Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Inhibition of development of peripheral neuropathy in streptozotocin-induced diabetic rats with N-acetylcysteine


N-acetylcysteine (NAC) is a precursor of glutathione (GSH) synthesis, a free radical scavenger and an inhibitor of tumour necrosis factor α (TNF). Because these functions might be beneficial in diabetic complications, in this study we examined whether NAC inhibits peripheral neuropathy. Motor nerve conduction velocity (MNCV) was significantly decreased in streptozotocin-induced-diabetic Wistar rats compared to control rats. Oral administration of NAC reduced the decline of MNCV in diabetic rats. Structural analysis of the sural nerve disclosed significant reduction of fibres undergoing myelin wrinkling and inhibition of myelinated fibre atrophy in NAC-treated diabetic rats. NAC treatment had no effect on blood glucose levels or on the nerve glucose, sorbitol and cAMP contents, whereas it corrected the decreased GSH levels in erythrocytes, the increased lipid peroxide levels in plasma and the increased lipopolysaccharide-induced TNF activity in sera of diabetic rats. Thus, NAC inhibited the development of functional and structural abnormalities of the peripheral nerve in streptozotocin-induced diabetic rats.

This is a preview of subscription content, log in to check access.



Tumour necrosis factor α








motor nerve conduction velocity




  1. 1.

    Boulton AJM (1993) Pathogenesis of diabetic neuropathy. In: Marshall SM, Home PD, Alberti KGMM, Krall LP (eds) The diabetes annual/7. Elsevier, Amsterdam, pp 192–210

  2. 2.

    Loven D, Schedl H, Wilson H et al. (1986) Effect of insulin and oral glutathione on glutathione levels and superoxide dismutase activities in organs of rats with streptozotocin-induced diabetes. Diabetes 35: 503–507

  3. 3.

    Tanaka S-I, Seino H, Satoh J et al. (1992) Increased in vivo production of tumor necrosis factor after development of diabetes in nontreated, long-term diabetic BB rats. Clin Immunol Immunopathol 62: 258–263

  4. 4.

    Sagara M, Satoh J, Zhu XP et al. (1994) Inhibition with N-acetylcysteine of enhanced production of tumor necrosis factor in streptozotocin-induced diabetic rats. Clin Immunol Immunopathol 71: 333–337

  5. 5.

    Beutler B, Cerami A (1987) Cachectin: more than a tumor necrosis factor. N Engl J Med 316: 379–385

  6. 6.

    Tracey KJ, Vlassara H, Cerami A (1989) Cachectin/tumour necrosis factor. Lancet I: 1122–1125

  7. 7.

    Editorial (1991) Acetylcysteine. Lancet 337: 1069–1070

  8. 8.

    Peristeris P, Clark BD, Gatti S et al. (1992) N-acetylcysteine and glutathione as inhibitors of tumor necrosis factor production. Cell Immunol 140: 390–399

  9. 9.

    Satoh J, Seino H, Abo T et al. (1989) Recombinant human tumor necrosis factor α suppresses autoimmune diabetes in nonobese diabetic mice. J Clin Invest 84: 1345–1348

  10. 10.

    Yagihashi S, Kamijo M, Ido Y, Mirrlees DJ (1990) Effects of long-term aldose reductase inhibition on development of experimental diabetic neuropathy. Diabetes 39: 690–696

  11. 11.

    Ellman GL (1958) A colorimetric method for determining low concentrations of mercaptons. Arch Biochem Biophys 74: 443–450

  12. 12.

    Yagi K (1976) A simple fluorometric assay for lipoperoxide in blood plasma. Biochem Med 15: 212–216

  13. 13.

    Malone JI, Knox G, Benford S, Tedesco TA (1980) Red cell sorbitol: an indicator of diabetic control. Diabetes 29: 861–864

  14. 14.

    Honma M, Satoh T, Takezawa J, Ui M (1977) An ultrasensitive method for the simultaneous determination of cyclic AMP and cyclic GMP in small-volume samples from blood and tissue. Biochem Med 18: 257–273

  15. 15.

    Dyck PJ, Karnes J, Lais A, Lofgren EP, Stevens JC (1984) Pathologic alterations of the peripheral nervous system of humans. In: Peripheral neuropathy. Dyck PJ, Thomas PK, Lambert EH, Bunge R (eds) Saunders, Philadelphia, pp 760–870

  16. 16.

    Yagihashi S, Kamijo M, Watanabe K (1990) Reduced myelinated fiber size correlates with loss of axonal neurofilaments in peripheral nerve of chronically streptozotocin diabetic rats. Am J Pathol 136: 1365–1373

  17. 17.

    Sima AAF, Zhang W-X, Tze WJ, Tai J, Nathaniel V (1988) Diabetic neuropathy in STZ-induced diabetic rat and effect of allogeneic islet cell transplantation. Diabetes 37: 1129–1136

  18. 18.

    Yasuda H, Sonobe M, Yamashita M et al. (1989) Effect of prostaglandin E1 analogue TFC612 on diabetic neuropathy in streptozocin-induced diabetic rats. Diabetes 38: 832–838

  19. 19.

    Burgunder JM, Varriale A, Lauterberg BH (1989) Effect of N-acetylcysteine on plasma cysteine and glutathione following paracetamol administration. Eur J Clin Pharmacol 36: 127–131

  20. 20.

    Meister A, Anderson ME (1983) Glutathione. Ann Rev Biochem 52: 711–760

  21. 21.

    Murakami K, Kondo T, Ohtsuka Y, Fujiwara Y, Shimada M, Kawakami Y (1989) Impairment of glutathione metabolism in erythrocytes from patients with diabetes mellitus. Metabolism 38: 753–758

  22. 22.

    Lu CS, Ge J, Kuhlenkamp J, Kaplowitz N (1992) Insulin and glucocorticoid dependence of hepatic γ-glutamylcysteine synthetase and glutathione synthesis in the rat. J Clin Invest 90: 524–532

  23. 23.

    Hunt VJ, Dean RT, Wolff SP (1988) Hydroxyl radical production and autoxidative glycosylation. Biochem J 256: 205–212

  24. 24.

    Barnett PA, Gonzalez RG, Chylack LT, Chylack LT Jr, Cheng H-M (1986) The effect of oxidation on sorbitol pathway kinetics. Diabetes 35: 426–432

  25. 25.

    Brownlee M, Cerami A, Vlassara H (1988) Advanced products of nonenzymatic glycosylation and the pathogenesis of diabetic vascular disease. Diab Metab Rev 4: 437–451

  26. 26.

    Romero FJ, Segura-Aguilar J, Monsalve E et al. (1990) Antioxidant and glutathione-related enzymatic activities in rat sciatic nerve. Neurotoxicol Teratol 12: 603–605

  27. 27.

    Kashiwagi A, Asahina T, Ikebuchi M et al. (1994) Abnormal glutathione metabolism and increased cytotoxicity caused by H2O2 in human umbilical vein endothelial cells cultured in high glucose medium. Diabetologia 37: 264–269

  28. 28.

    Chaudhri G, Clark IA (1989) Reactive oxygen species facilitate the in vitro and in vivo lipopolysaccharide-induced release of tumor necrosis factor. J Immunol 143: 1290–1294

  29. 29.

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

  30. 30.

    Bravenboer B, Kappelle AC, Hamers FPT, Van Buren T, Erkelens DW, Gispen WH (1992) Potential use of glutathione for prevention and treatment of diabetic neuropathy in the streptozotocin-induced diabetic rat. Diabetologia 35: 813–817

  31. 31.

    Low PA (1987) Recent advances in the pathogenesis of diabetic neuropathy. Muscle Nerve 10: 121–128

  32. 32.

    Spies JM, Westland KW, Hodgkinson SJ, Pollard JD (1994) Intraneuronal tumor necrosis factor causes focal breakdown of the blood nerve barrier. Proc Peripheral Nerve Society Meeting, St. Paul, June 12–16, pp 146 (Abstract)

  33. 33.

    Mayer M, Noble M (1994) N-Acetyl-L-cysteine is a pluripotent protector against cell death and enhancer of trophic factor-mediated cell survival in vitro. Proc Natl Acad Sci USA 91: 7496–7500

  34. 34.

    Vlassara H, Brownlee M, Manogue KR, Dinarello CA, Pasagian A (1988) Cachectin/TNF and IL-1 induced by glucose-modified proteins: role in normal tissue remodeling. Science 240: 1546–1548

Download references

Author information

Correspondence to Dr. J. Satoh.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Sagara, M., Satoh, J., Wada, R. et al. Inhibition of development of peripheral neuropathy in streptozotocin-induced diabetic rats with N-acetylcysteine. Diabetologia 39, 263–269 (1996). https://doi.org/10.1007/BF00418340

Download citation


  • N-acetylcysteine
  • glutathione
  • tumour necrosis factor α
  • diabetic neuropathy
  • motor nerve conduction velocity