Glutamate biomarkers in comprehensive diagnostics of acute and chronic brain ischemia

Cover Page


Cite item

Full Text

Abstract

The development and implementation of biomarkers of ischaemic brain damage at the pre-hospital and hospital stages, as well as during screening and regular medical examinations, are a priority in neurology. This review describes the role of NR2 peptide, a subunit of the NMDA ionotropic glutamate receptors, in the pathogenesis of cerebral ischemia. Experimental data are presented, showing that NR2 peptide expression increases in brain ischemia, its fragments passing through the blood-brain barrier and entering the bloodstream, thus stimulating the immune response and autoantibody production. Key studies are reviewed that have demonstrated the possibility of using glutamate receptors and their antibodies as potential biomarkers of acute and chronic cerebral ischemia. The sensitivity and specificity of NR2 peptide and NR2 antibodies in these studies averaged >90%. It has been shown that NR2A/B is the only marker with high negative and positive predictive value in people with suspected ischaemic stroke. Monitoring treatment effectiveness is another promising area of application for glutamate biomarkers.

Previous studies have shown that the NR2 peptide and its antibodies are potential biomarkers of cerebral infarction, transient ischaemic attack, and chronic cerebral ischemia and may become important components in a successful and comprehensive approach to treatment, screening, and monitoring of disease outcomes.

About the authors

Grigory V. Ponomarev

Pavlov First Saint Petersburg State Medical University

Author for correspondence.
Email: grigoryponomarev@yandex.ru
Russian Federation, St. Petersburg

Igor A. Vozniuk

Saint Petersburg I.I. Dzhanelidze Research Institute оf Emergency Medicine; Military Medical Academy named after S.M. Kirov

Email: grigoryponomarev@yandex.ru
Russian Federation, St. Petersburg

Marina A. Izumi

Pavlov First Saint Petersburg State Medical University

Email: grigoryponomarev@yandex.ru
Russian Federation, St. Petersburg

Alexander A. Skoromets

Pavlov First Saint Petersburg State Medical University

Email: grigoryponomarev@yandex.ru
Russian Federation, St. Petersburg

References

  1. Caprio F.Z., Sorond F.A. Cerebrovascular disease: primary and secondary stroke prevention. Med Clin North Am 2019; 103: 295–308. doi: 10.1016/j.mcna.2018.10.001. PMID: 30704682.
  2. Portegies M.L., Koudstaal P.J., Ikram M.A. Cerebrovascular disease. Handb Clin Neurol 2016; 138: 239–261. doi: 10.1016/B978-0-12-802973-2.00014-8. PMID: 27637962.
  3. Norrving B. Lacunar infarcts: no black holes in the brain are benign. Pract Neurol 2008; 8: 222–228. doi: 10.1136/jnnp.2008.153601. PMID: 18644908.
  4. Warlow C., Sudlow C., Dennis M. et al. Stroke. Lancet 2003;362:1211–1224. doi: 10.1016/s0140-6736(03)14544-8. PMID: 14568745.
  5. Fedin A.I. [Diagnosis and treatment of chronic cerebral ischemia]. Consilium Medicum 2016; 18(2): 8–12. doi: 10.26442/2075-1753_2016.2.8-12. (In Russ.)
  6. Levin O.S. [Distsirkulatorny encephalopathy: anachronism or clinical reality?] Sovremennaya terapiya v psikhiatrii i nevrologii 2012; (3): 40–46. (In Russ.)
  7. Glushakova O.Y., Glushakov A.V., Miller E.R. et al. Biomarkers for acute diagnosis and management of stroke in neurointensive care units. Brain Circ 2016; 2: 28–47. doi: 10.4103/2394-8108.178546. PMID: 30276272.
  8. Weissman J.D., Boiser J.C., Krebs C. et al. Imaging biomarkers: keys to decision-making in stroke. In: Peplow P., Martinez B., Dambinova S. (eds.) Stroke Biomarkers. Neuromethods N.Y., 2020: 259–296. doi: 10.1007/978-1-4939-9682-7_14.
  9. Castellanos M., Serena J. Applicability of biomarkers in ischemic stroke. Cerebrovasc Dis 2007; 24Suppl 1: 7–15. doi: 10.1159/000107374. PMID: 17971634.
  10. Stanca D.M., Mărginean I.C., Sorițău O., Mureşanu D.F. Plasmatic markers for early diagnostic and treatment decisions in ischemic stroke. J Med Life 2015; 8 Spec Issue: 21–25. PMID: 26366222.
  11. Ng G.J.L., Quek A.M.L., Cheung C. et al. Stroke biomarkers in clinical practice: a critical appraisal. NeurochemInt 2017; 107: 11–22. doi: 10.1016/j.neuint.2017.01.005. PMID: 28088349.
  12. Harpaz D., Eltzov E., Seet R.C.S. et al. Point-of-Care-Testing in acute stroke management: an unmet need ripe for technological harvest. Biosensors (Basel) 2017; 7: 30 doi: 10.3390/bios7030030. PMID: 28771209.
  13. Dambinova S.A., Skoromets A.A., Skoromets A.P. [Biomarkers of cerebral ischemia (development, research, and practical applications)]. Saint Petersburg, 2013. 336 p. (In Russ.)
  14. Skoromets A.A., Dambinova S.A., DyakonovМ.М. et al. [Biochemical markers in the diagnosis of cerebral ischemia]. Mezhdunarodnyy nevrologicheskiy zhurnal 2009; (5): 15–20. (In Russ.)
  15. González-García S., González-Quevedo A., Fernández-Concepción O. et al. Short-term prognostic value of serum neuron specific enolase and S100B in acute stroke patients. Clin Biochem 2012; 45: 1302–1307. doi: 10.1016/j.clinbiochem.2012.07.094. PMID: 22820433.
  16. Montaner J., Mendioroz M., Delgado P. et al. Differentiating ischemic from hemorrhagic stroke using plasma biomarkers: the S100B/RAGE pathway. J Proteomics 2012; 75: 4758–4765. doi: 10.1016/j.jprot.2012.01.033. PMID: 22343074.
  17. Purrucker J.C., Herrmann O., Lutsch J.K. et al. Serum protein S100 is a diagnostic biomarker for distinguishing posterior circulation stroke from vertigo of nonvascular causes. Eur Neurol 2014; 72: 278–284. doi: 10.1159/000363569. PMID: 25323105.
  18. Kumar H., Lakhotia M., Pahadiya H., Singh J. To study the correlation of serum S-100 protein level with the severity of stroke and its prognostic implication. J Neurosci Rural Pract 2015; 6: 326–330. doi: 10.4103/0976-3147.158751. PMID: 26167013.
  19. Schiff L., Hadker N., Weiser S., Rausch C. A literature review of the feasibility of glial fibrillary acidic protein as a biomarker for stroke and traumatic brain injury. Mol Diagn Ther 2012; 16: 79–92. doi: 10.2165/11631580-000000000-00000. PMID: 22497529.
  20. Foerch C., Pfeilschifter W., Zeiner P., Brunkhorst R. Glial fibrillary acidic protein in patients with symptoms of acute stroke: diagnostic marker of cerebral hemorrhage. Nervenarzt 2014; 85: 982–989. doi: 10.1007/s00115-014-4128-1. PMID: 25057113.
  21. Luger S., Witsch J., Dietz A. et al., BE FAST II and the IGNITE Study Groups. Glial fibrillary acidic protein serum levels distinguish between intracerebral hemorrhage and cerebral ischemia in the early phase of stroke. Clin Chem 2017; 63: 377–385. doi: 10.1373/clinchem.2016.263335. PMID: 27881450.
  22. Shibata D., Cain K., Tanzi P. et al. Myelin basic protein autoantibodies, white matter disease and stroke outcome. J Neuroimmunol 2012; 252: 106–112. doi: 10.1016/j.jneuroim.2012.08.006. PMID: 22939639.
  23. Zierath D., Kunze A., Fecteau L., Becker K. Promiscuity of autoimmune responses to MBP after stroke. J Neuroimmunol 2015; 285: 101–105. doi: 10.1016/j.jneuroim.2015.05.024. PMID: 26198925.
  24. Liu M.C., Akinyi L., Scharf D. et al. Ubiquitin C-terminal hydrolase-L1 as a biomarker for ischemic and traumatic brain injury in rats. Eur J Neurosci 2010; 31: 722–732. doi: 10.1111/j.1460-9568.2010.07097.x. PMID: 20384815.
  25. Ren C., Zoltewicz S., Guingab-Cagmat J. et al. Different expression of ubiquitin C-terminal hydrolase-L1 and II-spectrin in ischemic and hemorrhagic stroke: Potential biomarkers in diagnosis. Brain Res 2013; 1540: 84–91. doi: 10.1016/j.brainres.2013.09.051. PMID: 24140110.
  26. Wunderlich M.T., Lins H., Skalej M. et al. Neuron-specific enolase and tau protein as neurobiochemical markers of neuronal damage are related to early clinical course and long-term outcome in acute ischemic stroke. Clin Neurol Neurosurg 2006; 108: 558–563. doi: 10.1016/j.clineuro.2005.12.006. PMID: 16457947.
  27. Bharosay A., Bharosay V.V., Varma M. et al. Correlation of brain biomarker Neuron Specific Enolase (NSE) with degree of disability and neurological worsening in cerebrovascular stroke. Indian J Clin Biochem 2012; 27: 186–190. doi: 10.1007/s12291-011-0172-9. PMID: 23542317.
  28. Zaheer S., Beg M., Rizvi I. et al. Correlation between serum neuron specific enolase and functional neurological outcome in patients of acute ischemic stroke. Ann Indian Acad Neurol 2013; 16: 504–508. doi: 10.4103/0972-2327.120442. PMID: 24339568.
  29. Singh H.V., Pandey A., Shrivastava A.K. et al. Prognostic value of neuron specific enolase and IL-10 in ischemic stroke and its correlation with degree of neurological deficit. Clin Chim Acta 2013; 419: 136–138. doi: 10.1016/j.cca.2013.02.014. PMID: 23438682.
  30. Kim B.J., Kim Y.J., Ahn S.H. et al. The second elevation of neuron-specific enolase peak after ischemic stroke is associated with hemorrhagic transformation. J Stroke Cerebrovasc Dis 2014; 23: 2437–2443. doi: 10.1016/j.jstrokecerebrovasdis.2014.05.020. PMID: 25183561.
  31. Pandey A., Shrivastava A.K., Saxena K. Neuron specific enolase and c-reactive protein levels in stroke and its subtypes: correlation with degree of disability. Neurochem Res 2014; 39: 1426–1432. doi: 10.1007/s11064-014-1328-9. PMID: 24838548.
  32. Traenka C., Disanto G., Seiffge D.J. et al. Serum neurofilament light chain levels are associated with clinical characteristics and outcome in patients with cervical artery dissection. Cerebrovasc Dis 2015; 40: 222–227. doi: 10.1159/000440774. PMID: 26418549.
  33. Hesse C., Rosengren L., Vanmechelen E. et al. Cerebrospinal fluid markers for Alzheimer’s disease evaluated after acute ischemic stroke. J Alzheimers Dis 2000; 2: 199–206. doi: 10.3233/jad-2000-23-402. PMID: 12214084.
  34. Hesse C., Rosengren L., Andreasen N. et al. Transient increase in total tau but not phospho-tau in human cerebrospinal fluid after acute stroke. Neurosci Lett 2001; 297: 187–190. doi: 10.1016/s0304-3940(00)01697-9. PMID: 11137759.
  35. Allard L., Burkhard P.R., Lescuyer P. et al. PARK7 and nucleoside diphosphate kinase A as plasma markers for the early diagnosis of stroke. Clin Chem 2005; 51: 2043–2051. doi: 10.1373/clinchem.2005.053942. PMID: 16141287.
  36. Allard L., Turck N., Burkhard P.R. et al. Ubiquitin fusion degradation protein 1 as a blood marker for the early diagnosis of ischemic stroke. Biomark Insights 2007; 2: 155–164. PMID: 19662200.
  37. Park S.Y., Kim M.H., Kim O.J. et al. Plasma heart-type fatty acid binding protein level in acute ischemic stroke: comparative analysis with plasma S100B level for diagnosis of stroke and prediction of longterm clinical outcome. Clin Neurol Neurosurg 2013; 115: 405–410. doi: 10.1016/j.clineuro.2012.06.004. PMID: 22766253.
  38. Zimmermann-Ivol C.G., Burkhard P.R., Le Floch-Rohr J. et al. Fatty acid binding protein as a serum marker for the early diagnosis of stroke: a pilot study. Mol Cell Proteomics 2004; 3: 66–72. doi: 10.1074/mcp.M300066-MCP200. PMID: 14581522.
  39. Dolmans L.S., Rutten F.H., Koenen N.C.T. et al. Candidate biomarkers for the diagnosis of transient ischemic attack: a systematic review. Cerebrovasc Dis 2019; 47: 207–216. doi: 10.1159/000502449. PMID: 31473737.
  40. Dambinova S.A. [Glutamate Neuroreceptors]. Leningrad, 1989. (In Russ.)
  41. Dambinova S.A., Weissman J.D., Mullins J.D. Challenges in using biomarkers in central nervous system application. In: Peplow P.V., Dambinova S.A., Gennarelli T.A., Martinez B. (eds.) Acute brain impairment: scientific discoveries and translational research. London, 2018: 276–288. doi: 10.1039/9781788012539-00198.
  42. Bespalov A.Yu., Zvartau E.E. [Neuropsychopharmacology of NMDA receptor antagonists]. Saint Petersburg, 2000. (In Russ.)
  43. Solntseva E.I., Rogozin P.D., Skrebitsky V.G. [Group I metabotropic glutamate receptors (mGluR1/5) and neurodegenerative diseases]. Annals of clinical and experimental neurology 2019; 13(4): 54–64. doi: 10.25692/ACEN.2019.4.8. (In Russ.)
  44. Furukawa H., Singh S.K., Mancusso R., Gouaux E. Subunit arrangement and function in NMDA receptors. Nature 2005; 438: 185–192. doi: 10.1038/nature04089. PMID: 16281028.
  45. Sharp C.D., Fowler M., Jackson T.H.4th et al. Human neuroepithelial cells express NMDA receptors. BMC Neurosci 2003; 4: 28. doi: 10.1186/1471-2202-4-28. PMID: 14614784.
  46. Karadottir R., Cavelier P., Bergersen L.H., Attwell D. NMDA receptors are expressed in oligodendrocytes and activated in ischaemia. Nature 2005; 438: 1162–1166. doi: 10.1038/nature04302. PMID: 16372011.
  47. Del Valle-Pinero A.Y., Suckow S.K., Zhou Q. et al. Expression of the N-methyl-D-aspartate receptor NR1 splice variants and NR2 subunit subtypes in the rat colon. Neuroscience 2007; 147: 164–173. doi: 10.1016/j.neuroscience.2007.02.063. PMID: 17509768.
  48. Burns G.A., Stephens K.E., Benson J.A. Expression of mRNA for the N-methyl-D-aspartate (NMDAR1) receptor by the enteric neurons of the rat. Neurosci Lett 1994; 170: 87–90. doi: 10.1016/0304-3940(94)90245-3. PMID: 8041519.
  49. Gappoeva M.U., Izykenova G.A., Granstrem O.K., Dambinova S.A. Expression of NMDA neuroreceptors in experimental ischemia. Biochemistry (Mosc) 2003; 68: 696–702. doi: 10.1023/a:1024678112357. PMID: 12943515.
  50. Gascon S., Deogracias R., Sobrado M. et al. Transcription of the NR1 subunit of the N-methyl-D-aspartate receptor is down-regulated by excitotoxic stimulation and cerebral ischemia. J Biol Chem 2005; 280: 35018–35027. doi: 10.1074/jbc.M504108200. PMID: 16049015.
  51. Gascon S., Sobrado M., Roda J.M. et al. Excitotoxicity and focal cerebral ischemia induce truncation of the NR2A and NR2B subunits of the NMDA receptor and cleavage of the scaffolding protein PSD-95. Mol Psychiatry 2008; 13: 99–114. doi: 10.1038/sj.mp.4002017. PMID: 17486105.
  52. Dong Y.N., Waxman E.A., Lynch D.R. Interactions of postsynaptic density-95 and the NMDA receptor 2 subunit control calpainmediated cleavage of the NMDA receptor. J Neurosci 2004; 24: 11035–11045. doi: 10.1523/JNEUROSCI.3722-04.2004. PMID: 15590920.
  53. Dambinova S.A., Khounteev G.A., Skoromets A.A. Multiple panel of biomarkers for TIA/stroke evaluation. Stroke 2002; 33: 1181–1182. doi: 10.1161/01.str.0000014922.83673.86. PMID: 11988587.
  54. Dambinova S.A., Khounteev G.A., Izykenova G.A. et al. Blood test detecting autoantibodies to N-methyl-D-aspartate neuroreceptors for evaluation of patients with transient ischemic attack and stroke. Clin Chem 2003; 49: 1752–1762. doi: 10.1373/49.10.1752. PMID: 14500616.
  55. Weissman J.D., Khunteev G.A., Dambinova S.A. Biomarkers in acute stroke. J Med Assoc Ga 2012; 101: 20–22. PMID: 22792678.
  56. Guttmann R.P., Sokol S., Baker D.L. et al. Proteolysis of the N-methyl-d-aspartate receptor by calpainin situ. J Pharmacol Exp Ther 2002; 302: 1023–1030. doi: 10.1124/jpet.102.036962. PMID: 12183659.
  57. Dambinova S.A., Bettermann K., Glynn T. et al. Diagnostic potential of the NMDA receptor peptide assay for acute ischemic stroke. PloS One 2012; 7: e42362. doi: 10.1371/journal.pone.0042362. PMID: 22848761.
  58. Weissman J.D., Khunteev G.A., Heath R., Dambinova S.A. NR2 antibodies: Risk assessment of transient ischemic attack (TIA)/stroke in patients with history of isolated and multiple cerebrovascular events. J Neurol Sci 2011; 300: 97–102. doi: 10.1016/j.jns.2010.09.023. PMID: 20934192.
  59. Stanca D.M., Mărginean I.C., Sorițău O. et al. GFAP and antibodies against NMDA receptor subunit NR2 as biomarkers for acute cerebrovascular diseases. J Cell Mol Med 2015; 19: 2253–2261. doi: 10.1111/jcmm.12614. PMID: 26081945.
  60. Bokesch P.M., Izykenova G.A., Justice J.B. et al. NMDA receptor antibodies predict adverse neurological outcome after cardiac surgery in high-risk patients. Stroke 2006; 37: 1432–1436. doi: 10.1161/01.STR.0000221295.14547.c8. PMID: 16627793.
  61. Kidher E., Patel V.M., Nihoyannopoulos P. et al. Aortic stiffness is related to the ischemic brain injury biomarker N-methyl-D-aspartate receptor antibody levels in aortic valve replacement. Neurol Res Int 2014; 2014: 970793. doi: 10.1155/2014/970793. PMID: 25054065.
  62. Bidari A., Vaziri S., Moazen Zadeh E., Talachian E. The value of serum NR2 antibody in prediction of post-cardiopulmonary resuscitation survival. Emerg (Tehran) 2015; 3: 89–94 PMID: 26495391.
  63. Ochkolyas V.N., Sokurenko G.Y. [The evaluation of expression of cerebral ischemia after surgical treatment of the internal carotid artery pathology by determining the autoantibody level to NR2A subunit of NMDA glutamate receptors]. Novosti khirurgii 2014; 22(2): 171–178. doi: 10.18484/2305-0047.2014.2.171. (In Russ.)
  64. Ponomarev G.V., Lalayan T.V., Dambinova S.A. et al. [The neurotoxicity biomarkers as potential indicators of the spinal cord ischemia]. Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova 2018; 118(2): 52–57. doi: 10.17116/jnevro20181182152-57. (In Russ.)
  65. Skitek M., JerinA. N-methyl-D-aspartate-receptor antibodies, S100 protein, and neuro-specific enolase before and after cardiac surgery: association with ischemic brain injury and epythropoetin prophylaxis. Lab Medicine 2013; 44(1):56–62. doi: 10.1309/LMZI8CEAATHRXR74.
  66. Gusev E.I., Skvortsova V.I., Dambinova S.A. et al. Neuroprotective effects of glycine for therapy of acute ischaemic stroke. Cerebrovasc Dis 2000; 10: 49–60. doi: 10.1159/000016025. PMID: 10629347.
  67. Dambinova S.A., Aliev K.T., Bondarenko E.V. et al. [The biomarkers of cerebral ischemia as a new method for the validation of the efficacy of cytoprotectivetherapy]. Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova 2017; 117(5): 62–67. doi: 10.17116/jnevro20171175162-67. (In Russ.)
  68. Khunteev G.A., Zavolokov I.G., CherkasIu.V., Dambinova S.A. [Significance of the level of auto-antibodies for the NMDA type glutamate receptors in diagnosis of chronic cerebral circulation disorders]. Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova 2001; 101(11): 44–47. (In Russ.)
  69. Granstrem O.K., Dambinova S.A., Dyakonov M.M. et al. [The dynamics of biomarkers of cerebral ischemia in discirculatory encephalopathy during treatment with cortexin]. Medlayn-Ekspress 2009; 4–5(203): 29–33. (In Russ.)
  70. Smolko D.H. [The level of NMDA-receptor antibodies in patients with chronic cerebrovascular insufficiency]. Mezhdunarodnyy nevrologicheskiy zhurnal 2016; 3(81): 66–68. (In Russ.)
  71. Skoromets А.А., Dambinova S.А., Dyakonov М.М. et al. [New biomarkers of brain damages]. Neyroimmunologiya 2009; VII(2): 18–23.
  72. González-García S., González-Quevedo A., Hernandez-Diaz Z. et al. Circulating autoantibodies against the NR2 peptide of the NMDA receptor are associated with subclinical brain damage in hypertensive patients with other pre-existing conditions for vascular risk. J Neurol Sci 2017; 375: 324–330. doi: 10.1016/j.jns.2017.02.028. PMID: 28320161.

Supplementary files

Supplementary Files
Action
1. JATS XML

Copyright (c) 2020 Ponomarev G.V., Vozniuk I.A., Izumi M.A., Skoromets A.A.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС 77-83204 от 12.05.2022.


This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies