The site of the Media Sphera Publishers contains materials intended solely for healthcare professionals.
By closing this message, you confirm that you are a certified medical professional or a student of a medical educational institution.

Login
EN
+7 (495) 482-4118
+7 (495) 482-4329
+8 800 250-18-12
  • (toll-free number for subscriptions)
    Mon-Fri from 10 a.m. to 6 p.m.

  • © 1998-2026
+7 (495) 482-43-29
EN
All journals
Journal
Year
Year
Search result: 0

Kuz'mina U.Sh.

Institut biohimii i genetiki Ufimskiĭ nauchnyĭ tsentr RAN, Ufa

Zainullina L.F.

Institute of Biochemistry and Genetics Ufa Federal Research Center, Russian Academy of Scienses, Ufa, Russia

Vakhitov V.A.

Institute of Biochemistry and Genetics Ufa Federal Research Center, Russian Academy of Scienses, Ufa, Russia

Bakhtiiarova K.Z.

Bashkirskiĭ gosudarstvennyĭ meditsinskiĭ universitet, Ufa

Vahitova Ju.V.

Institut biohimii i genetiki Ufimskiĭ nauchnyĭ tsentr RAN, Ufa

The role of glutamate in the pathogenesis of multiple sclerosis

Authors:

Kuz'mina U.Sh., Zainullina L.F., Vakhitov V.A., Bakhtiiarova K.Z., Vahitova Ju.V.

More about the authors

Journal: S.S. Korsakov Journal of Neurology and Psychiatry. 2019;119(8): 160‑167

DOI: 10.17116/jnevro2019119081160

Read: 3217 times

Download PDF (RU)
Contact the author
Table of contents

THE ROLE OF GLUTAMATE IN THE PATHOGENESIS OF MULTIPLE SCLEROSIS
THE ROLE OF GLUTAMATE IN THE PATHOGENESIS OF MULTIPLE SCLEROSIS

To cite this article:

Kuz'mina USh, Zainullina LF, Vakhitov VA, Bakhtiiarova KZ, Vahitova JuV. The role of glutamate in the pathogenesis of multiple sclerosis. S.S. Korsakov Journal of Neurology and Psychiatry. 2019;119(8):160‑167. (In Russ.)
https://doi.org/10.17116/jnevro2019119081160

Подписка 2026 Журнал неврологии и психиатрии им. С.С. Корсакова (S.S. Korsakov Journal of Neurology and Psychiatry)
МСФ на ЯМ
Использование инфографики авторами научных работ
Close metadata
Recommended articles:
A clinical case of X-linked adre­noleukodystrophy. S.S. Korsakov Journal of Neurology and Psychiatry. 2025;(4):102-107
Cognitive impairment in patients with multiple scle­rosis. S.S. Korsakov Journal of Neurology and Psychiatry. 2025;(4-2):67-73
Arti­ficial inte­lligence capa­bilities in multiple scle­rosis. S.S. Korsakov Journal of Neurology and Psychiatry. 2025;(5):14-21
Mole­cular mechanisms of acute disseminated ence­phalomyelitis. S.S. Korsakov Journal of Neurology and Psychiatry. 2025;(7-2):7-11
The role of mono­cytes in the immu­nopathogenesis of multiple scle­rosis. S.S. Korsakov Journal of Neurology and Psychiatry. 2025;(7-2):23-27
Resu­lts of a 5-year project for the early diagnosis of multiple scle­rosis in first-line blood rela­tives (RADIRS program). S.S. Korsakov Journal of Neurology and Psychiatry. 2025;(7-2):28-33
Current epidemiology of MS with onset in childhood and adolescence (pediatric multiple scle­rosis). S.S. Korsakov Journal of Neurology and Psychiatry. 2025;(7-2):34-38
Features of the clinical course of multiple scle­rosis as a factor in persistent disa­bility. S.S. Korsakov Journal of Neurology and Psychiatry. 2025;(7-2):39-44
Quantitative analysis of cere­brospinal fluid flow in multiple scle­rosis patients. S.S. Korsakov Journal of Neurology and Psychiatry. 2025;(7-2):45-50
Resu­lts of 4 years of therapy with divo­zilimab in patients with rela­psing multiple scle­rosis. S.S. Korsakov Journal of Neurology and Psychiatry. 2025;(7-2):51-59
Abstract:

The results of recent studies indicate that the hyperactivation of the glutamatergic system plays an important role in the pathophysiology of multiple sclerosis (MS). In addition to the well-known direct toxic effect of the excessive extracellular level of the glutamate neurotransmitter on neurons, additional mechanisms of glutamate-induced cell damage have been described in the literature, including effects on oligodendrocytes, astrocytes, endothelial cells and immune cells. The study of these toxic effects will reveal the possible link between various pathological hallmarks of MS, such as axonal damage, oligodendrocyte death, demyelination, neurodegeneration, autoimmune reactions and dysfunction of blood-brain barrier. Understanding the mechanisms underlying the glutamate toxicity will contribute to the development of new therapeutic approaches for the diagnosis and treatment of patients with MS. This review focuses on the mechanisms that lead to an increase in the concentration of neurotransmitter glutamate and excitotoxicity in the context of the pathogenesis of this disease. Also the authors present the data on existing and currently developed medicines and therapeutic approaches to regulate the activity of the glutamatergic system.

Keywords:

glutamate
glutamate receptors
excitotoxicity of glutamate
NMDA-receptors
T-cells
multiple sclerosis

Authors:

Kuz'mina U.Sh.

Institut biohimii i genetiki Ufimskiĭ nauchnyĭ tsentr RAN, Ufa

Zainullina L.F.

Institute of Biochemistry and Genetics Ufa Federal Research Center, Russian Academy of Scienses, Ufa, Russia

Vakhitov V.A.

Institute of Biochemistry and Genetics Ufa Federal Research Center, Russian Academy of Scienses, Ufa, Russia

Bakhtiiarova K.Z.

Bashkirskiĭ gosudarstvennyĭ meditsinskiĭ universitet, Ufa

Vahitova Ju.V.

Institut biohimii i genetiki Ufimskiĭ nauchnyĭ tsentr RAN, Ufa

Close metadata

References:

  1. Dantzer R. Neuroimmune Interactions: From the Brain to the Immune System and Vice Versa. Physiol Rev. 2018;98(1):477-504. https://doi.org/10.1152/physrev.00039.2016
  2. Levite M. Neurotransmitters activate T-cells and elicit crucial functions via neurotransmitter receptors. Curr Opin Pharmacol. 2008;8(4):460-471. https://doi.org/10.1016/j.coph.2008.05.001
  3. Talbot S, Foster SL, Woolf CJ. Neuroimmunity: Physiology and Pathology. Annu Rev Immunol. 2016;34:421-447. https://doi.org/10.1146/annurev-immunol-041015-055340
  4. Shmidt TE, Jahno NN. Multiple sclerosis. A guide for doctors. 5th edition. M.: MEDpress-inform; 2016. (In Russ.)
  5. Rajda C, Pukoli D, Bende Z, Majláth Z, Vécsei L. Excitotoxins, Mitochondrial and Redox Disturbances in Multiple Sclerosis. Int J Mol Sci. 2017;18(2):353. https://doi.org/10.3390/ijms18020353
  6. Prins M, Schul E, Geurts J, van der Valk P, Drukarch B, van Dam AM. Pathological differences between white and grey matter multiple sclerosis lesions. Ann NY Acad Sci. 2015;1351:99-113. https://doi.org/10.1111/nyas.12841
  7. Calabrese M, Magliozzi R, Ciccarelli O, Geurts JJ, Reynolds R, Martin R. Exploring the origins of grey matter damage in multiple sclerosis. Nat Rev Neurosci. 2015;16:147-158. https://doi.org/10.1038/nrn3900
  8. Frischer JM, Bramow S, Dal-Bianco A, Lucchinetti CF, Rauschka H, Schmidbauer M, Laursen H, Sorensen PS, Lassmann H. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain. 2009;132:1175-1189. https://doi.org/10.1093/brain/awp070
  9. Bojko AN, Petrov SV, Nesterova VA, Gusev EI. Mechanisms of development of neurodegenerative processes in multiple sclerosis: neuroprotective influence of beta-interferons today and neurotrophic factors — tomorrow. Zhurnal Nevrologii i Psikhiatrii im. S.S. Korsakova (Spec.). 2003;2:83-90. (In Russ.)
  10. Levite M. Glutamate, T cells and multiple sclerosis. J Neural Transm (Vienna). 2017;124(7):775-798. https://doi.org/10.1007/s00702-016-1661-z
  11. Stojanovic IR, Kostic M, Ljubisavljevic S. The role of glutamate and its receptors in multiple sclerosis. J Neural Transm. 2014;121:945-955. https://doi.org/10.1007/s00702-014-1188-0
  12. Macrez R, Stys PK, Vivien D, Lipton SA, Docagne F. Mechanisms of glutamate toxicity in multiple sclerosis: biomarker and therapeutic opportunities. Lancet Neurol. 2016;15(10):1089-1102. https://doi.org/10.1016/S1474-4422(16)30165-X
  13. Kostic M, Zivkovic N, Stojanovic I. Multiple sclerosis and glutamate excitotoxicity. Rev Neurosci. 2013;24(1):71-88. https://doi.org/10.1515/revneuro-2012-0062
  14. Stover JF, Pleines UE, Morganti-Kossmann MC, Kossmann T, Lowitzsch K, Kempski OS. Neurotransmitters in cerebrospinal fluid reflect pathological activity. Eur J Clin Invest. 1997;27:1038-1043.
  15. Srinivasan R, Sailasuta N, Hurd R, Nelson S, Pelletier D. Evidence of elevated glutamate in multiple sclerosis using magnetic resonance spectroscopy at 3 T. Brain. 2005;128:1016-1025. https://doi.org/10.1093/brain/awh467
  16. Pitt D, Werner P, Raine CS. Glutamate excitotoxicity in a model of multiple sclerosis. Nat Med. 2000;6:67-70. https://doi.org/10.1038/71555
  17. Zavalishin IA, Peresedova AV. Rasseyannyy skleroz: sovremennaya kontseptsiya patogeneza i patogeneticheskogo lecheniya. Annaly Klinicheskoy i Eksperimental’noy Nevrologii. 2007;1(1):32-40. (In Russ.)
  18. Werner P, Pitt D, Raine CS. Multiple sclerosis: altered glutamate homeostasis in lesions correlates with oligodendrocyte and axonal damage. Ann Neurol. 2001;50:169-180.
  19. Castegna A, Palmieri L, Spera I, Porcelli V, Palmieri F, Fabis-Pedrini MJ, Kean RB, Barkhouse DA, Curtis MT, Hooper DC. Oxidative stress and reduced glutamine synthetase activity in the absence of inflammation in the cortex of mice with experimental allergic encephalomyelitis. Neuroscience. 2011;185:97-105. https://doi.org/10.1016/j.neuroscience.2011.04.041
  20. Ohgoh M, Hanada T, Smith T, Hashimoto T, Ueno M, Yamanishi Y, Watanabe M, Nishizawa Y. Altered expression of glutamate transporters in experimental autoimmune encephalomyelitis. J Neuroimmunol. 2002;125:170-178.
  21. Mitosek-Szewczyk K, Sulkowski G, Stelmasiak Z, Struzyńska L. Expression of glutamate transporters GLT-1 and GLAST in different regions of rat brain during the course of experimental autoimmune encephalomyelitis. Neuroscience. 2008;155:45-52. https://doi.org/10.1016/j.neuroscience.2008.05.025
  22. Stadtman ER. Protein oxidation and aging. Science. 1992;257:1220-1224. https://doi.org/10.1080/10715760600918142
  23. Domercq M, Sanchez-Gomez MV, Sherwin C, Etxebarria E, Fern R, Matute C. System xc- and glutamate transporter inhibition mediates microglial toxicity to oligodendrocytes. J Immunol. 2007;178:6549-6556.
  24. Kornek B, Storch MK, Bauer J, Djamshidian A, Weissert R, Wallstroem E, Stefferl A, Zimprich F, Olsson T, Linington C, Schmidbauer M, Lassmann H. Distribution of a calcium channel subunit in dystrophic axons in multiple sclerosis and experimental autoimmune encephalomyelitis. Brain. 2001;124:1114-1124.
  25. Doyle S, Hansen DB, Vella J, Bond P, Harper G, Zammit C, Valentino M, Fern R. Vesicular glutamate release from central axons contributes to myelin damage. Nat Commun. 2018;9(1):1032. https://doi.org/10.1038/s41467-018-03427-1
  26. Craner MJ, Newcombe J, Black JA, Hartle C, Cuzner ML, Waxman SG. Molecular changes in neurons in multiple sclerosis: altered axonal expression of Nav1.2 and Nav1.6 sodium channels and Na+/Ca2+exchanger. Proc Natl Acad Sci USA. 2004;101:8168-8173. https://doi.org/10.1073/pnas.0402765101
  27. Yawata I, Takeuchi H, Doi Y, Liang J, Mizuno T, Suzumura A. Macrophage-induced neurotoxicity is mediated by glutamate and attenuated by glutaminase inhibitors and gap junction inhibitors. Life Sci. 2008;82:1111-1116. https://doi.org/10.1016/j.lfs.2008.03.010
  28. Pampliega O, Domercq M, Soria FN, Villoslada P, Rodríguez-Antigüedad A, Matute C. Increased expression of cystine/glutamate antiporter in multiple sclerosis. J Neuroinflammation. 2011;8:63. https://doi.org/10.1186/1742-2094-8-63
  29. Evonuk KS, Baker BJ, Doyle RE, Moseley CE, Sestero CM, Johnston BP, De Sarno P, Tang A, Gembitsky RI, Hewett SJ, Weaver CT, Raman C, De Silva TM. Inhibition of system Xc-transporter attenuates autoimmune inflammatory demyelination. J Immunol. 2015;195:450-463. https://doi.org/10.4049/jimmunol.1401108
  30. Szabó C, Ischiropoulos H, Radi R. Peroxynitrite: biochemistry, pathophysiology and development of therapeutics. Nat Rev Drug Discov. 2007;6:662-680. https://doi.org/10.1038/nrd2222
  31. Pais TF, Figueiredo C, Peixoto, Braz MH, Chatterjee S. Necrotic neurons enhance microglial neurotoxicity through induction of glutaminase by a MyD88-dependent pathway. J Neuroinflammation. 2008;5:43. https://doi.org/10.1186/1742-2094-5-43
  32. Siffrin V, Radbruch H, Glumm R, Niesner R, Paterka M, Herz J, Leuenberger T, Lehmann SM, Luenstedt S, Rinnenthal JL, Laube G, Luche H, Lehnardt S, Fehling HJ, Griesbeck O, Zipp F. In vivo imaging of partially reversible th17 cell-induced neuronal dysfunction in the course of encephalomyelitis. Immunity. 2010;33:424-436. https://doi.org/10.1016/j.immuni.2010.08.018
  33. Julio-Pieper M, Flor PJ, Dinan TG, Cryan JF. Exciting times beyond the brain: metabotropic glutamate receptors in peripheral and non-neural tissues. Pharmacol Rev. 2011;63(1):35-58. https://doi.org/10.1124/pr.110.004036
  34. Boldyrev AA, Bryushkova EA, Vladychenskaya EA. NMDA receptors in immune competent cells. Biochemistry (Moscow). 2012;77(2):128-134. (In Russ.)
  35. Geurts JJ, Wolswijk G, Bo L, Polman CH, Troost D, Aronica E. Altered expression patterns of group I and II metabotropic glutamate receptors in multiple sclerosis. Brain. 2003;126:1755-1766. https://doi.org/10.1093/brain/awg179
  36. Nanou E, Kyriakatos A, Kettunen P, El Manira A. Separate signalling mechanisms underlie mGluR1 modulation of leak channels and NMDA receptors in the network underlying locomotion. J Physiol. 2009;587:3001-3008. https://doi.org/10.1113/jphysiol.2009.172452
  37. Fazio F, Notartomaso S, Aronica E, Storto M, Battaglia G, Vieira E, Gatti S, Bruno V, Biagioni F, Gradini R, Nicoletti F, Di Marco R. Switch in the expression of mGlu1 and mGlu5 metabotropic glutamate receptors in the cerebellum of mice developing experimental autoimmune encephalomyelitis and in autoptic cerebellar samples from patients with multiple sclerosis. Neuropharmacology. 2008;55:491-499. https://doi.org/10.1016/j.neuropharm.2008.06.066
  38. Sulkowski G, Dabrowska-Bouta B, Kwiatkowska-Patzer B, Struzyńska L. Alterations in glutamate transport and group I metabotropic glutamate receptors in the rat brain during acute phase of experimental autoimmune encephalomyelitis. Folia Neuropathol. 2009;47:329-337.
  39. Taylor DL, Diemel LT, Cuzner ML, Pocock JM. Activation of group II metabotropic glutamate receptors underlies microglial reactivity and neurotoxicity following stimulation with chromogranin A, a peptide up-regulated in Alzheimer’s disease. J Neurochem. 2002;82:1179-1191.
  40. Pinteaux-Jones F, Sevastou IG, Fry VA, Heales S, Baker D, Pocock JM. Myelin-induced microglial neurotoxicity can be controlled by microglial metabotropic glutamate receptors. J Neurochem. 2008;106:442-454. https://doi.org/10.1111/j.1471-4159.2008.05426.x
  41. Fallarino F, Volpi C, Fazio F, Notartomaso S, Vacca C, Busceti C, Bicciato S, Battaglia G, Bruno V, Puccetti P, Fioretti MC, Nicoletti F, Grohmann U, Di Marco R. Metabotropic glutamate receptor-4 modulates adaptive immunity and restrains neuroinflammation. Nat Med. 2010;16:897-902. https://doi.org/10.1038/nm.2183
  42. Traynelis SF, Wollmuth LP, McBain CJ, Menniti FS, Vance KM, Ogden KK, Hansen KB, Yuan H, Myers SJ, Dingledine R. Glutamate receptor ion channels: structure, regulation, and function. Pharmacol Rev. 2010;62:405-496. https://doi.org/10.1124/pr.109.002451
  43. Newcombe J, Uddin A, Dove R, Patel B, Turski L, Nishizawa Y, Smith T. Glutamate receptor expression in multiple sclerosis lesions. Brain Pathol. 2008;18(1):52-61. https://doi.org/10.1111/j.1750-3639.2007.00101.x
  44. Alberdi E, Sanchez-Gomez MV, Marino A, Matute C. Ca2+ influx through AMPA or kainate receptors alone is sufficient to initiate excitotoxicity in cultured oligodendrocytes. Neurobiol Dis. 2002;9:234-243. https://doi.org/10.1006/nbdi.2001.0457
  45. Alberdi E, Sanchez-Gomez MV, Torre I, Domercq M, Perez-Samartin A, Perez-Cerda F, Matute C. Activation of kainate receptors sensitizes oligodendrocytes to complement attack. J Neurosci. 2006;26:3220-3228. https://doi.org/10.1523/JNEUROSCI.3780-05.2006
  46. Ouardouz M, Coderre E, Zamponi GW, Hameed S, Yin X, Trapp BD, Stys PK. Glutamate receptors on myelinated spinal cord axons: II. AMPA and GluR5 receptors. Ann Neurol. 2009;65(2):160-166. https://doi.org/10.1002/ana.21539
  47. Pachernegg S, Strutz-Seebohm N, Hollmann M. GluN3 subunit-containing NMDA receptors: not just one-trick ponies. Trends Neurosci. 2012;35:240-249. https://doi.org/10.1016/j.tins.2011.11.010
  48. Hardingham GE, Bading H. Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nature Rev Neurosci. 2010;11(10):682-696. https://doi.org/10.1038/nrn2911
  49. Bading H, Segal MM, Sucher NJ, Dudek H, Lipton SA, Greenberg ME. N-methyl-D-aspartate receptors are critical for mediating the effects of glutamate on intracellular calcium concentration and immediate early gene expression in cultured hippocampal neurons. Neuroscience. 1995;64(3):653-664.
  50. Wong R. NMDA receptors expressed in oligodendrocytes. Bioessays. 2006;28:460-464. https://doi.org/10.1002/bies.20402
  51. Karadottir R, Cavelier P, Bergersen LH, Attwell D. NMDA receptors are expressed in oligodendrocytes and activated in ischaemia. Nature. 2005;438:1162-1166. https://doi.org/10.1038/nature04302
  52. Reijerkerk A, Kooij G, Van Der Pol SMA, Leyen T, Lakeman K, Van Het Hof B, Vivien D, De Vries HE. The NR1 subunit of NMDA receptor regulates monocyte transmigration through the brain endothelial cell barrier. J Neurochemistry. 2010;113(2):447-453. https://doi.org/10.1111/j.1471-4159.2010.06598.x
  53. Zainullina LF, Yamidanov RS, Vakhitov VA, Vakhitova YV. NMDA receptors as a possible component of store-operated Ca² entry in human T-lymphocytes. Biochemistry (Moscow). 2011;76(11):1220-1226. (In Russ.) https://doi.org/10.1134/S0006297911110034
  54. Izquierdo JH, Bonilla-Abadía F, Cañas CA, Tobón GJ. Calcium, channels, intracellular signaling and autoimmunity. Reumatol Clin. 2014;10(1):43-47. https://doi.org/10.1016/j.reuma.2013.05.008
  55. Shafaroudi MM, Zarei H, Shafaroudi AM, Karimi N, Abedini M. The Relationship between Glutamate and Multiple Sclerosis. J Int Biol Biomed. 2018;4(1):1-13. Accessed June 25, 2018. http://ibbj.org/article-1-148-en.html
  56. Landi D, Vollaro S, Pellegrino G, Mulas D, Ghazaryan A, Falato E, Pasqualetti P, Rossini PM, Filippi MM. Oral fingolimod reduces glutamate-mediated intracortical excitability in relapsing-remitting multiple sclerosis. Clin Neurophysiol. 2015;126:165-169. https://doi.org/10.1016/j.clinph.2014.05.031
  57. Luchtman D, Gollan R, Ellwardt E, Birkenstock J, Robohm K, Siffrin V, Zipp F. In vivo and in vitro effects of multiple sclerosis immunomodulatory therapeutics on glutamatergic excitotoxicity. J Neurochem. 2016;136:971-980. https://doi.org/10.1111/jnc.13456
  58. Ganor Y, Levite M. The neurotransmitter glutamate and human T cells: glutamate receptors and glutamate-induced direct and potent effects on normal human T cells, cancerous human leukemia leukemia and lymphoma T cells, and autoimmune human T cells. J Neural Transm. 2014;121(8):983-1006. https://doi.org/10.1007/s00702-014-1167-5
  59. Vyshkina T, Kalman B. Autoantibodies and neurodegeneration in multiple sclerosis. Laboratory Investigation. 2008;88:796-807. https://doi.org/10.1038/labinvest.2008.53
  60. Macrez R, Ortega MC, Bardou I, Mehra A, Fournier A, Van der Pol SMA, Haelewyn B, Maubert E, Lesept F, Chevilley A, de Castro F, De Vries HE, Vivien D, Clemente D, Docagne F. Neuroendothelial NMDA receptors as therapeutic targets in experimental autoimmune encephalomyelitis. Brain. 2016;139:2406-2419. https://doi.org/10.1093/brain/aww172
  61. Leibowitz A, Boyko M, Shapira Y, Zlotnik A. Blood glutamate scavenging: insight into neuroprotection. Int J Mol Sci. 2012;13:10041-10066. https://doi.org/10.3390/ijms130810041
  62. Li Y, Hou X, Qi Q, Wang L, Luo L, Yang S, Zhang Y, Miao Z, Zhang Y, Wang F, Wang H, Huang W, Wang Z, Shen Y, Wang Y. Scavenging of blood glutamate for enhancing brain-to-blood glutamate efflux. Mol Med Rep. 2014;9:305-310. https://doi.org/10.3892/mmr.2013.1793
Contact the author
Email
Message
The publishing house "Media Sphere" does not provide treatment services, does not give recommendations on contacting medical institutions and specific specialists, on the prescription of medicines and dietary supplements.

Email Confirmation

An email was sent to test@gmail.com with a confirmation link. Follow the link from the letter to complete the registration on the site.

Email Confirmation

Submit Application

You can become an author of one of our magazines, send a request and we will consider it in during the day.

Name
Phone
E-mail
Message
Login
Registration
E-mail
Password
Forgot Password?

Log in to the site using your account in one of the services

Password recovery
E-mail
Login
Register

We use cооkies to improve the performance of the site. By staying on our site, you agree to the terms of use of cооkies. To view our Privacy and Cookie Policy, please. click here.