Abstract
Objectives
Restless legs syndrome (RLS) is a common neurological condition. Oxidative stress plays an important role in its pathogenesis. Thiol-disulphide homeostasis (TDH) is a new biomarker of oxidative stress. We studied plasma TDH to determine whether TDH could be used as a new biomarker for RLS and evaluated correlations between TDH and various disease severity rating scales.
Methods
A total of 25 RLS patients and 25 healthy controls were included into the study. TDH status was determined using an automated spectrophotometric analysis method and correlations were analyzed between the TDH status and various disease rating scales in the RLS patients.
Results
Plasma total (401±27 μmol/L) and native thiol (354±30 μmol/L) levels were significantly lower, but disulphide level (24±6 μmol/L) was significantly (<0.0001) higher in the RLS patients compared to the controls (455±36, 424±37, 15±5 μmol/L, respectively). The disulphide/native thiol and disulphide/total thiol ratios increased, in contrast, native thiol/total thiol ratio decreased significantly in the RLS patients compared to the healthy controls (<0.0001). The disulphide levels correlated positively with age and various rating scores of the RLS patients. International Restless Legs Syndrome Study Group (IRLSSG) rating score and age correlated negatively with the total and native thiol levels.
Conclusions
Our findings indicate increased oxidative stress in the RLS patients reflected by decreased native and total thiol, and increased disulphide levels and positive correlations between the disulphide levels and various rating scores. We suggest dynamic TDH status to be used as a novel biomarker for the diagnosis and follow-up of the RLS patients.
Research funding: None declared.
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Competing interests: Authors state no conflict of interest.
Informed consent: Informed consent was obtained from all individuals included in this study.
Ethical approval: The local Institutional Review Board deemed the study exempt from review.
References
1. Venkateshiah, SB, Ioachimescu, OC. Restless legs syndrome. Crit Care Clin 2015;31:459–72. https://doi.org/10.1016/j.ccc.2015.03.003.Search in Google Scholar
2. Trenkwalder, C, Allen, R, Hogl, B, Clemens, S, Patton, S, Schormair, B, et al.. Comorbidities, treatment, and pathophysiology in restless legs syndrome. Lancet Neurol 2018;17:994–1005. https://doi.org/10.1016/s1474-4422(18)30311-9.Search in Google Scholar
3. Muth, CC. Restless legs syndrome. J Am Med Assoc 2017;317:780. https://doi.org/10.1001/jama.2016.21375.Search in Google Scholar PubMed
4. Gottlieb, DJ, Somers, VK, Punjabi, NM, Winkelman, JW. Restless legs syndrome and cardiovascular disease: a research roadmap. Sleep Med 2017;31:10–17. https://doi.org/10.1016/j.sleep.2016.08.008.Search in Google Scholar PubMed PubMed Central
5. Hanikoglu, A, Kucuksayan, E, Akduman, RC, Ozben, T. A review on melatonin’s effects in cancer: potential mechanisms. Anti Canc Agents Med Chem 2018;18:985–92. https://doi.org/10.2174/1871520617666171121120223.Search in Google Scholar PubMed
6. Aslan, M, Ozcan, F, Kucuksayan, E. Increased small dense LDL and decreased paraoxonase enzyme activity reveals formation of an atherogenic risk in streptozotocin-induced diabetic guinea pigs. J Diabetes Res 2013;2013:860190. https://doi.org/10.1155/2013/860190.Search in Google Scholar PubMed PubMed Central
7. Kucuksayan, E, Cort, A, Timur, M, Ozdemir, E, Yucel, SG, Ozben, T. N-acetyl-L-cysteine inhibits bleomycin induced apoptosis in malignant testicular germ cell tumors. J Cell Biochem 2013;114:1685–94. https://doi.org/10.1002/jcb.24510.Search in Google Scholar PubMed
8. Kucuksayan, E, Konuk, EK, Demir, N, Mutus, B, Aslan, M. Neutral sphingomyelinase inhibition decreases ER stress-mediated apoptosis and inducible nitric oxide synthase in retinal pigment epithelial cells. Free Radic Biol Med 2014;72:113–23. https://doi.org/10.1016/j.freeradbiomed.2014.04.013.Search in Google Scholar PubMed
9. Ozekinci, M, Kucuksayan, E, Erdogan, G, Aslan, M, Pestereli, E, Canpolat, M, et al.. Histopathological and biochemical assessment of a novel diagnostic method for ovarian torsion. Biotech Histochem 2020;95:203–9. https://doi.org/10.1080/10520295.2019.1663558.Search in Google Scholar PubMed
10. Dursun, E, Timur, M, Dursun, B, Suleymanlar, G, Ozben, T. Protein oxidation in Type 2 diabetic patients on hemodialysis. J Diabet Complicat 2005;19:142–6. https://doi.org/10.1016/j.jdiacomp.2004.11.001.Search in Google Scholar PubMed
11. Aslan, M, Ozben, T. Reactive oxygen and nitrogen species in Alzheimer’s disease. Curr Alzheimer Res 2004;1:111–9. https://doi.org/10.2174/1567205043332162.Search in Google Scholar PubMed
12. Scoditti, E, Massaro, M, Garbarino, S, Toraldo, DM. Role of diet in chronic obstructive pulmonary disease prevention and treatment. Nutrients 2019;11. https://doi.org/10.3390/nu11061357.Search in Google Scholar PubMed PubMed Central
13. Lushchak, VI. Free radicals, reactive oxygen species, oxidative stress and its classification. Chem Biol Interact 2014;224:164–75. https://doi.org/10.1016/j.cbi.2014.10.016.Search in Google Scholar PubMed
14. Bresgen, N, Eckl, PM. Oxidative stress and the homeodynamics of iron metabolism. Biomolecules 2015;5:808–47. https://doi.org/10.3390/biom5020808.Search in Google Scholar PubMed PubMed Central
15. Wachnowsky, C, Fidai, I, Cowan, JA. Iron-sulfur cluster biosynthesis and trafficking – impact on human disease conditions. Metallomics 2018;10:9–29. https://doi.org/10.1039/c7mt00180k.Search in Google Scholar PubMed PubMed Central
16. Nagababu, E, Gulyani, S, Earley, CJ, Cutler, RG, Mattson, MP, Rifkind, JM. Iron-deficiency anaemia enhances red blood cell oxidative stress. Free Radic Res 2008;42:824–9. https://doi.org/10.1080/10715760802459879.Search in Google Scholar PubMed PubMed Central
17. Cikrikcioglu, MA, Hursitoglu, M, Erkal, H, Kinas, BE, Sztajzel, J, Cakirca, M, et al.. Oxidative stress and autonomic nervous system functions in restless legs syndrome. Eur J Clin Invest 2011;41:734–42. https://doi.org/10.1111/j.1365-2362.2010.02461.x.Search in Google Scholar PubMed
18. Beal, MF. Does impairment of energy metabolism result in excitotoxic neuronal death in neurodegenerative illnesses? Ann Neurol 1992;31:119–30. https://doi.org/10.1002/ana.410310202.Search in Google Scholar PubMed
19. Hsu, M, Srinivas, B, Kumar, J, Subramanian, R, Andersen, J. Glutathione depletion resulting in selective mitochondrial complex I inhibition in dopaminergic cells is via an NO-mediated pathway not involving peroxynitrite: implications for Parkinson’s disease. J Neurochem 2005;92:1091–103. https://doi.org/10.1111/j.1471-4159.2004.02929.x.Search in Google Scholar PubMed
20. Erel, O, Erdogan, S. Thiol disulfide homeostasis: an integrated approach with biochemical and clinical aspects. Turk J Med Sci 2020;50:1728–38. https://doi.org/10.3906/sag-2003-64.Search in Google Scholar PubMed PubMed Central
21. Frijhoff, J, Winyard, PG, Zarkovic, N, Davies, SS, Stocker, R, Cheng, D, et al.. Clinical relevance of biomarkers of oxidative stress. Antioxidants Redox Signal 2015;23:1144–70. https://doi.org/10.1089/ars.2015.6317.Search in Google Scholar PubMed PubMed Central
22. Erel, O, Neselioglu, S. A novel and automated assay for thiol/disulphide homeostasis. Clin Biochem 2014;47:326–32. https://doi.org/10.1016/j.clinbiochem.2014.09.026.Search in Google Scholar PubMed
23. Medicine AAoS. The international classification of sleep disorders, 3rd ed. Darien, IL, USA: American Academy of Sleep Medicine; 2014.Search in Google Scholar
24. Bilgilisoy Filiz, M, Çakır, T. Restless legs syndrome with current diagnostic criteria. Turk Osteoporoz Derg 2015;21:87–95. https://doi.org/10.4274/tod.71601.Search in Google Scholar
25. Ağargün, MYKH, Anlar, Ö. Pittsburgh Uyku Kalitesi İndeksi’nin geçerliği ve güvenirliği. Türk Psikiyatri Derg 1996;7:107–15.Search in Google Scholar
26. Izci, B, Ardic, S, Firat, H, Sahin, A, Altinors, M, Karacan, I. Reliability and validity studies of the Turkish version of the Epworth sleepiness scale. Sleep Breath 2008;12:161–8. https://doi.org/10.1007/s11325-007-0145-7.Search in Google Scholar PubMed
27. Beck, AT, Ward, CH, Mendelson, M, Mock, J, Erbaugh, J. An inventory for measuring depression. Arch Gen Psychiatr 1961;4:561–71. https://doi.org/10.1001/archpsyc.1961.01710120031004.Search in Google Scholar PubMed
28. Garcia-Martin, E, Jimenez-Jimenez, FJ, Alonso-Navarro, H, Martinez, C, Zurdo, M, Turpin-Fenoll, L, et al.. Heme oxygenase-1 and 2 common genetic variants and risk for restless legs syndrome. Medicine (Baltim) 2015;94:e1448. https://doi.org/10.1097/md.0000000000001448.Search in Google Scholar PubMed PubMed Central
29. Schipper, HM. Heme oxygenase-1: transducer of pathological brain iron sequestration under oxidative stress. Ann N Y Acad Sci 2004;1012:84–93. https://doi.org/10.1196/annals.1306.007.Search in Google Scholar PubMed
30. Nakamura, K, Wang, W, Kang, UJ. The role of glutathione in dopaminergic neuronal survival. J Neurochem 1997;69:1850–8. https://doi.org/10.1046/j.1471-4159.1997.69051850.x.Search in Google Scholar PubMed
31. Yazar, HO, Yazar, T, Yildirim, T, Keskek, A, Altunkaynak, Y. Assessment of serum uric acid levels in patients with restless legs syndrome. Acta Neurol Belg 2019;119:461–6. https://doi.org/10.1007/s13760-019-01177-5.Search in Google Scholar PubMed
32. Higuchi, T, Abe, M, Mizuno, M, Yamazaki, T, Suzuki, H, Moriuchi, M, et al.. Association of restless legs syndrome with oxidative stress and inflammation in patients undergoing hemodialysis. Sleep Med 2015;16:941–8. https://doi.org/10.1016/j.sleep.2015.03.025.Search in Google Scholar PubMed
33. Topaloglu Tuac, S, Ozben, S, Koseoglu Bitnel, M, Koksal, A, Kucuksayan, E, Hanikoglu, A, et al.. Plasma copeptin levels in patients with restless legs syndrome. Acta Neurol Scand 2018;137:316–20. https://doi.org/10.1111/ane.12866.Search in Google Scholar PubMed
34. Sonmez, MG, Kozanhan, B, Deniz, CD, Iyisoy, MS, Kilinc, MT, Ecer, G, et al.. Dynamic thiol/disulfide homeostasis as a novel indicator of oxidative stress in patients with urolithiasis. Invest Clin Urol 2019;60:258–66. https://doi.org/10.4111/icu.2019.60.4.258.Search in Google Scholar PubMed PubMed Central
35. Gumusyayla, S, Vural, G, Bektas, H, Neselioglu, S, Deniz, O, Erel, O. A novel oxidative stress marker in migraine patients: dynamic thiol-disulphide homeostasis. Neurol Sci 2016;37:1311–7. https://doi.org/10.1007/s10072-016-2592-z.Search in Google Scholar PubMed
36. Gumusyayla, S, Vural, G, Bektas, H, Deniz, O, Neselioglu, S, Erel, O. A novel oxidative stress marker in patients with Alzheimer’s disease: dynamic thiol-disulphide homeostasis. Acta Neuropsychiatr 2016;28:315–20. https://doi.org/10.1017/neu.2016.13.Search in Google Scholar PubMed
37. Hanikoglu, F, Hanikoglu, A, Kucuksayan, E, Alisik, M, Gocener, AA, Erel, O, et al.. Dynamic thiol/disulphide homeostasis before and after radical prostatectomy in patients with prostate cancer. Free Radic Res 2016;50:S79–84. https://doi.org/10.1080/10715762.2016.1235787.Search in Google Scholar PubMed
38. Vural, G, Gumusyayla, S, Bektas, H, Deniz, O, Alisik, M, Erel, O. Impairment of dynamic thiol-disulphide homeostasis in patients with idiopathic Parkinson’s disease and its relationship with clinical stage of disease. Clin Neurol Neurosurg 2017;153:50–5. https://doi.org/10.1016/j.clineuro.2016.12.009.Search in Google Scholar PubMed
39. Incecik, F, Avcioglu, G, Erel, O, Neselioglu, S, Besen, S, Altunbasak, S. Dynamic thiol/disulphide homeostasis in children with neurofibromatosis type 1 and tuberous sclerosis. Acta Neurol Belg 2019;119:419–22. https://doi.org/10.1007/s13760-019-01100-y.Search in Google Scholar PubMed
40. Cansever, MS, Zubarioglu, T, Oruc, C, Kiykim, E, Gezdirici, A, Neselioglu, S, et al.. Oxidative stress among L-2-hydroxyglutaric aciduria disease patients: evaluation of dynamic thiol/disulfide homeostasis. Metab Brain Dis 2019;34:283–8. https://doi.org/10.1007/s11011-018-0354-8.Search in Google Scholar PubMed
41. Baskol, G, Korkmaz, S, Erdem, F, Caniklioglu, A, Kocyigit, M, Aksu, M. Assessment of nitric oxide, advanced oxidation protein products, malondialdehyde, and thiol levels in patients with restless legs syndrome. Sleep Med 2012;13:414–8. https://doi.org/10.1016/j.sleep.2011.11.012.Search in Google Scholar PubMed
© 2021 Walter de Gruyter GmbH, Berlin/Boston
