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Role of chondroitin sulfate in the regulation of neuroimmunoendocrine network interactions in patients with neurological symptoms in the post-covid period

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 The review discusses the prospects for the use of chondroitin sulfate and its derivatives for new indications in patients with and myalgic encephalomyelitis/chronic fatigue syndrome after SARS-CoV-2 infection. The epidemiology, clinical  manifestations, main mechanisms of the development of the dysregulation of neuroimmunoendocrine network interactions  in long-term COVID-19 are considered. Modern data on the relationship between mechanisms of neuroprotective effects of  chondroitin sulfate and its derivatives and their chemical  structure characteristics have been analyzed. The position is  argued according to which chondroitin sulfate and its  derivatives can become promising drugs in prevention of the  development of neuroimmunoendocrine network interactions  disorders in COVID-19. 

About the Authors

I. V. Sarvilina
Medical Centre «Novomeditsina»
Russian Federation

 74, Sotsialisticheskaya St., Rostov-on-Don 344002, Russia 

O. A. Gromova
Institute of pharmacoinformatics, Federal Research Center «Informatics and Management», Russian Academy of Sciences; Big Data Storage and Analysis Center, National Center for Digital Economy, M.V. Lomonosov Moscow State University
Russian Federation

 42, Vavilova St., Build. 2, Moscow 119333, Russia

27, Lomonosovsky Prosp., Build. 1, Moscow 119192, Russia 

M. Yu. Maksimova
Research Center of Neurology
Russian Federation

 80, Volokolamskoe Shosse, Moscow 125367, Russia 

M. N. Sharov
A.I. Evdokimov Moscow State University of Medicine and Dentistry, Ministry of Health of Russia; S.I. Spasokukotsky Moscow City Clinical Hospital, Moscow Healthcare Department
Russian Federation

20, Delegatskaya St., Build. 1, Moscow 127473, Russia

21, Vuchetich St., Moscow 127206, Russia 

Yu. S. Prokofyeva
A.I. Evdokimov Moscow State University of Medicine and Dentistry, Ministry of Health of Russia
Russian Federation

 20, Delegatskaya St., Build. 1, Moscow 127473, Russia 



2. Baral R, Ali O, Brett I, et al. COVID-19: a pan-organ pandemic. Oxf Med Case Rep. 2020 Dec 5;2020(12):omaa107. doi: 10.1093/omcr/omaa107. eCollection 2020 Dec.

3. COVID-19 Coronovirus Pandemic – Worldometer. Available from: (accessed 25.04.2021).

4. Townsend L, Dowds J, O'Brien K, et al. Persistent Poor Health Post-COVID-19 Is Not Associated with Respiratory Complications or Initial Disease Severity. Ann Am Thorac Soc. 2021 Jun;18(6):997-1003. doi: 10.1513/AnnalsATS.202009-1175OC

5. Townsend L, Dyer A, Jones K, et al. Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection. PLoS One. 2020 Nov 9;15(11):e0240784. doi: 10.1371/journal.pone.0240784. eCollection 2020.

6. Komaroff A, Lipkin W. Insights from myalgic encephalomyelitis/chronic fatigue syndrome may help unravel the pathogenesis of postacute COVID-19 syndrome. Trends Mol Med. 2021 Sep;27(9):895-906. doi: 10.1016/j.molmed.2021.06.002. Epub 2021 Jun 7.

7. Fraternale A, Paoletti M, Casabianca A, et al. GSH and analogs in antiviral therapy. Mol Aspects Med. Feb-Apr 2009;30(1-2):99-110. doi: 10.1016/j.mam.2008.09.001. Epub 2008 Sep 27.

8. Barinov AN, Moshkhoeva LS, Parkhomenko EV, et al. Clinical features, pathogenesis and treatment of long-haul COVID-19 impact on nervous system. Meditsinskiy alfavit = Medical alphabet. 2021;(3):14-22. doi: 10.33667/2078-5631-2021-3-14-22 (In Russ.).

9. Monfort J, Martel-Pelletier J, Pelletier J. Chondroitin sulphate for symptomatic osteoarthritis:critical appraisal of metaanalyses. Curr Med Res Opin. 2008 May;24(5):1303-8. doi: 10.1185/030079908x297231. Epub 2008 Apr 15.

10. Mao L, Jin H, Wang M, et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol. 2020 Jun 1;77(6):683-90. doi: 10.1001/jamaneurol.2020.1127

11. Liotta EM, Batra A, Clark JR, et al. Frequent neurologic manifestations and encephalopathy-associated morbidity in Covid-19 patients. Ann Clin Transl Neurol. 2020 Nov;7(11):2221-30. doi: 10.1002/acn3.51210. Epub 2020 Oct 5.

12. Romero-Sanchez CM, Diaz-Maroto I, Fernandez-Diaz E, et al. Neurologic manifestations in hospitalized patients with COVID-19: the ALBACOVID registry. Neurology. 2020 Aug 25;95(8):e1060-e1070. doi: 10.1212/WNL.0000000000009937. Epub 2020 Jun 1.

13. Nannoni S, de Groot R, Bell S, Markus HS. Stroke in COVID-19: a systematic review and meta-analysis. Int J Stroke. 2021 Feb;16(2):137-49. doi: 10.1177/1747493020972922. Epub 2020 Nov 11.

14. Uncini A, Vallat JM, Jacobs BC. GuillainBarre syndrome in SARS-CoV-2 infection: an instant systematic review of the first six months of pandemic. J Neurol Neurosurg Psychiatry. 2020 Oct;91(10):1105-10. doi: 10.1136/jnnp-2020-324491. Epub 2020 Aug 27.

15. Lopez-Leon S, Wegman-Ostrosky T, Perelman C, et al. More than 50 Long-term effects of COVID-19: a systematic review and meta-analysis. medRxiv preprint. doi: 10.1101/2021.01.27.21250617

16. Huang C, Huang L, Wang Y, et al. 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study. Lancet. 2021 Jan 16;397(10270):220-32. doi: 10.1016/S0140-6736(20)32656-8. Epub 2021 Jan 8.

17. World Health Organization. Manual of the International Statistical Classification of Diseases, Injuries, Causes of Death Based on the Recommendations of the Eighth Revision Conference (PDF). 2 (Eighth ed.). Geneva: WHO; 1969. 173 p. Available from: Epidemic_myalgic_encephalomyelitis (accessed 25.04.2021).

18. Davis H, Assaf G, McCorkell L, et al. Characterizing Long COVID in an international cohort: 7 months of symptoms and their impact. EClinicalMedicine. 2021 Aug;38:101019. doi: 10.1016/j.eclinm.2021.101019. Epub 2021 Jul 15.

19. Kedor C, Freitag H, Meyer-Arndt L, et al. Chronic COVID-19 Syndrome and Chronic Fatigue Syndrome (ME/CFS) following the first pandemic wave in Germany – a first analysis of a prospective observational study. medRxiv. 2021;02.06.21249256. doi: 10.1101/2021.02.06.21249256

20. Nath A. Neurologic complications of coronavirus infections. Neurology. 2020 May 12;94(19):809-10. doi: 10.1212/WNL.0000000000009455. Epub 2020 Mar 30.

21. Lersy F, Benotmane I, Helms J, et al. Cerebrospinal fluid features in COVID-19 patients with neurologic manifestations: correlation with brain MRI findings in 58 patients. J Infect Dis. 2021 Feb 24;223(4):600-9. doi: 10.1093/infdis/jiaa745

22. Baig A, Khaleeq A, Ali U, Syeda H. Evidence of the COVID-19 virus targeting the CNS: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms. ACS Chem Neurosci. 2020 Apr 1;11(7):995-8. doi: 10.1021/acschemneuro.0c00122. Epub 2020 Mar 13.

23. Turner A, Hiscox J, Hooper N. ACE2: from vasopeptidase to SARS virus receptor. Trends Pharmacol Sci. 2004 Jun;25(6):291-4. doi: 10.1016/

24. Lee M, Perl DP, Nair G, et al. Microvascular injury in the brains of patients with Covid-19. N Engl J Med. 2021 Feb 4;384(5):481-3. doi: 10.1056/NEJMc2033369. Epub 2020 Dec 30.

25. Kim Y, Nijst P, Kiefer K, Tang W. Endothelial Glycocalyx as Biomarker for Cardiovascular Diseases: Mechanistic and Clinical Implications. Curr Heart Fail Rep. 2017 Apr;14(2):117-26. doi: 10.1007/s11897-017-0320-5

26. Lopatko Fagerström I, Stahl A, Mossberg M, et al. Blockade of the kallikreinkinin system reduces endothelial complement activation in vascular inflammation. eBioMedicine. 2019 Sep;47:319-28. doi: 10.1016/j.ebiom.2019.08.020. Epub 2019 Aug 20.

27. Yamaoka-Tojo M. Endothelial glycocalyx damage as a systemic inflammatory microvascular endotheliopathy in COVID-19. Biomed J. 2020 Oct;43(5):399-413. doi: 10.1016/ Epub 2020 Aug 24.

28. Cecchini R, Cecchini A. SARS-CoV-2 infection pathogenesis is related to oxidative stress as a response to aggression. Med Hypotheses. 2020 Oct;143:110102. doi: 10.1016/j.mehy.2020.110102. Epub 2020 Jul 13.

29. Kabbani N, Olds J. Does COVID19 infect the brain? If so, smokers might be at a higher risk. Mol Pharmacol. 2020 May;97(5):351-3. doi: 10.1124/molpharm.120.000014. Epub 2020 Apr 1.

30. Lapina C, Peschanski D, Mesmoudi S. The potential genetic network of human brain SARS-CoV-2 infection. bioRxiv. 2020. doi: 10.1101/2020.04.06.027318

31. Li Y, Bai W, Hashikawa T. The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients. J Med Virol. 2020 Jun;92(6):552-5. doi: 10.1002/jmv.25728. Epub 2020 Mar 11.

32. Wong S, Lui R, Sung J. Covid-19 and the digestive system. J Gastroenterol Hepatol. 2020 May;35(5):744-8. doi: 10.1111/jgh.15047. Epub 2020 Apr 19.

33. Nagy-Szakal D, Williams BL, Mishra N, et al. Fecal metagenomic profiles in subgroups of patients with myalgic encephalomyelitis/chronic fatigue syndrome. Microbiome. 2017 Apr 26;5(1):44. doi: 10.1186/s40168-017-0261-y

34. Wan S, Yi Q, Fan S, et al. Characteristics of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized patients with 2019 novel coronavirus pneumonia (NCP). medRxiv. 2020. doi: 10.1101/2020.02.10.20021832

35. Chen C, Zhang X, Ju Z, He W. Advances in the research of cytokine storm mechanism induced by Corona Virus Disease 2019 and the corresponding immunotherapies. Zhonghua Shao Shang Za Zhi. 2020;36:E005. doi: 10.3760/cma.j.cn501120-20200224-00088

36. Felger J. Imaging the role of inflammation in mood and anxiety-related disorders. Curr Neuropharmacol. 2018;16(5):533-58. doi: 10.2174/1570159X15666171123201142

37. Mandarano AH, Maya J, Giloteaux L, et al. Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations. J Clin Invest. 2020 Mar 2;130(3):1491-505. doi: 10.1172/JCI132185

38. Ramos S, Brenu E, Broadley S, et al. Regulatory T, natural killer T and γδ T cells in multiple sclerosis and chronic fatigue syndrome/myalgic encephalomyelitis: a comparison. Asian Pac J Allergy Immunol. 2016 Dec;34(4):300-5. doi: 10.12932/AP0733

39. Milivojevic M, Che X, Bateman L, et al. Plasma proteomic profiling suggests an association between antigen driven clonal B cell expansion and ME/CFS. PLoS One. 2020 Jul 21;15(7):e0236148. doi: 10.1371/journal.pone.0236148. eCollection 2020.

40. Wang EY, Mao T, Klein J, et al. Diverse functional autoantibodies in patients with COVID-19. Nature. 2021 Jul;595(7866):283-8. doi: 10.1038/s41586-021-03631-y. Epub 2021 May 19.

41. Fujii H, Sato W, Kimura Y, et al. Altered structural brain networks related to adrenergic/muscarinic receptor autoantibodies in chronic fatigue syndrome. J Neuroimaging. 2020 Nov;30(6):822-7. doi: 10.1111/jon.12751. Epub 2020 Jul 1.

42. Shoenfeld Y, Ryabkova VA, Scheibenbogen C, et al. Complex syndromes of chronic pain, fatigue and cognitive impairment linked to autoimmune dysautonomia and small fiber neuropathy. Clin Immunol. 2020 May;214:108384. doi: 10.1016/j.clim.2020.108384. Epub 2020 Mar 17.

43. Costa-Mattioli M, Walter P. The integrated stress response: from mechanism to disease. Science. 2020 Apr 24;368(6489):eaat5314. doi: 10.1126/science.aat5314

44. Mackay A. A neuro-inflammatory model can explain the onset, symptoms and flare-ups of myalgic encephalomyelitis/chronic fatigue syndrome. J Prim Health Care. 2019;11:300-7. doi: 10.1071/HC190414

45. Olson K, Marc M, Grude L, et al. The hypothalamic pituitary-adrenal axis: the actions of the Central Nervous System and Potential Biomarkers. Antiaging Therapeut. 2012;13:91-100. doi: 10.3389/fneur.2021.701419

46. Ferguson A, Latchford K, Samson W. The paraventricular nucleus of the hypothalamus – a potential target for integrative treatment of autonomic dysfunction. Expert Opin Ther Targets. 2008 Jun;12(6):717-27. doi: 10.1517/14728222.12.6.717

47. Mueller C, Lin JC, Sheriff S, et al. Evidence of widespread metabolite abnormalities in myalgic encephalomyelitis/chronic fatigue syndrome: assessment with whole-brain magnetic resonance spectroscopy. Brain Imaging Behav. 2020 Apr;14(2):562-72. doi: 10.1007/s11682-018-0029-4

48. Baraniuk J, Shivapurkar N. Exercise-induced changes in cerebrospinal fluid miRNAs in Gulf War Illness, Chronic Fatigue Syndrome and sedentary control subjects. Sci Rep. 2017 Nov 10;7(1):15338. doi: 10.1038/s41598-017-15383-9

49. Rolls A, Cahalon L, Bakalash S, et al. A sulfated disaccharide derived from chondroitin sulfate proteoglycan protects against inflammation-associated neurodegeneration. FASEB J. 2006 Mar;20(3):547-9. doi: 10.1096/fj.05-4540fje. Epub 2006 Jan 5.

50. Canas N, Valero T, Villarroya M, et al. Chondroitin sulfate protects SH-SY5Y cells from oxidative stress by inducing hemeoxygenase-1via phosphatidylinositol 3-kinase/Akt. J Pharmacol Exp Ther. 2007 Dec;323(3):946-53. doi: 10.1124/jpet.107.123505. Epub 2007 Sep 20.

51. Sivasankaran R, Pei J, Wang K, et al. PKC mediates inhibitory effects of myelin and chondroitin sulfate proteoglycans on axonal regeneration. Nat Neurosci. 2004 Mar;7(3):261-8. doi: 10.1038/nn1193. Epub 2004 Feb 8.

52. Sato Y, Nakanishi K, Tokita Y, et al. A highly sulfated chondroitin sulfate preparation, CS-E, prevents excitatory aminoacid-induced neuronal cell death. J Neurochem. 2008 Mar;104(6):1565-76. doi: 10.1111/j.1471-4159.2007.05107.x. Epub 2007 Nov 7.

53. Torshin IYu, Lila AM, Naumov AV, et al. Meta-analysis of clinical trials of osteoarthritis treatment effectiveness with Chondroguard. FARMAKOEKONOMIKA. Sovremennaya farmakoekonomika i farmakoepidemiologiya. 2020; 13(4):18-29. (In Russ.).

54. Siebert J, Steencken A, Osterhout D. Chondroitin Sulfate Proteoglycans in the Nervous System: Inhibitors to Repair. BioMed Res Int. 2014;2014:845323. doi: 10.1155/2014/845323. Epub 2014 Sep 18.

For citation:

Sarvilina I.V., Gromova O.A., Maksimova M.Yu., Sharov M.N., Prokofyeva Yu.S. Role of chondroitin sulfate in the regulation of neuroimmunoendocrine network interactions in patients with neurological symptoms in the post-covid period. Neurology, Neuropsychiatry, Psychosomatics. 2021;13(6):105-110. (In Russ.)

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