Skip to main content
SpringerLink
Log in

Superoxide dismutase (SOD), advanced oxidation protein products (AOPP), and disease-modifying treatment are related to better relapse recovery after corticosteroid treatment in multiple sclerosis

  • Original Article
  • Published:
Neurological Sciences Aims and scope Submit manuscript

Abstract

Objectives

The aim of our study was to analyze oxidative stress (OS) markers in multiple sclerosis (MS) patients during relapse and remission and to evaluate the effects of corticosteroid relapse treatment on oxidative status, and also to determine possible relationship between OS markers and relapse disability recovery after corticosteroid treatment.

Methods

Our study included 118 MS patients, (59 relapse/59 remission) 70 females and 48 males, mean age 40.2 ± 9.4 years, and 88 matched healthy controls. Undergoing disease-modifying therapy (DMT) was present in 30.5% of relapse and 88% of remission MS patients. We analyzed in plasma/serum the following: pro-oxidative–antioxidative balance (PAB), nitrates and nitrites (NO3 + NO2), malondialdehyde (MDA), advanced oxidation protein products (AOPP) superoxide dismutase (SOD), catalase (CAT), uric acid, bilirubin, albumin, and transferrin in all patients and additionally after corticosteroid relapse treatment. Neurological disability was measured using the Extended Disability Status Scale (EDSS).

Results

Better clinical recovery after relapse treatment was associated with increased baseline SOD, decreased AOPP, and ongoing DMT (all p < 0.05). There was no difference between OS markers in relapse and remission. MS patients had higher MDA, NO3 + NO2, PAB, SOD, CAT, lower AOPP, uric acid, albumin, bilirubin, and transferrin compared to controls (all p < 0.05). Corticosteroids caused significant decrease of all OS markers (all p < 0.05).

Conclusion

Increased baseline antioxidative activity of SOD and decreased baseline levels of pro-oxidant AOPP along with ongoing DMT were related to better clinical recovery after corticosteroid relapse treatment. Increase of pro-oxidants and antioxidant enzyme activity in relapse and remission confirms ongoing oxidative injury irrelevant of MS clinical presentation.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Data availability

All data generated or analyzed during this study are included in this published article (and its supplementary material). All additional data are available from the corresponding author.

References

  1. Filippi M, Bar-Or A, Piehl F, Preziosa P, Solari A, Vukusic S, Rocca MA (2018) Multiple sclerosis. Nat Rev Dis Primers 4(1):43

    Article  Google Scholar 

  2. Lublin FD, Reingold SC, Cohen JA, Cutter GR, Sørensen PS, Thompson AJ, Wolinsky JS, Balcer LJ et al (2014) Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology 83(3):278–286

    Article  Google Scholar 

  3. Comi G, Radaelli M (2015) Oral corticosteroids for multiple sclerosis relapse. Lancet. 386(9997):937–939

    Article  Google Scholar 

  4. Miller H, Newell D, Ridley A (1961) Multiple sclerosis: treatment of acute exacerbations with corticotrophin (ACTH). Lancet 2(7212):1120–1122

    Article  CAS  Google Scholar 

  5. Zivadinov R, Rudick RA, De Masi R, Nasuelli D, Ukmar M, Pozzi-Mucelli RS, Grop A, Cazzato G, Zorzon M (2001) Effects of IV methylprednisolone on brain atrophy in relapsing-remitting MS. Neurology 57(7):1239–1247

    Article  CAS  Google Scholar 

  6. Milligan NM, Newcombe R, Compston DA (1987) A double-blind controlled trial of high dose methylprednisolone in patients with multiple sclerosis: 1. Clinical effects. J Neurol Neurosurg Psychiatry 50(5):511–516

    Article  CAS  Google Scholar 

  7. Obradović D, Kataranovski M, Dincić E, Obradović S, Colić M (2012) Tumor necrosis factor-alfa and interleukin-4 in cerebrospinal fluid and plasma in different clinical forms of multiple sclerosis. Vojnosanit Pregl 69(2):151–156

    Article  Google Scholar 

  8. van Horssen J, Schreibelt G, Drexhage J, Hazes T, Dijkstra CD, van der Valk P, de Vries HE (2008) Severe oxidative damage in multiple sclerosis lesions coincides with enhanced antioxidant enzyme expression. Free Radic Biol Med 45(12):1729–1737

    Article  Google Scholar 

  9. Cobley JN, Fiorello ML, Bailey DM (2018) 13 reasons why the brain is susceptible to oxidative stress. Redox Biol 15:490–503

    Article  CAS  Google Scholar 

  10. Mezzaroba L, Simao ANC, Oliveira SR, Flauzino T, Alfieri DF, de Carvalho Jennings Pereira WL, Kallaur AR, Lozovoy MAB, Kaimen-Maciel DR, Maes M, Reiche EMV (2020) Antioxidant and anti-inflammatory diagnostic biomarkers in multiple sclerosis: a machine learning study. Mol Neurobiol 57(5):2167–2178

    Article  CAS  Google Scholar 

  11. Oliveira SR, Kallaur AP, Reiche EMV, Kaimen-Maciel DR, Panis C, Lozovoy MAB, Morimoto HK, Maes M, Dichi I, Simão ANC (2017) Albumin and protein oxidation are predictors that differentiate relapsing-remitting from progressive clinical forms of multiple sclerosis. Mol Neurobiol 54(4):2961–2968

    Article  CAS  Google Scholar 

  12. Jovicic A, Jovanovic M, Djordjevic D, Magdic B, Dincic E, Malicevic Z (1997) Oxidative and antioxidative activity in the patients with disseminated demyelination disease of the central nervous system. Vojnosanit Pregl 54(3):193–202

    CAS  PubMed  Google Scholar 

  13. Tavazzi B, Batocchi AP, Amorini AM, Nociti V, D'Urso S, Longo S, Gullotta S, Picardi M, Lazzarino G (2011) Serum metabolic profile in multiple sclerosis patients. Mult Scler Int 2011:167156. https://doi.org/10.1155/2011/167156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Amorini AM, Petzold A, Tavazzi B, Eikelenboom J, Keir G, Belli A, Giovannoni G, Di Pietro V, Polman C, D’Urso S, Vagnozzi R, Uitdehaag B, Lazzarino G (2009) Increase of uric acid and purine compounds in biological fluids of multiple sclerosis patients. Clin Biochem 42(10–11):1001–1006

    Article  CAS  Google Scholar 

  15. Toncev G, Milicic B, Toncev S, Samardzic G (2002) High-dose methylprednisolone therapy in multiple sclerosis increases serum uric acid levels. Clin Chem Lab Med 40(5):505–508

    Article  CAS  Google Scholar 

  16. Keles M, Taysi S, Aksoy H, Sen N, Polat F, Akcay F (2001) The effects of the corticosteroids on serum and cerebrospinal fluid nitric oxide levels in multiple sclerosis. Clin Chem Lab Med 39(9):827–829

    Article  CAS  Google Scholar 

  17. Mitosek-Szewczyk K, Gordon-Krajcer W, Walendzik P, Stelmasiak Z (2010) Free radical peroxidation products in cerebrospinal fluid and serum of patients with multiple sclerosis after glucocorticoid therapy. Folia Neuropathol 48(2):116–122

    CAS  PubMed  Google Scholar 

  18. Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, Fujihara K, Havrdova E, Hutchinson M, Kappos L, Lublin FD, Montalban X, O’Connor P, Sandberg-Wollheim M, Thompson AJ, Waubant E, Weinshenker B, Wolinsky JS (2011) Diagnostic criteria for multiple sclerosis: 2010 revisions to the “McDonald Criteria”. Ann Neurol 69(2):292–302

    Article  Google Scholar 

  19. Kurtzke JF (1983) Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurol 33(11):1444–1452

    Article  CAS  Google Scholar 

  20. Girotti MJ, Khan N, McLellan BA (1991) Early measurement of systemic lipid peroxidation products in the plasma of major blunt trauma patients. J Trauma 31(1):32–35

    Article  CAS  Google Scholar 

  21. Navarro-Gonzalez JA, Garcia-Benayas C, Arenas J (1998) Semiautomated measurement of nitrate in biological fluids. Clin Chem 44(3):679–681

    Article  Google Scholar 

  22. Alamdari DH, Paletas K, Pegiou T, Sarigianni M, Befani C, Koliakos G (2007) A novel assay for the evaluation of the prooxidant-antioxidant balance, before and after antioxidant vitamin administration in type II diabetes patients. Clin Biochem 40(3–4):248–254

    Article  CAS  Google Scholar 

  23. Witko-Sarsat V, Friedlander M, Capeillère-Blandin C, Nguyen-Khoa T, Nguyen AT, Zingraff J, Jungers P, Descamps-Latscha B (1996) Advanced oxidation protein products as a novel marker of oxidative stress in uremia. Kidney Int 49(5):1304–1313

    Article  CAS  Google Scholar 

  24. Sun M, Zigman S (1978) An improved spectrophotometric assay for superoxide dismutase based on epinephrine autoxidation. Anal Biochem 90(1):81–89

    Article  CAS  Google Scholar 

  25. Góth L (1991) A simple method for determination of serum catalase activity and revision of reference range. Clin Chim Acta 196(2–3):143–151

    Article  Google Scholar 

  26. Kantarci OH, Zeydan B, Atkinson EJ, Conway BL, Castrillo-Viguera C, Rodriguey M (2020) Relapse recovery: The forgotten variable in multiple sclerosis clinical trials. Neurol Neuroimmunol Neuroinflamm 7(2):1–9;e653. https://doi.org/10.1212/NXI.0000000000000653

    Article  Google Scholar 

  27. Lublin FD, Cutter G, Giovannoni G, Pace A, Campbell NR, Belachew S (2014) Natalizumab reduces relapse clinical severity and improves relapse recovery in MS. Mult Scler Relat Disord 3(6):705–711

    Article  Google Scholar 

  28. Scott TF, Kieseier BC, Newsome SD, Arnold DL, You X, Hung S, Sperling B (2016) Improvement in relapse recovery with peginterferon beta-1a in patients with multiple sclerosis. Mult Scler J Exp Transl Clin 2:1–8. https://doi.org/10.1177/2055217316676644

    Article  Google Scholar 

  29. Berridge MJ (2015) Vitamin D cell signaling in health and disease. Biochem Biophys Res Commun 460(1):53–71

    Article  CAS  Google Scholar 

  30. Robledinos-Antón N, Fernández-Ginés R, Manda G, Cuadrado A (2019) Activators and inhibitors of NRF2: a review of their potential for clinical development. Oxid Med Cell Longev. 10.1155/2019/9372182. eCollection 2019

  31. Siotto M, Filippi MM, Simonelli I, Landi D, Ghazaryan A, Vollaro S, Ventriglia M, Pasqualetti P, Rongioletti MCA, Squitti R, Vernieri F (2019) Oxidative stress related to Iron metabolism in relapsing remitting multiple sclerosis patients with low disability. Front Neurosci 13:86. https://doi.org/10.3389/fnins.2019.00086eCollection 2019

    Article  PubMed  PubMed Central  Google Scholar 

  32. Acar G, Idiman F, Idiman E, Kirkali G, Cakmakçi H, Ozakbaş S (2003) Nitric oxide as an activity marker in multiple sclerosis. J Neurol 250(5):588–592

    Article  CAS  Google Scholar 

  33. Nasser MA, Rabah AM, Rasher LA, Hassan A, Fouad AM (2020) Glutamate and nitric oxide as biomarkers for disease activity in patients with multiple sclerosis. Mult Scler Relat Disord 38:101873. https://doi.org/10.1016/j.msard.2019.101873

    Article  Google Scholar 

  34. Guerrero AL, Gutiérrez F, Iglesias F, Martín-Polo J, Merino S, Martín-Serradilla JI, Laherra’n SE, Tejero MA (2011) Serum uric acid levels in multiple sclerosis patients inversely correlate with disability. Neurol Sci 32(2):347–350

    Article  CAS  Google Scholar 

  35. Burt MG, Johannsson G, Umpleby AM, Chisholm DJ, Ho KK (2007) Impact of acute and chronic low-dose glucocorticoids on protein metabolism. J Clin Endocrinol Metab 92(10):3923–3929

    Article  CAS  Google Scholar 

  36. Oakley RH, Cidlowski JA (2011) Cellular processing of the glucocorticoid receptor gene and protein:new mechanisms for generating tissue-specific actions of glucocorticoids. J Biol Chem 286(5):3177–3184

    Article  CAS  Google Scholar 

  37. Song IH, Buttgereit F (2006) Non-genomic glucocorticoid effects to provide the basis for new drug developments. Mol Cell Endocrinol 246(1–2):142–146

    Article  CAS  Google Scholar 

  38. Kratschmar DV, Calabrese D, Walsh J, Lister A, Birk J, Appenzeller-Herzog C, Moulin P, Goldring CE, Odermatt A (2012) Suppression of the Nrf2-dependent antioxidant response by glucocorticoids and 11β-HSD1-mediated glucocorticoid activation in hepatic cells. PLoS One 7(5):e36774. https://doi.org/10.1371/journal.pone.0036774

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wang P, Xie K, Wang C, Bi J (2014) Oxidative stress induced by lipid peroxidation is related with inflammation of demyelination and neurodegeneration in multiple sclerosis. Eur Neurol 72(3–4):249–254

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Neurology Clinic, Military Medical Academy, Faculty of Medicine, University of Defense, Belgrade, Serbia

    Dragana Obradovic

  2. Institute of Medical Biochemistry, Military Medical Academy, Faculty of Medicine, University of Defense, Belgrade, Serbia

    Tamara Andjelic & Bratislav Dejanovic

  3. Institute for Medical Research, Military Medical Academy, Faculty of Medicine, University of Defense, Belgrade, Serbia

    Milica Ninkovic

  4. Institute of Medical Biochemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia

    Jelena Kotur-Stevuljevic

Authors
  1. Dragana Obradovic
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tamara Andjelic
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Milica Ninkovic
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bratislav Dejanovic
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jelena Kotur-Stevuljevic
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study concept and design. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Dragana Obradovic.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval

Approval was obtained from the Ethics Committee of Military Medical Academy. The procedures used in this study adhere to the tenets of the Declaration of Helsinki.

Consent to participate

Informed consent was obtained from all individual participants included in the study.

Consent for publication

Additional informed consent was obtained from all individual participants for whom identifying information is included in this article.

Code availability

Not applicable

Additional information

Publisher’s note

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

Supplementary information

ESM 1

(DOCX 12 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Obradovic, D., Andjelic, T., Ninkovic, M. et al. Superoxide dismutase (SOD), advanced oxidation protein products (AOPP), and disease-modifying treatment are related to better relapse recovery after corticosteroid treatment in multiple sclerosis. Neurol Sci 42, 3241–3247 (2021). https://doi.org/10.1007/s10072-020-04928-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10072-020-04928-y

Keywords

Search

Navigation