Hyperhomocysteinemia and endothelial dysfunction in multiple sclerosis

For a comprehensive study of such a socially significant disease as multiple sclerosis (MS), which occurs predominantly in people of working age and in which neuroinflammation and neurodegeneration go hand in hand, resulting in irreversible damage to the brain and spinal cord, the key point is to decipher the pathophysiological mechanisms of its development and progression. Despite the established relationship between hyperhomocysteinemia and secondary endothelial damage, data on the possible role of homocysteine (Hcy) in disease progression are quite contradictory.

Objective: to investigate the informative value of determining the content of markers of oxidative stress, mitochondrial and endothelial dysfunction in patients with MS.

Material and methods. The study included 63 patients with MS (40 women, 23 men) aged 35 [30; 43] years. The control group consisted of 43 healthy volunteers (22 men, 21 women) aged 37 [32; 44] years. Depending on the therapy received, patients were divided into two groups: those receiving first-line and second-line therapy; patients receiving natalizumab therapy were considered separately. A neurological examination of patients was performed with an assessment of disease severity using the EDSS scale, and the disease progression index was calculated. The following biomarkers were also determined in the blood of patients and volunteers using enzyme-linked immunosorbent assay: intercellular adhesion molecules (ICAM-1), S-adenosylmethionine, S-adenosylhomocysteine, cysteine, cysteinylglycine, glutathione, and Hcy.

Results. A statistically significant correlation was found between disease severity (EDSS disability level) and increased Hcy levels. A statistically significant increase in ICAM-1 levels was also found in patients during periods of disease activity (clinical exacerbation, activity according to MRI data), which allows this molecule to be considered as a biomarker of endothelial dysfunction and inflammation.

Conclusion. The results of the study indicate the need to continue studying the pathophysiological causes of the onset and progression of MS, further identifying new biomarkers for predicting the course of MS, and evaluating the effectiveness of drugs that alter the course of MS.

1. Jakimovski D, Bittner S, Zivadinov R, et al. Multiple sclerosis. Lancet. 2024 Jan 13;403(10422):183-202. doi: 10.1016/S0140-6736(23)01473-3. Epub 2023 Nov 7.

2. Clinical guidelines. Multiple sclerosis. Moscow; 2022 (In Russ.).

3. Aliyu M, Zohora FT, Ceylan A, et al. Immunopathogenesis of multiple sclerosis: molecular and cellular mechanisms and new immunotherapeutic approaches. Immunopharmacol Immunotoxicol. 2024 Jun;46(3):355-77. doi: 10.1080/08923973.2024.2330642. Epub 2024 Apr 18.

4. Amezcua L. Progressive Multiple Sclerosis. Continuum (Minneap Minn). 2022 Aug 1;28(4):1083-103. doi: 10.1212/CON.0000000000001157

5. Kavaliunas A, Danylaite Karrenbauer V, Hillert J. Socioeconomic consequences of multiple sclerosis – A systematic literature review. Acta Neurol Scand. 2021 Jun;143(6):587-601. doi: 10.1111/ane.13411. Epub 2021 Mar 22.

6. Kuhlmann T, Moccia M, Coetzee T, et al; International Advisory Committee on Clinical Trials in Multiple Sclerosis. Multiple sclerosis progression: time for a new mechanism-driven framework. Lancet Neurol. 2023 Jan;22(1):78-88. doi: 10.1016/S1474-4422(22)00289-7. Epub 2022 Nov 18.

7. Rida Zainab S, Zeb Khan J, Khalid Tipu M, et al. A review on multiple sclerosis: Unravelling the complexities of pathogenesis, progression, mechanisms and therapeutic innovations. Neuroscience. 2025 Feb 16;567:133-49. doi: 10.1016/j.neuroscience.2024.12.029. Epub 2024 Dec 19.

8. Milo R, Korczyn AD, Manouchehri N, Stüve O. The temporal and causal relationship between inflammation and neurodegeneration in multiple sclerosis. Mult Scler. 2020 Jul;26(8):876-86. doi: 10.1177/1352458519886943. Epub 2019 Nov 4.

9. Ramos-Gonzalez EJ, Bitzer-Quintero OK, Ortiz G, et al. Relationship between inflammation and oxidative stress and its effect on multiple sclerosis. Neurologia (Engl Ed). 2024 Apr;39(3):292-301. doi: 10.1016/j.nrleng.2021.10.010

10. Dubchenko E, Ivanov A, Spirina N, et al. Hyperhomocysteinemia and Endothelial Dysfunction in Multiple Sclerosis. Brain Sci. 2020 Sep 16;10(9):637. doi: 10.3390/brainsci10090637

11. Li X, Yuan J, Han J, Hu W. Serum levels of Homocysteine, Vitamin B12 and Folate in Patients with Multiple Sclerosis: an Updated Meta-Analysis. Int J Med Sci. 2020 Mar 5;17(6):751-61. doi: 10.7150/ijms.42058

12. Jamroz-Wisniewska A., Beltowski J., Wojcicka G., et al. Cladribine Treatment Improved Homocysteine Metabolism and Increased Total Serum Antioxidant Activity in Secondary Progressive Multiple Sclerosis Patients. Oxid Med Cell Longev. 2020;2020:1654754. doi: 10.1155/2020/1654754

13. Zhu X, Wei J, Li J, et al. The causal role of homocysteine in multiple diseases: a systematic review of Mendelian randomization studies. Nutr Metab (Lond). 2025 May 20;22(1):45. doi: 10.1186/s12986-025-00933-0

14. Mititelu RR, Albu CV, Bacanoiu MV, et al. Homocysteine as a Predictor Tool in Multiple Sclerosis. Discoveries (Craiova). 2021 Sep 28;9(3):e135. doi: 10.15190/d.2021.14

15. Jakubowski H, Witucki L. Homocysteine Metabolites, Endothelial Dysfunction, and Cardiovascular Disease. Int J Mol Sci. 2025 Jan 16;26(2):746. doi: 10.3390/ijms26020746

16. Smith AD, Refsum H. Homocysteine – from disease biomarker to disease prevention. J Intern Med. 2021 Oct;290(4):826-54. doi: 10.1111/joim.13279. Epub 2021 Apr 6.

17. McCaddon A, Miller JW. Homocysteine – a retrospective and prospective appraisal. Front Nutr. 2023 Jun 13;10:1179807. doi: 10.3389/fnut.2023.1179807

18. Cao X, Wang T, Mu G, et al. Dysregulated homocysteine metabolism and cardiovascular disease and clinical treatments. Mol Cell Biochem. 2025 May 10. doi: 10.1007/s11010025-05284-1. Epub ahead of print.

19. Li X, Zhou Z, Tao Y, et al. Linking homocysteine and ferroptosis in cardiovascular disease: insights and implications. Apoptosis. 2024 Dec;29(11-12):1944-58. doi: 10.1007/s10495024-01999-6. Epub 2024 Jul 23.

20. Cordaro M, Siracusa R, Fusco R, et al. Involvements of Hyperhomocysteinemia in Neurological Disorders. Metabolites. 2021 Jan 6;11(1):37. doi: 10.3390/metabo11010037

21. Ansari R, Mahta A, Mallack E, Luo JJ. Hyperhomocysteinemia and neurologic disorders: a review. J Clin Neurol. 2014 Oct;10(4):281-8. doi: 10.3988/jcn.2014.10.4.281. Epub 2014 Oct 6. Erratum in: J Clin Neurol. 2015 Jan;11(1):106. doi: 10.3988/jcn.2015.11.1.106

22. Dardiotis E, Arseniou S, Sokratous M, et al. Vitamin B12, folate, and homocysteine levels and multiple sclerosis: A meta-analysis. Mult Scler Relat Disord. 2017 Oct;17:190-7. doi: 10.1016/j.msard.2017.08.004. Epub 2017 Aug 16.

23. Kararizou E, Paraskevas G, Triantafyllou N, et al. Plasma homocysteine levels in patients with multiple sclerosis in the Greek population. J Chin Med Assoc. 2013;76:611-4. doi: 10.1016/j.jcma.2013.07.002

24. Fahmy EM, Elfayoumy NM, Abdelalim AM, et al. Relation of serum levels of homocysteine, vitamin B12 and folate to cognitive functions in multiple sclerosis patients. Int J Neurosci. 2018 Sep;128(9):835-41. doi: 10.1080/00207454.2018.1435538. Epub 2018 Feb 21.

25. Imeni Kashan A, Mirzaasgari Z, Nouri Shirazi S. Relationship between serum levels of folic acid and homocysteine with cognitive impairment in patients diagnosed with multiple sclerosis. Medicine (Baltimore). 2024 Jul 12;103(28):e38680. doi: 10.1097/MD.0000000000038680

26. Adamczyk-Sowa M, Sowa P, Adamczyk J, et al. Effect of melatonin supplementation on plasma lipid hydroperoxides, homocysteine concentration and chronic fatigue syndrome in multiple sclerosis patients treated with interferons-beta and mitoxantrone. J Physiol Pharmacol. 2016;67:235-42.

27. Ivanov AV, Popov MA, Aleksandrin VV, et al. Determination of glutathione in blood via capillary electrophoresis with pH-mediated stacking. Electrophoresis. 2022 Oct;43(1819):1859-70. doi: 10.1002/elps.202200119. Epub 2022 Jul 29. Erratum in: Electrophoresis. 2022 Dec;43(23-24):2466. doi: 10.1002/elps.202270142

28. Ivanov AV, Dubchenko EA, Kruglova MP, et al. Determination of S-adenosylmethionine and S-adenosylhomocysteine in blood plasma by UPLC with fluorescence detection. J Chromatogr B Analyt Technol Biomed Life Sci. 2019 Aug 15;1124:366-74. doi: 10.1016/j.jchromb.2019.06.032. Epub 2019 Jun 27.

29. Moghaddasi M, Mamarabadi M, Mohebi N, et al. Homocysteine, vitamin B12 and folate levels in Iranian patients with Multiple Sclerosis: a case control study. Clin Neurol Neurosurg. 2013 Sep;115(9):1802-5. doi: 10.1016/j.clineuro.2013.05.007. Epub 2013 Jun 10.

30. Teunissen CE, Killestein J, Kragt JJ, et al. Serum homocysteine levels in relation to clinical progression in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2008 Dec;79(12):1349-53. doi: 10.1136/jnnp.2008.151555. Epub 2008 Aug 1.

31. Guzel I, Mungan S, Oztekin ZN, Ak F. Is there an association between the Expanded Disability Status Scale and inflammatory markers in multiple sclerosis? J Chin Med Assoc. 2016 Feb;79(2):54-7. doi: 10.1016/j.jcma.2015.08.010. Epub 2015 Nov 14.

32. Jasiak-Zatonska M, Pietrzak A, Wyciszkiewicz A, et al. Different blood-brainbarrier disruption profiles in multiple sclerosis, neuromyelitis optica spectrum disorders, and neuropsychiatric systemic lupus erythematosus. Neurol Neurochir Pol. 2022;56(3):246-55. doi: 10.5603/PJNNS.a2022.0013. Epub 2022 Feb 4.

33. Hartung HP, Michels M, Reiners K, et al. Soluble ICAM-1 serum levels in multiple sclerosis and viral encephalitis. Neurology. 1993 Nov;43(11):2331-5. doi: 10.1212/wnl.43.11.2331

34. Sharief MK, Noori MA, Ciardi M, et al. Increased levels of circulating ICAM-1 in serum and cerebrospinal fluid of patients with active multiple sclerosis. Correlation with TNF-alpha and blood-brain barrier damage. J Neuroimmunol. 1993 Mar;43(1-2):15-21. doi: 10.1016/0165-5728(93)90070-f

35. Alexander JS, Chervenak R, Weinstock-Guttman B, et al. Blood circulating microparticle species in relapsing-remitting and secondary progressive multiple sclerosis. A casecontrol, cross sectional study with conventional MRI and advanced iron content imaging outcomes. J Neurol Sci. 2015 Aug 15;355(1-2):84-9. doi: 10.1016/j.jns.2015.05.027. Epub 2015 May 28.

36. Singhal NK, Li S, Arning E, et al. Changes in Methionine Metabolism and Histone H3 Trimethylation Are Linked to Mitochondrial Defects in Multiple Sclerosis. J Neurosci. 2015 Nov 11;35(45):15170-86. doi: 10.1523/JNEUROSCI.4349-14.2015

37. Spurgeon S, Yu M, Phillips JD, Epner EM. Cladribine: not just another purine analogue? Expert Opin Investig Drugs. 2009 Aug;18(8):1169-81. doi: 10.1517/13543780903071038

38. Li H, Lu H, Tang W, Zuo J. Targeting methionine cycle as a potential therapeutic strategy for immune disorders. Expert Opin Ther Targets. 2017 Aug 23:1-17. doi: 10.1080/14728222.2017.1370454. Epub ahead of print.

39. Bystricka Z, Laubertova L, Durfinova M, Paduchova Z. Methionine metabolism and multiple sclerosis. Biomarkers. 2017 Dec;22(8):747-54. doi: 10.1080/1354750X.2017.1334153. Epub 2017 Jun 6.