Skip to main content

The Role of Oxidative Stress in Peripheral Neuropathy

Abstract

Peripheral neuropathy (PN) is a common disease affecting about 5% of the general population after the age of 50. Causes of PN are numerous and include genetic, diabetes, alcohol, vitamin deficiencies, and gluten sensitivity among others. This systematic review aimed to study the association between oxidative stress and PN in an attempt to better understand PN pathogenesis. A computer-based, systematic search was conducted on the PubMed database, and ensuing data from included articles was analyzed and discussed in this review. Sixty-nine papers were eligible and were used for this review. Peripheral neuropathy is associated with an increase of reactive oxygen species and a decrease in endogenous antioxidants. Genetic predisposition to oxidative damage may be a factor. Antioxidant treatment is promising regarding treatment. Though further research is necessary to better understand the underlying mechanism, it is evident that oxidative stress is implicated in the pathogenesis of – or is at least systematically present in – PN.

This is a preview of subscription content, access via your institution.

Fig. 1

References

  1. Ahlbeck K, Fredriksson K, Rooyackers O, Måbäck G, Remahl S, Ansved T, Eriksson L, Radell P (2009) Signs of critical illness polyneuropathy and myopathy can be seen early in the ICU course. Acta Anaesthesiol Scand 53:717–723

    PubMed  CAS  Google Scholar 

  2. Ametov A, Barinov A, Dyck P, Hermann R, Kozlova N, Litchy WJ, Low PA, Nehrdich D, Novosadova M, O'Brien PC, Reljanovic M, Samigullin R, Schuette K, Strokov I, Tritschler HJ, Wessel K, Yakhno N, Ziegler D, SYDNEY Trial Study Group (2003) The sensory symptoms of diabetic polyneuropathy are improved with alpha-lipoic acid: the SYDNEY trial. Diabetes Care 26:770–776

    PubMed  CAS  Google Scholar 

  3. Babizhayev M, Strokov I, Nosikov V et al (2015) The role of oxidative stress in diabetic neuropathy: generation of free radical species in the glycation reaction and gene polymorphisms encoding antioxidant enzymes to genetic susceptibility to diabetic neuropathy in population of type I diabetic patient. Cell Biochem Biophys 71:1425–1443

    PubMed  CAS  Google Scholar 

  4. Baracca A, Sgarbi G, Mattiazzi M, Casalena G, Pagnotta E, Valentino ML, Moggio M, Lenaz G, Carelli V, Solaini G (2007) Biochemical phenotypes associated with the mitochondrial ATP6 gene mutations at nt8993. Biochim Biophys Acta 1767:913–919

    PubMed  CAS  Google Scholar 

  5. Bertolotto F, Massone A (2012) Combination of alpha lipoic acid and superoxide dismutase leads to physiological and symptomatic improvements in diabetic neuropathy. Drugs R D 12:29–34

    PubMed  PubMed Central  CAS  Google Scholar 

  6. Betteridge D (2000) What is oxidative stress? Metabolism 49(2 Suppl 1):3–8

    PubMed  CAS  Google Scholar 

  7. Bito T, Misaki T, Yabuta Y et al (2017) Vitamin B12 deficiency results in severe oxidative stress, leading to memory retention impairment in Caenorhabditis elegans. Redox Biol 11:21–29

    PubMed  CAS  Google Scholar 

  8. Boghdady NE, Badr G (2012) Evaluation of oxidative stress markers and vascular risk factors in patients with diabetic peripheral neuropathy. Cell Biochem Funct 30(4):328–334

    PubMed  Google Scholar 

  9. Buraczynska M, Buraczynska K, Dragan M, Ksiazek A (2017) Pro198Leu polymorphism in the glutathione peroxidase 1 gene contributes to diabetic peripheral neuropathy in type 2 diabetes patients. NeuroMolecular Med 19:147–153

    PubMed  CAS  Google Scholar 

  10. Christiakov D, Zotova E, Savost'anov K et al (2006) The 262 T>C promoter polymorphism of the catalase gene is associated with diabetic neuropathy in type 1 diabetic Russian patients. Diabetes Metab 32:63–68

    Google Scholar 

  11. Christiakov D, Spitsina E, Nikitin A et al (2009) A splice variant of GNB3 and peripheral polyneuropathy in type 1 diabetes. Dis Markers 26:111–117

    Google Scholar 

  12. Coriat R, Alexandre J, Nicco C, Quinquis L, Benoit E, Chéreau C, Lemaréchal H, Mir O, Borderie D, Tréluyer JM, Weill B, Coste J, Goldwasser F, Batteux F (2014) Treatment of oxaliplatin-induced peripheral neuropathy by intravenous mangafodipir. J Clin Invest 124:262–272

    PubMed  CAS  Google Scholar 

  13. Di Cesare Mannelli L, Zanardelli M, Failli P et al (2013) Oxaliplatin-induced oxidative stress in nervous system-derived cellular models: could it correlate with in vivo neuropathy? Free Radic Biol Med 61:143–150

    PubMed  Google Scholar 

  14. DiNicolantonio J, McCarty M, O'Keefe J (2018) Antioxidant bilirubin works in multiple ways to reduce risk for obesity and its health complications. Open Heart 5(2):e000914

    PubMed  PubMed Central  Google Scholar 

  15. Eckhoff L, Feddersen S, Knoop A et al (2015) Docetaxel-induced neuropathy: a pharmacogenetic case-control study of 150 women with early-stage breast cancer. Acta Oncol 54:530–537

    PubMed  CAS  Google Scholar 

  16. Erel O (2004) A novel automated direct measurement method for total antioxidant capacity using a new generation, more stable ABTS radical cation. Clin Biochem 37(4):277–285

    PubMed  CAS  Google Scholar 

  17. Fiszman M, Di Egidio M, Ricart K et al (2003) Evidence of oxidative stress in familial amyloidotic polyneuropathy type 1. Arch Neurol 60:593–597

    PubMed  Google Scholar 

  18. Fong V, Vieira A (2013) Transthyretin aggregates induce production of reactive nitrogen species. Neurodegener Dis 11:42–48

    PubMed  Google Scholar 

  19. Forsberg E, Xu C, Grunler J et al (2015) Coenzyme Q10 and oxidative stress, the association with peripheral sensory neuropathy and cardiovascular disease in type 2 diabetes mellitus. J Diabetes Complicat 29:1152–1158

    PubMed  Google Scholar 

  20. T. Ganz, J. Wainstein, S. Gilad et al (2017) Serum asymmetric dimethylarginine and arginine levels predict microvascular and macrovascular complications in type 2 diabetes mellitus. Diabetes Metab Res Rev, vol. 33

  21. Gerrits E, Lutgers H, Kleefstra N et al (2008) Skin autofluorescence: a tool to identify type 2 diabetic patients at risk for developing microvascular complications. Diabetes Care 31:517–521

    PubMed  CAS  Google Scholar 

  22. Glimelius B, Manojlovic N, Pfeiffer P, Mosidze B, Kurteva G, Karlberg M, Mahalingam D, Buhl Jensen P, Kowalski J, Bengtson M, Nittve M, Näsström J (2018) Persistent prevention of oxaliplatin-induced peripheral neuropathy using calmangafodipir (PledOx): a placebo-controlled randomised phase II study (PLIANT). Acta Oncol 57:393–402

    PubMed  CAS  Google Scholar 

  23. Greenlee H, Hershman D, Shi Z et al (2016) "BMI, lifestyle factors and taxane-induced neuropathy in breast cancer patients: the pathways study," J Natl Cancer Inst, vol. 109

  24. Hahm J, Kim B, Kim K (2004) Clinical experience with thioctacid (thioctic acid) in the treatment of distal symmetric polyneuropathy in Korean diabetic patients. J Diabetes Complicat 18:79–85

    PubMed  Google Scholar 

  25. Hahn K, Robinson B, Anderson C, Li W, Pardo CA, Morgello S, Simpson D, Nath A (2008) DIfferential effects of HIV infected macrophages on dorsal root ganglia neurons and axons. Exp Neurol 210:30–40

    PubMed  CAS  Google Scholar 

  26. Haslbeck K, Schleicher E, Friess U, Kirchner A, Neundörfer B, Heuss D (2002) N(ε)-carboxymethyllisine in diabetic and non-diabetic polyneuropathies. Acta Neuropathol 104:45–52

    PubMed  CAS  Google Scholar 

  27. Herder C, Kannenberg J, Huth C et al (2018) Myeloperoxidase, superoxide dismutase-3, cardiometabolic risk factors, and distal sensorimotor polyneuropathy: the KORA F4/FF4 study. Diabetes Metab Res Rev 34:e3000

    PubMed  Google Scholar 

  28. Hernandez-Ojeda J, Cardona-Munoz E, Roman-Pintos L et al (2012) The effect of ubiquinone in diabetic polyneuropathy: a randomized double-blind placebo-controlled study. J Diabetes Complicat 26:352–358

    PubMed  Google Scholar 

  29. Hsu Y, Tseng Y, Lo Y (2013) Berberine, a natural antidiabetes drug, attenuates glucose neurotoxicity and promotes Nrf2-related neurite outgrowth. Toxicol Appl Pharmacol 272:787–796

    PubMed  CAS  Google Scholar 

  30. Jin H, Joung S, Park J, Baek HS, Park TS (2007) The effect of alpha-lipoic acid on symptoms and skin blood flow in diabetic neuropathy. Diabet Med 24:1034–1038

    PubMed  CAS  Google Scholar 

  31. Kartha V, Krishnamurthy S (1977) Antioxidant function of vitamin A. Int J Nutr Res 47(4):349–401

    Google Scholar 

  32. Khairy E, Attia M (2019) Protective effects of vitamin D on neurophysiologic alterations in brain aging: role of brain-derived neurotrophic factor (BDNF). Nutr Neurosci 16:1–10

    Google Scholar 

  33. Kim E, Lee S, Mo E et al (2015) Inverse association between serum total bilirubin levels and diabetic peripheral neuropathy in patients with type 2 diabetes. Endocrine 50:405–415

    PubMed  CAS  Google Scholar 

  34. Kober K, Olshen A, Conley Y et al (2018) Expression of mitochondrial dysfunction-related genes and pathways in paclitaxel-induced peripheral neuropathy in breast cancer survivors. Mol Pain:1–16

  35. Kugimiya T, Jono H, Saito S, Maruyama T, Kadowaki D, Misumi Y, Hoshii Y, Tasaki M, Su Y, Ueda M, Obayashi K, Shono M, Otagiri M, Ando Y (2011) Loss of functional albumin triggers acceleration of transthyretin amyloid fibril formation in familial amyloidotic polyneuropathy. Lab Investig 91:1219–1228

    PubMed  CAS  Google Scholar 

  36. Laczy B, Cseh J, Mohas M et al (2009) Effects of pentoxifylline and pentosan polysulphate combination therapy on diabetic neuropathy in type 2 diabetes mellitus. Acta Diabetol 46:105–111

    PubMed  CAS  Google Scholar 

  37. Lebiedzinska M, Karkucinska-Wieckowska A, Wojtala A et al (2013) Disrupted ATP synthase activity and mitochondrial hyperpolarisation-dependent oxidative stress is associated with p66Shc phosphorylation in fibroblasts of NARP patients. Int J Biochem Cell Biol 45:141–150

    PubMed  CAS  Google Scholar 

  38. Marrali G, Salamone P, Casale F, Fuda G, Cugnasco P, Caorsi C, Amoroso A, Calvo A, Lopiano L, Cocito D, Chiò A (2016) NADPH oxidase 2 (NOX2) enzyme activation in patients with chronic inflammatory demyelinating polyneuropathy. Eur J Neurol 23:958–963

    PubMed  CAS  Google Scholar 

  39. Martinez-Hervas S, Mendez M, Folgado J et al (2017) Altered Semmes-Weinstein monofilament test results are associated with oxidative stress markers in type 2 diabetic subjects. J Transl Med 15:187

    PubMed  PubMed Central  Google Scholar 

  40. Martyn C, Hughes R (1997) Epidemiology of peripheral neuropathy. J Neurol Neurosurg Psychiatry 62:310–318

    PubMed  PubMed Central  CAS  Google Scholar 

  41. Massicot F, Hache G, David L et al (2013) P2X7 cell death receptor activation and mitochondrial impairment in oxaliplatin-induced apoptosis and neuronal injury: cellular mechanisms and in vivo approach. PLoS One 8:e66830

    PubMed  PubMed Central  CAS  Google Scholar 

  42. Mattiazzi M, Vijayvergiya C, Gajewski C, DeVivo D, Lenaz G, Wiedmann M, Manfredi G (2004) The mtDNA T8993G (NARP) mutation results in an impairment of oxidative phosphorylation that can be improved by antioxidants. Hum Mol Genet 13:869–879

    PubMed  CAS  Google Scholar 

  43. Medeiros R, Girardi K, Cardoso F, Mietto BS, Pinto TG, Gomez LS, Rodrigues LS, Gandini M, Amaral JJ, Antunes SL, Corte-Real S, Rosa PS, Pessolani MC, Nery JA, Sarno EN, Batista-Silva LR, Sola-Penna M, Oliveira MF, Moraes MO, Lara FA (2016) Subversion of Schwann cell glucose metabolism by Mycobacterium leprae. J Biol Chem 291:21375–21387

    PubMed  PubMed Central  Google Scholar 

  44. Mendez M, Folgado J, Tormo C, Artero A, Ascaso M, Martinez-Hervás S, Chaves FJ, Ascaso JF, Real JT (2015) Altered glutathione system is associated with the presence of distal symmetric peripheral polyneuropathy in type 2 diabetic subjects. J Diabetes Complicat 29:923–927

    PubMed  Google Scholar 

  45. Mir O, Alexandre J, Tran A, Durand JP, Pons G, Treluyer JM, Goldwasser F (2009) Relationship between GSTP1 Ile(105)Val polymorphism and docetaxel-induced peripheral neuropathy: clinical evidence of a role of oxidative stress in taxane toxicity. Ann Oncol 20:736–740

    PubMed  CAS  Google Scholar 

  46. Monk B, Kauderer J, Moxley K, Bonebrake AJ, Dewdney SB, Secord AA, Ueland FR, Johnston CM, Aghajanian C (2018) A phase II evaluation of elesclomol sodium and weekly paclitaxel in the treatment of recurrent or persistent platinum-resistant ovarian, fallopian tube or primary peritoneal cancer: an NRG oncology/gynecologic oncology group study. Gynecol Oncol 151:422–427

    PubMed  PubMed Central  CAS  Google Scholar 

  47. Mrakic-Sposta S, Vezzoli A, Maderna L et al (2018) R(+)-Thioctic acid effects on oxidative stress and peripheral neuropathy in type II diabetic patients: preliminary results by electron paramagnetic resonance and electroneurography. Oxid Med Cell Lengev 2018:1767265

    Google Scholar 

  48. Osio M, Muscia F, Zampini L et al (2006) Acetyl-L-carnitine in the treatment of painful antiretroviral toxic neuropathy in human immunodeficiency virus patients: an open label study. J Peripher Nerv Syst 11:72–76

    PubMed  CAS  Google Scholar 

  49. Ozuguz U, Oruc S, Ulu M et al (2016) Does vitamin D have any role in the improvement of diabetic peripheral neuropathy in type 1 diabetic patients? J Endocrine Invest 39:1411–1417

    CAS  Google Scholar 

  50. Rabing Christensen E, Stegger M, Jensen-Fangel S, Laursen AL, Ostergaard L (2004) Mitochondrial DNA levels in fat and blood cells from patients with lipodystrophy or peripheral neuropathy and the effect of 90 days of high-dose coenzyme Q treatment: a randomized, double-blind, placebo-controlled pilot study. Clin Infect Dis 39:1371–1379

    PubMed  Google Scholar 

  51. Rajanandh M, Kosey S, Prathiksha G (2014) Assessment of antioxidant supplementation on the neuropathic pain score and quality of life in diabetic neuropathy patients - a randomized controlled study. Pharmacol Rep 66:44–48

    PubMed  CAS  Google Scholar 

  52. Sayin R, Aslan M, Kucukoglu M et al (2014) Serum prolidase enzyme activity and oxidative stress levels in patients with diabetic neuropathy. Endocrine 47:146–151

    PubMed  CAS  Google Scholar 

  53. Sofic E, Rustembegovic A, Kroyer G et al (2002) Serum antioxidant capacity in neurological, psychiatric, renal diseases and cardiomyopathy. J Neural Transm (Vienna) 109:711–719

    CAS  Google Scholar 

  54. Solomon L (2011) Diabetes as a cause of clinically significant functional cobalamin deficiency. Diabetes Care 34:1077–1080

    PubMed  PubMed Central  CAS  Google Scholar 

  55. Solomon L (2016) Vitamin B12-responsive neuropathies: a case series. Nutr Neurosci 19:132–138

    Google Scholar 

  56. Strokov I, Manukhina E, Bakhtina L, Malyshev IY, Zoloev GK, Kazikhanova SI, Ametov AS (2000) The function of endogenous protective systems in patients with insulin-dependent diabetes mellitus and polyneuropathy: effect of antioxidant therapy. Bull Exp Biol Med 130:986–990

    PubMed  CAS  Google Scholar 

  57. Strokov I, Bursa T, Drepa O et al (2003) Predisposing genetic factors for diabetic polyneuropathy in patients with type 1 diabetes: a population-based case-control study. Acta Diabetol 40:S375–S379

    PubMed  CAS  Google Scholar 

  58. Strom A, Kaul K, Bruggermann J et al (2017) Lower serum extracellular superoxide dismutase levels are associated with polyneuropathy in recent-onset diabetes. Exp Mol Med 49:e394

    PubMed  PubMed Central  CAS  Google Scholar 

  59. Tahrani A, Ali A, Raymon N et al (2012) Obstructive sleep apnea and diabetic neuropathy: a novel association in patients with type 2 diabetes. Am J Respir Crit Care Med 186:434–441

    PubMed  PubMed Central  Google Scholar 

  60. Tang T, Prior S, Li K et al (2012) Association between the rs1050450 glutathione peroxidase-1 (C>T) gene variant and peripheral neuropathy in two independent samples of subjects with diabetes mellitus. Nutr Metab Cardiovasc Dis 22:417–425

    PubMed  CAS  Google Scholar 

  61. Tang H, Ho H, Chiu D et al (2017) Alterations of plasma concentrations of lipophilic antioxidants are associated with Guillain-Barre syndrome. Clin Chim Acta 470:75–80

    PubMed  CAS  Google Scholar 

  62. Tecilazich F, Dinh T, Lyons T et al (2013) Postexercice phosphocreatine recovery, an index of mitochondrial oxidative phosphorylation, is reduced in diabetic patients with lower extremity complications. J Vasc Surg 57:997–1005

    PubMed  PubMed Central  Google Scholar 

  63. Tsuzura S, Ikeda Y, Suehiro T et al (2004) Correlation of plasma oxidized low-density lipoprotein levels to vascular complications and human serum paraoxonase in patients with type 2 diabetes. Metabolism 53(53):297–302

    PubMed  CAS  Google Scholar 

  64. Turk H, Sevinc A, Camci C, Cigli A, Buyukberber S, Savli H, Bayraktar N (2002) Plasma lipid peroxidation products and antioxidant enzyme activities in patients with type 2 diabetes mellitus. Acta Diabetol 39:117–122

    PubMed  CAS  Google Scholar 

  65. Uzar E, Tamam Y, Evliyaoglu O et al (2012) Serum prolidase activity and oxidative status in patients with diabetic neuropathy. Neurol Sci 33:875–880

    PubMed  Google Scholar 

  66. Valensi P, Le Devehat C, Richard J et al (2005) A multicenter, double-blind, safety study of QR-333 for the treatment of symptomatic diabetic peripheral neuropathy. A preliminary report. J Diabetes Complicat 19:247–253

    PubMed  Google Scholar 

  67. Villegas-Rivera G, Roman-Pintos L, Cardona-Munoz E et al (2015) Effects of ezetimibe/simvastatin and rosuvastatin on oxidative stress in diabetic neuropathy: a randomized, double-blind, placebo-controlled clinical trial. Oxidative Med Cell Longev 2015:756294

    Google Scholar 

  68. Vincent A, Brownlee M, Russel J (2002) Oxidative stress and programmed cell death in diabetic neuropathy. Ann N Y Acad Sci 959:368–383

    PubMed  CAS  Google Scholar 

  69. Vural G, Gumusyayla S (2018) Monocyte-to-high density lipoprotein ratio is associated with a decreased compound muscle action potential amplitude in patients with diabetic axonal polyneuropathy. Medicine (Baltimore) 97:e12857

    Google Scholar 

  70. Willems D, Dorchy H, Dufrasne D (1998) Serum antioxidant status and oxidized LDL in well-controlled young type 1 diabetic patients with and without subclinical complications. Atherosclerosis 137:S61–S64

    PubMed  CAS  Google Scholar 

  71. Zejaczkowska MK-KR, Leppert W, Wrzosek A, Mika J, Wordliczek J (2019) Mechanisms of chemotherapy-induced peripheral neuropathy. Int J Mol Sci 20(6):1451

    Google Scholar 

  72. Ziberna L, Martelanc M, Franco M, Passamonti S (2016) Bilirubin is an endogenous antioxidant in human vascular endothelial cells. Sci Rep 6:29240

    PubMed  PubMed Central  CAS  Google Scholar 

  73. Ziegler D, Hanefeld M, Ruhnau K, Hasche H, Lobisch M, Schütte K, Kerum G, Malessa R (1999) Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a 7-month multicenter randomized controlled trial (ALADIN III study). ALADIN III study group. Alpha-lipoic acid in diabetic neuropathy. Diabetes Care 22:1296–1301

    PubMed  CAS  Google Scholar 

  74. Ziegler D, Sohr C, Nourooz-Zadeh J (2004) Oxidative stress and antioxidant defense in relation to the severity of diabetic polyneuropathy and cardiovascular autonomic neuropathy. Diabetes Care 27:2178–2183

    PubMed  CAS  Google Scholar 

  75. Ziegler D, Low P, Litchy W, Boulton AJ, Vinik AI, Freeman R, Samigullin R, Tritschler H, Munzel U, Maus J, Schütte K, Dyck PJ (2011) Efficacy and safety of antioxidant treatment with α-lipoic acid over 4 years in diabetic polyneuropathy: the NATHAN 1 trial. Diabetes Care 34:2054–2060

    PubMed  PubMed Central  CAS  Google Scholar 

  76. Ziegler D, Buchholz S, Sohr C et al (2015) Oxidative stress predicts progression of peripheral and cardiac autonomic nerve dysfunction over 6 years in diabetic patients. Acta Diabetol 52:65–72

    PubMed  CAS  Google Scholar 

  77. Zis P, Sarrigianis P, Rao D et al (2016) Chronic idiopathic axonal polyneuropathy: a systematic review. J Neurol 263:1903–1910

    PubMed  Google Scholar 

  78. Zis P, McHugh P, Manca M, Sarrigiannis PG, Rao DG, Hadjivassiliou M (2018) Increased oxidative stress as a risk factor in chronic idiopathic axonal polyneuropathy. J Mol Neurosci 66:547–551

    PubMed  PubMed Central  CAS  Google Scholar 

Download references

Funding

No funding was received for this work.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Panagiotis Zis.

Ethics declarations

Conflict of Interest

None of the authors has any conflict of interest to disclose.

Ethical Publication Statement

We confirm that we have read the journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. This is a systematic review of the current literature and, therefore, no human participants and/or animals were involved. Hence, there was no need to obtain any form of informed consent.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Mallet, ML., Hadjivassiliou, M., Sarrigiannis, P.G. et al. The Role of Oxidative Stress in Peripheral Neuropathy. J Mol Neurosci 70, 1009–1017 (2020). https://doi.org/10.1007/s12031-020-01495-x

Download citation

Keywords

  • Neuropathy
  • Polyneuropathy
  • Oxidative stress
  • Reactive oxugen species