP decrease in endothelial cells by ginkgo biloba extract and bilobalide. Biochem Pharmacol 1995; 50: 991–9.

    Article  Google Scholar 

  31. Jung F, Mrowietz C, Kiesewetter H, Wenzel E. Effect of Ginkgo biloba on fluidity of blood and peripheral microcirculation in voluteers. Arzneimittel-Forschung 1990; 40: 589–93.

    PubMed  CAS  Google Scholar 

  32. Witte S, Anadere I, Walitza E. Improvement of hemorheology with ginkgo biloba extract. Decreasing a cardiovascular risk factor. Fortschritte der Medizin 1992; 110: 247–50.

    PubMed  CAS  Google Scholar 

  33. Karasu C, Dewhurst M, Stevens EJ, Tomlinson DR. Effects of anti-oxidant treatment on sciatic nerve dysfunction in streptozotocin-diabetic rats; comparison with essential fatty acids. Diabetologia 1995; 38: 129–34.

    PubMed  Article  CAS  Google Scholar 

  34. Low PA, Nickander KK, Tritchler HJ. The role of oxidative stress and antioxidant treatment in diabetic neuropathy. Diabetes 1997; 46 Suppl 2: 38–42.

    Google Scholar 

  35. Packer L, Tritchler HJ, Wessel K. Neuroprotection by the metabolic antioxidant alpha-lipoic acid. Free Radic Biol Med 1997; 22: 359–78.

    PubMed  Article  CAS  Google Scholar 

  36. Hotta N, Nakamura J, Kakuta H, et al. Niceritrol prevents the decrease in red blood cell 2,3-diphosphoglycerate and neuropathy in streptozotocin-induced diabetic rats. J Diabet complic 1995; 9: 133–9.

    Article  CAS  Google Scholar 

  37. 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 

  38. Yagi K. Assay for blood plasma or serum. Methods Enzymol, 105. New York: Academic Press, 1984: 328–31.

    Google Scholar 

  39. Yokoyama K, Tsukita S, Ishikawa H, Kurokawa M. Early changes in the neuronal cytoskeleton caused by β, β’iminodipropionitrile: selective impairment of neurofilament polypeptides. Biomed Res 1980; 1: 537–47.

    CAS  Google Scholar 

  40. Yokoyama K, Araki S. Assessment of slow axonal transport in lead-exposed rats. Environ Res 1992; 59: 440–6.

    PubMed  Article  CAS  Google Scholar 

  41. Benstead TJ, Sangalang VE, Dyck PJ. Acute endothelial swelling is induced in endoneurial microvessels by ischemia. J Neurol Sci 1990; 99: 37–49.

    PubMed  Article  CAS  Google Scholar 

  42. Timperley WR, Boulton AJM, Davies-Jones GAB, Jarratt JA, Ward JD. Small vessel disease in progressive in diabetic neuropathy associated with good metabolic control. J Clin Pathol 1985; 38: 1030–8.

    PubMed  Article  CAS  Google Scholar 

  43. 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: 2513–7.

    PubMed  Article  CAS  Google Scholar 

  44. Malik RA, Tesfaye S, Thompson SD, et al. Endoneurial localisation of microvascular damage in human diabetic neuropathy. Diabetologia 1993; 36: 454–9.

    PubMed  Article  CAS  Google Scholar 

  45. Seif-El-Nasr M El-Fattah AA. Lipid peroxide, phospholipids, glutathione levels and superoxide dismutase activity in rat brain after ischaemia: effect of ginkgo biloba extract. Pharmacol Res 1995; 32: 273–8.

    PubMed  Article  CAS  Google Scholar 

  46. Oyama Y, Chikahisa L, Ueha T, Kanemaru K, Noda K. Ginkgo biloba extract protects brain neurons against oxidative stress induced by hydrogen peroxide. Brain Res 1996; 712: 349–52.

    PubMed  Article  CAS  Google Scholar 

  47. Apaydin C, Oguz Y, Yargicoglu P, Demir N, Aksu G. Visual evoked potentials and optic nerve histopathology in normal and diabetic rats and effect of ginkgo biloba extract. Acta Ophthalmol 1993; 71: 623–8.

    CAS  Article  Google Scholar 

  48. Smith PF, Maclennan K, Darlington CL. The neuroprotective properties of the Ginkgo biloba leaf: a review of the possible relationship to platelet-activating factor (PAF). J Ethnopharmacol 1996; 50: 131–9.

    PubMed  Article  CAS  Google Scholar 

  49. Auguet M, Delaflotte S, Hellegouarch A, Clostre F. Pharmacological bases of the vascular impact of Ginkgo biloba extract. Presse Med 1986; 15: 1524–8.

    PubMed  CAS  Google Scholar 

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Kim, J., Yokoyama, K. & Araki, S. The effects of Ginkgo biloba extract (GBe) on axonal transport microvasculature and morphology of sciatic nerve in streptozotocin-induced diabetic rats. Environ Health Prev Med 5, 53 (2000). https://doi.org/10.1007/BF02932004

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  • DOI: https://doi.org/10.1007/BF02932004

Key words

  • Ginkgo alkaloides
  • neuropathy
  • tublin
  • actin
  • neurofilament