Glutamate Receptor Peptides as Potential Neurovascular Biomarkers of Acute Stroke

  • Svetlana A. Dambinova
  • J. D. Mullins
  • J. D. Weissman
  • A. A. Potapov
Part of the Neuromethods book series (NM, volume 147)


In this chapter different scenarios of biomarkers evaluating ischemic stroke caused by small vessel occlusions and leading to cerebral infarction are considered. Results of assays detecting glutamate receptor (GluR) peptides alone or combined into biomarkers panel to assess microvessel and small vessel strokes are explored in case report studies. A clinical protocol of neurovascular biomarkers implying GluR peptides is suggested for translational research assessing the severity of acute ischemic events based on structural location of cerebral infarction. It is proposed that the combination of clinical, biochemical, and radiological data might increase the diagnostic certainty of suspected acute ischemic stroke due to small occlusions in selected patients for timely and personalized therapy.

Key words

Neurovascular biomarkers Glutamate receptors Acute ischemic stroke Small vessel occlusion Cerebral infarction Lacunar stroke 


  1. 1.
    Spence JD (1999) New approaches to atherosclerosis based on endothelial function. In: Bogousslavsky J, Fisher M (eds) Cerebrovascular disease, 4th edn. Current Medicine Inc., Philadelphia, PA, pp 1–14Google Scholar
  2. 2.
    Roach ES, Bettermann K, Jose Biller J (2010) Toole’s cerebrovascular disorders, 6th edn. Cambridge University Press, Cambridge, p 422. Scholar
  3. 3.
    The personalized medicine report 2017: opportunity, challenges, and future. Accessed on 19 Sept 2019
  4. 4.
    Ng GJL, The Ei Z, Ng MY, Quek AML, Seet RCS (2018) Resolving difficult case scenarios by incorporating stroke biomarkers in clinical decision-making. In: Peplow PV, Dambinova SA, Gennarelli TA, Martinez B (eds) Acute brain impairment: scientific discoveries and translational research. Royal Society of Chemistry, London, pp 289–314. Scholar
  5. 5.
    Zhang JH, Badaut J, Tang J, Obenaus A, Hartman R, Pearce WJ (2012) The vascular neural network – a new paradigm in stroke pathophysiology. Nat Rev Neurol 8(12):711–716. Scholar
  6. 6.
    Barber PA (2013) Magnetic resonance imaging of ischemia viability thresholds and the neurovascular unit. Sensors (Basel) 13(6):6981–7003. Scholar
  7. 7.
    Terasaki Y, Liu Y, Hayakawa K, Pham LD, Lo EH, Ji X, Arai K (2014) Mechanisms of neurovascular dysfunction in acute ischemic brain. Curr Med Chem 21(18):2035–2042. PMID: 24372202CrossRefGoogle Scholar
  8. 8.
    Sommer CJ (2017) Ischemic stroke: experimental models and reality. Acta Neuropathol 133(2):245–261. Scholar
  9. 9.
    Katan M, Elkind MSV (2018) The potential role of blood biomarkers in patients with ischemic stroke: an expert opinion. Clin Transl Neurosci.
  10. 10.
    Iadecola C (2017) The neurovascular unit coming of age: a journey through neurovascular coupling in health and disease. Neuron 96(1):17–42. Scholar
  11. 11.
    Hayashi MK (2018) Structure-function relationship of transporters in the glutamate-glutamine cycle of the central nervous system. Int J Mol Sci 19(4):pii: E1177. Scholar
  12. 12.
    Dambinova SA (2012) Neurodegradomics: the source of biomarkers for mild traumatic brain injury. In: Dambinova SA, Hayes RL, Wang KKW (eds) Biomarkers for TBI. Royal Society of Chemistry, London, pp 66–86. Scholar
  13. 13.
    Sharp CD, Fowler M, Jackson TH 4th, Houghton J, Warren A, Nanda A, Chandler I, Cappell B, Long A, Minagar A, Alexander JS (2003) Human neuroepithelial cells express NMDA receptors. BMC Neurosci 4:28. PMID: 14614784CrossRefGoogle Scholar
  14. 14.
    Brand-Schieber E, Lowery SL, Werner P (2004) Select ionotropic glutamate AMPA/kainate receptors are expressed at the astrocyte-vessel interface. Brain Res 1007(1–2):178–182. PMID: 15064149CrossRefGoogle Scholar
  15. 15.
    Liu H, Leak RK, Hu X (2016) Neurotransmitter receptors on microglia. Stroke Vasc Neurol 1(2):52–58. Scholar
  16. 16.
    Sanz-Clemente A, Nicoll RA, Roche KW (2013) Diversity in NMDA receptor composition: many regulators, many consequences. Neuroscientist 19(1):62–75. Scholar
  17. 17.
    Christensen PC, Samadi-Bahrami Z, Pavlov V, Stys PK, Moore GRW (2016) Ionotropic glutamate receptor expression in human white matter. Neurosci Lett 630:1–8. Scholar
  18. 18.
    Jin XT, Smith Y (2011) Localization and functions of kainate receptors in the basal ganglia. Adv Exp Med Biol 717:27–37. Scholar
  19. 19.
    McConnell HL, Kersch CN, Woltjer RL, Neuwelt EA (2017) The translational significance of the neurovascular unit. J Biol Chem 292(3):762–770. Scholar
  20. 20.
    Dambinova SA, Khounteev GA, Skoromets AA (2002) Multiple panel of biomarkers for TIA/stroke evaluation. Stroke 33(5):1181–1182. PMID: 11988587CrossRefGoogle Scholar
  21. 21.
    Dambinova S, Bettermann K, Glynn T, Tews M, Olson D, Weissman JD, Sowell RL (2012) Diagnostic potential of the NMDA receptor peptide assay to distinguish acute ischemic stroke and stroke mimics. PLoS One 7:e42362. Scholar
  22. 22.
    Dambinova SA (2008) Biomarkers for transient ischemic attack (TIA) and ischemic stroke. Clin Lab Int 32(7):7–10. Scholar
  23. 23.
    Blanco PJ, Müller LO, Spence JD (2017) Blood pressure gradients in cerebral arteries: a clue to pathogenesis of cerebral small vessel disease. Stroke Vasc Neurol 2(3):108–117. Scholar
  24. 24.
    Yuan H, Hansen KB, Vance KM, Ogden KK, Traynelis SF (2009) Control of NMDA receptor function by the NR2 subunit amino-terminal domain. J Neurosci 29(39):12045–12058. Scholar
  25. 25.
    Möykkynen T, Coleman SK, Semenov A, Keinänen K (2014) The N-terminal domain modulates α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor desensitization. J Biol Chem 289(19):13197–13205. Scholar
  26. 26.
    Sheng N, Shi YS, Nicoll RA (2017) Amino-terminal domains of kainate receptors determine the differential dependence on Neto auxiliary subunits for trafficking. Proc Natl Acad Sci U S A 114(5):1159–1164. Scholar
  27. 27.
    Hansen KB, Ogden KK, Yuan H, Traynelis SF (2014) Distinct functional and pharmacological properties of triheteromeric GluN1/GluN2A/GluN2B NMDA receptors. Neuron 81(5):1084–1096. Scholar
  28. 28.
    Greger IH, Watson JF, Cull-Candy SG (2017) Structural and functional architecture of AMPA-type glutamate receptors and their auxiliary proteins. Neuron 94(4):713–730. Scholar
  29. 29.
    Fisher MT, Fisher JL (2014) Contributions of different kainate receptor subunits to the properties of recombinant homomeric and heteromeric receptors. Neuroscience 278:70–80. Scholar
  30. 30.
    Paramo T, Brown PMGE, Musgaard M, Bowie D, Biggin PC (2017) Functional validation of heteromeric kainate receptor models. Biophys J 113(10):2173–2177. Scholar
  31. 31.
    Yuan H, Vance KM, Junge CE, Geballe MT, Snyder JP, Hepler JR, Yepes M, Low CM, Traynelis SF (2009) The serine protease plasmin cleaves the amino-terminal domain of the NR2A subunit to relieve zinc inhibition of the N-methyl-D-aspartate receptors. J Biol Chem 284(19):12862–12873. Scholar
  32. 32.
    Gennarelli T, Dambinova SA, Weissman JD (2018) Advances in diagnostics and treatment of neurotoxicity after sport-related injuries. In: Peplow PV, Dambinova SA, Gennarelli TA, Martinez B (eds) Acute brain impairment: scientific discoveries and translational research. Royal Society of Chemistry, London, pp 141–161. Scholar
  33. 33.
    Dambinova SA, Khounteev GA, Izykenova GA, Zavolokov IG, Ilyukhina AY, Skoromets AA (2003) Blood test detecting autoantibodies to N-methyl-D-aspartate neuroreceptors for evaluation of patients with transient ischemic attack and stroke. Clin Chem 49(10):1752–1762. PMID: 14500616CrossRefGoogle Scholar
  34. 34.
    Ponomarev GV, Dambinova SA, Skoromets AA (2018) Neurotoxicity in spinal cord impairments. In: Peplow PV, Dambinova SA, Gennarelli TA, Martinez B (eds) Acute brain impairment: scientific discoveries and translational research. Royal Society of Chemistry, London, pp 198–213. Scholar
  35. 35.
    Sharp CD, Houghton J, Elrod JW, Warren A, Jackson TH 4th, Jawahar A, Nanda A, Minagar A, Alexander JS (2005) N-methyl-D-aspartate receptor activation in human cerebral endothelium promotes intracellular oxidant stress. Am J Physiol Heart Circ Physiol 288(4):H1893–H1899. Scholar
  36. 36.
    Abraham HM, Wolfson L, Moscufo N, Guttmann CR, Kaplan RF, White WB (2016) Cardiovascular risk factors and small vessel disease of the brain: blood pressure, white matter lesions, and functional decline in older persons. J Cereb Blood Flow Metab 36(1):132–142. Scholar
  37. 37.
    Bettermann K, Slocomb J, Shivkumar V, Quillen D, Gardner TW, Lott ME (2017) Impaired retinal vasoreactivity: an early marker of stroke risk in diabetes. J Neuroimaging 27(1):78–84. Scholar
  38. 38.
    Dambinova SA, Aliev KT, Bondarenko EV, Ponomarev GV, Skoromets AA, Skoromets AP, Skoromets TA, Smolko DG, Shumilina MV (2017) The biomarkers of cerebral ischemia as a new method for the validation of the efficacy of cytoprotective therapy. Zh Nevrol Psikhiatr Im S S Korsakova 117(5):62–67. Scholar
  39. 39.
    Brightwell RE (2007) Plasma biomarkers for the early diagnosis of stroke. 29th charing cross intern symposium, CX Innovations Showcase, LondonGoogle Scholar
  40. 40.
    Weissman JD, Ponomarev G, Heath R, Boiser J, Dambinova S (2018) Rapid point-of-care NR2 peptide test for acute stroke detection., Session P9, Abstract WP212, Jan 24Google Scholar
  41. 41.
    Hirai S, Hotta K, Kubo Y, Nishino A, Okabe S, Okamura Y, Okado H (2017) AMPA glutamate receptors are required for sensory-organ formation and morphogenesis in the basal chordate. Proc Natl Acad Sci U S A 114(15):3939–3944. Scholar
  42. 42.
    Beppu K, Kosai Y, Kido MA, Akimoto N, Mori Y, Kojima Y, Fujita K, Okuno Y, Yamakawa Y, Ifuku M, Shinagawa R, Nabekura J, Sprengel R, Noda M (2013) Expression, subunit composition, and function of AMPA-type glutamate receptors are changed in activated microglia; possible contribution of GluA2 (GluR-B)-deficiency under pathological conditions. Glia 61(6):881–891. Scholar
  43. 43.
    Torres-Platas SG, Comeau S, Rachalski A, Bo GD, Cruceanu C, Turecki G, Giros B, Mechawar N (2014) Morphometric characterization of microglial phenotypes in human cerebral cortex. J Neuroinflammation 11:12. Scholar
  44. 44.
    Li S, Stys PK (2000) Mechanisms of ionotropic glutamate receptor-mediated excitotoxicity in isolated spinal cord white matter. J Neurosci 20(3):1190–1198CrossRefGoogle Scholar
  45. 45.
    Dambinova SA, Gill S, St. Onge L, Sowell R (2012) Biomarkers for subtle brain dysfunction. In: Dambinova SA, Hayes RL, Wang KKW (eds) Biomarkers for TBI. Royal Society of Chemistry, London, pp 134–147. Scholar
  46. 46.
    Dambinova SA, Maroon JC, Sufrinko AM, Mullins JD, Alexandrova EV, Potapov AA (2016) Functional, structural, and neurotoxicity biomarkers in integrative assessment of concussions. Front Neurol 7:172. Scholar
  47. 47.
    Pires PW, Dams Ramos CM, Matin N, Dorrance AM (2013) The effects of hypertension on the cerebral circulation. Am J Physiol Heart Circ Physiol 304(12):H1598–H1614. Scholar
  48. 48.
    Hoiland RL, Bain AR, Rieger MG, Bailey DM, Ainslie PN (2016) Hypoxemia, oxygen content, and the regulation of cerebral blood flow. Am J Physiol Regul Integr Comp Physiol 310(5):R398–R413. Scholar
  49. 49.
    Zwank MD, Dummer BW, Danielson LT, Haake BC (2014) Lacunar stroke in a teenager after minor head trauma: case report and literature review. J Child Neurol 29(9):NP65–NP68. Scholar
  50. 50.
    Chalela JA, Kidwell CS, Nentwich LM et al (2007) Magnetic resonance imaging and computed tomography in the emergency assessment of patient’s with suspected acute stroke: a prospective comparison. Lancet 369:293–298. Scholar
  51. 51.
    van der Worp HB, van Gijn J (2007) Acute ischemic stroke. N Engl J Med 357:572–912. Scholar
  52. 52.
    Hand PJ, Kwan J, Lindley RI et al (2006) Distinguishing between stroke and mimic at the bedside: the brain attack study. Stroke 37:769–775. Scholar
  53. 53.
    Hand PJ, Wardlaw JM, Rowat AM, Haisma JA, Lindley RI, Dennis MS (2005) Magnetic resonance brain imaging in patients with acute stroke: feasibility and patient related difficulties. J Neurol Neurosurg Psychiatry 76(11):1525–1527. Scholar
  54. 54.
    von Kummer R, Dzialowski I (2007) MRI versus CT in acute stroke. Lancet 369(9570):1341–1342. Scholar
  55. 55.
    Kloppenborg RP, Nederkoorn PJ, Grool AM, De Cocker LJL, Mali WPTM, van der Graaf Y, Geerlings MI for the SMART Study Group (2017) Do lacunar infarcts have different etiologies? Risk factor profiles of lacunar infarcts in deep white matter and basal Ganglia: the second manifestations of arterial disease-magnetic resonance study. Cerebrovasc Dis 43:161–168. Scholar
  56. 56.
    Radu RA, Terecoasă EO, Băjenaru OA, Tiu C (2017) Etiologic classification of ischemic stroke: where do we stand? Clin Neurol Neurosurg 159:93–106. Scholar
  57. 57.
    Izykenova GA, Balswin R, Oldenburg SJ (2018) Development of novel test platforms for the assessment of brain injury. In: Peplow PV, Dambinova SA, Gennarelli TA, Martinez B (eds) Acute brain impairment: scientific discoveries and translational research. Royal Society of Chemistry, London, pp 315–326. Scholar
  58. 58.
    Hernandez-Diaz Z, Barroso-Garcia E, González-García S, González-Quevedo A, Reyes-Berazain A, Arteche-Prior M (2017) Confounding imaging findings in subacute-chronic cerebral infarction. Austin J Cerebrovasc Dis Stroke 4(3):1063–1068. ISSN:2381-9103Google Scholar
  59. 59.
    George MG, Tong X, McGruder H, Yoon P, Rosamond W, Winquist A, Hinchey J, Wall HK, Pandey DK (2009) Paul Coverdell National Acute Stroke Registry Surveillance - four states, 2005–2007. Centers for Disease Control and Prevention (CDC). MMWR Surveill Summ 58(7):1–23. PMID: 19893482PubMedGoogle Scholar
  60. 60.
    Gibson LM, Whiteley W (2013) The differential diagnosis of suspected stroke: a systematic review. J R Coll Physicians Edinb 43(2):114–118. Scholar
  61. 61.
    González-García S, González-Quevedo A, Hernandez-Diaz Z et al (2017) 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 375:324–330. Scholar
  62. 62.
    Glober NK, Sporer KA, Guluma KZ, Serra JP, Barger JA, Brown JF, Gilbert iGH, Koenig KL, Rudnick EM, Salvucci AA (2016) Acute stroke: current evidence-based recommendations for prehospital care. West J Emerg Med 17(2):104–128. Scholar
  63. 63.
    Abboud ME, Band R, Jia J, Pajerowski W, David G, Guo M, Mechem CC, Messé SR, Carr BG, Mullen MT (2016) Recognition of stroke by EMS is associated with improvement in emergency department quality measures. Prehosp Emerg Care 20(6):729–736. Scholar
  64. 64.
    Tong D, Reeves MJ, Hernandez AF, Zhao X, Olson DM, Fonarow GC, Schwamm LH, Smith EE (2012) Times from symptom onset to hospital arrival in the get with the guidelines—stroke program 2002 to 2009: temporal trends and implications. Stroke 43(7):1912–1917. Scholar
  65. 65.
    Hsieh F, Turnbull B (1996) Nonparametric and semiparametric estimation of the receiver operating characteristic curve. Ann Stat 24(1):25–40CrossRefGoogle Scholar
  66. 66.
    Lin D, Wei LJ, Ying Z (1993) Checking the Cox model with cumulative sums of martingale-based residuals. Biometrika 80(3):557–572CrossRefGoogle Scholar
  67. 67.
    Brunser AM, Hoppe A, Illanes S, Díaz V, Muñoz P, Cárcamo D, Olavarria V, Valenzuela M, Lavados P (2013) Accuracy of diffusion-weighted imaging in the diagnosis of stroke in patients with suspected cerebral infarct. Stroke 44(4):1169–1171. Scholar
  68. 68.
    Edlow BL, Hurwitz S, Edlow JA (2017) Diagnosis of DWI-negative acute ischemic stroke: a meta-analysis. Neurology 89(3):256–262. Scholar
  69. 69.
    Alcántara JP (2014) Diffusion tensor imaging in acute ischemic stroke: the role of anisotropy in determining the time of onset and predicting long-term motor outcome. Ph.D. thesis, University of Girona, Girona, Catalonia.

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2020

Authors and Affiliations

  • Svetlana A. Dambinova
    • 1
    • 2
  • J. D. Mullins
    • 4
  • J. D. Weissman
    • 3
  • A. A. Potapov
    • 5
  1. 1.Brain Biomarkers Research LabEmory Decatur Hospital, Emory HealthcareDecaturUSA
  2. 2.Institute of PharmacyI.M. Sechenov First Moscow State Medical UniversityMoscowRussia
  3. 3.Emory Decatur Hospital, DeKalb MedicalEmory HealthcareDecaturUSA
  4. 4.Department of SurgeryPiedmont HospitalAtlantaUSA
  5. 5.Burdenko National Science and Practical Centre for NeurosurgeryMoscowRussia

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