S100 B: A new concept in neurocritical care

  • Omidvar Rezaei Skull Base Research Center, Loghman Hakim Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  • Hossein Pakdaman Brain Mapping Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  • Kurosh Gharehgozli Brain Mapping Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  • Leila Simani Clinical Research Development Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  • Amir Vahedian-Azimi Trauma Research Center, School of Nursing, Baqiyatallah University of Medical Sciences, Tehran, Iran
  • Sina Asadi Clinical Research Development Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  • Zahra Sahraei Department of Clinical Pharmacy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  • Mohammadreza Hajiesmaeili Anesthesiology Research Center, Loghman Hakim Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Biologic Marker, Surrogate Marker, Serum Marker, S100B Protein, Progressive Patient Care


After brain injuries, concentrations of some brain markers such as S100B protein in serum and cerebrospinal fluid (CSF) are correlated with the severity and outcome of brain damage. To perform an updated review of S100B roles in human neurocritical care domain, an electronic literature search was carried among articles published in English prior to March 2017. They were retrieved from PubMed, Scopus, EMBSCO, CINAHL, ISC and the Cochrane Library using keywords including “brain”, “neurobiochemical marker”, “neurocritical care”, and “S100B protein”. The integrative review included 48 studies until March 2017. S100B protein can be considered as a marker for blood brain barrier damage. The marker has an important role in the development and recovery of normal central nervous system (CNS) after injury. In addition to extra cerebral sources of S100B, the marker is principally built in the astroglial and Schwann cells. The neurobiochemical marker, S100B, has a pathognomonic role in the diagnosis of a broad spectrum of brain damage including traumatic brain injury (TBI), brain tumor, and stroke. Moreover, a potential predicting role for the neurobiochemical marker has been presumed in the efficiency of brain damage treatment and prognosis. However further animal and human studies are required before widespread routine clinical introduction of S100 protein.


1. Johnsson P. Markers of cerebral ischemia after cardiac surgery. J Cardiothorac Vasc Anesth 1996; 10(1): 120-6.
2. Rezaei O, Gharagozli K,Jelvehmoghadam H, Goharani R,Hajiesmaeili M. Biochemical markers inneurocritical care. J Cell Mol Anesth2016; 1(3): 115-9.
3. Vaage J, Anderson R. Biochemical markers of neurologic injury in cardiac surgery: The rise and fall of S100beta. J Thorac Cardiovasc Surg 2001; 122(5):853-5.
4. Yardan T, Erenler AK, Baydin A, Aydin K, Cokluk C. Usefulness of S100B protein in neurological disorders. J PakMed Assoc 2011; 61(3): 276-81.
5. Stammet P. Blood biomarkers of hypoxic-ischemic brain injury after cardiac arrest. Semin Neurol 2017; 37(1):75-80.
6. Green AJE, Harvey RJ, Thompson EJ, Rossor MN. Increased S100 β in the cerebrospinal fluid of patients withfrontotemporal dementia. Neurosci Lett 1997; 235(1-2): 5-8.
7. Zetterberg H, Smith DH, Blennow K. Biomarkers of mild traumatic brain injury in cerebrospinal fluid and blood. Nat Rev
Neurol 2013; 9(4): 201-10.
8. Lam V, Albrecht MA, Takechi R, Giles C, James AP, Foster JK, et al. The serum concentration of the calcium binding
protein s100b is positively associated with cognitive performance in older adults. Front Aging Neurosci 2013; 5: 61.
9. Liu W, Huo X, Liu D, Zeng X, Zhang Y, Xu X. S100beta in heavy metal-related child attention-deficit hyperactivity
disorder in an informal e-waste recycling area. Neurotoxicology 2014; 45: 185-91.
10. Qin B, Panickar KS, Anderson RA. Cinnamon polyphenols attenuate the hydrogen peroxide-induced down regulation of S100beta secretion by regulating sirtuin 1 in C6 rat glioma cells. Life Sci 2014; 102(1): 72-9.
11. Brunnekreef GB, Heijmen RH, Gerritsen WB, Schepens MA, ter Beek HT, van Dongen EP. Measurements of cerebrospinal fluid concentrations of S100beta protein during and after thoracic endovascular stent grafting. Eur JVasc Endovasc Surg 2007; 34(2): 169-72.
12. Donato R, Sorci G, Riuzzi F, Arcuri C, Bianchi R, Brozzi F, et al. S100B's double life: intracellular regulator and extracellular signal. Biochim Biophys Acta 2009; 1793(6): 1008-22.
13. Qin B, Panickar KS, Anderson RA. Cinnamon polyphenols regulate S100beta, sirtuins, and neuroactiveproteins in rat C6 glioma cells. Nutrition 2014; 30(2): 210-7.
14. Gerlach R, Demel G, Konig HG, Gross U, Prehn JH, Raabe A, et al. Active secretion of S100B from astrocytes during metabolic stress. Neuroscience 2006; 141(4): 1697-701.
15. de Souza DF, Leite MC, Quincozes- Santos A, Nardin P, Tortorelli LS, Rigo MM, et al. S100B secretion is stimulated by IL-1beta in glial cultures and hippocampal slices of rats: Likely involvement of MAPK pathway. J Neuroimmunol 2009; 206(1-2): 52-7.
16. Donato R. S100: A multigenic family of calcium-modulated proteins of the EFhand type with intracellular and extracellular functional roles. Int J Biochem Cell Biol 2001; 33(7): 637-68.
17. Selinfreund RH, Barger SW, Pledger WJ, Van Eldik LJ. Neurotrophic protein S100 beta stimulates glial cell proliferation.
Proc Natl Acad Sci U S A 1991; 88(9):3554-8.
18. Rothermundt M, Peters M, Prehn JH,Arolt V. S100B in brain damage and neurodegeneration. Microsc Res Tech 2003; 60(6): 614-32.
19. Sen J, Belli A. S100B in neuropathologic states: The CRP of the brain? J Neurosci Res 2007; 85(7): 1373-80.
20. Hu J, Ferreira A, Van Eldik LJ. S100 β Induces neuronal cell death through nitric oxide release from astrocytes. J Neurochem 1997; 69(6): 2294-301.
21. Iuvone T, Esposito G, De Filippis D,Bisogno T, Petrosino S, Scuderi C, et al. Cannabinoid CB1 receptor stimulation affords neuroprotection in MPTP-induced neurotoxicity by attenuating S100B upregulation in vitro. J Mol Med (Berl) 2007; 85(12): 1379-92.
22. Bianchi R, Kastrisianaki E, Giambanco I,Donato R. S100B protein stimulates microglia migration via RAGE-dependent
up-regulation of chemokine expression and release. J Biol Chem 2011; 286(9):7214-26.
23. Donato R. Functional roles of S100 proteins, calcium-binding proteins of the EF-hand type. Biochim Biophys Acta 1999; 1450(3): 191-231.
24. Hofmann MA, Drury S, Fu C, Qu W,Taguchi A, Lu Y, et al. RAGE mediates a novel proinflammatory axis: A central cell surface receptor for S100/calgranulin polypeptides. Cell 1999; 97(7): 889-901.
25. Kerkhoff C, Klempt M, Sorg C. Novel insights into structure and function of MRP8 (S100A8) and MRP14 (S100A9).Biochim Biophys Acta 1998; 1448(2):200-11.
26. Villarreal A, Aviles Reyes RX, Angelo MF, Reines AG, Ramos AJ. S100B alters neuronal survival and dendrite extension
via RAGE-mediated NF-kappaB signaling. J Neurochem 2011; 117(2):321-32.
27. Huttunen HJ, Kuja-Panula J, Sorci G,Agneletti AL, Donato R, Rauvala H. Coregulation of neurite outgrowth and cell survival by amphoterin and S100 proteins through receptor for advanced glycation end products (RAGE) activation. J Biol Chem 2000; 275(51):40096-105.
28. Businaro R, Leone S, Fabrizi C, Sorci G,Donato R, Lauro GM, et al. S100B protects LAN-5 neuroblastoma cells against A? amyloid-induced neurotoxicity via RAGE engagement at low doses but increases A? amyloid neurotoxicity at
high doses. J Neurosci Res 2006; 83(5):897-906.
29. Kogel D, Peters M, Konig HG, Hashemi SM, Bui NT, Arolt V, et al. S100B potently activates p65/c-Rel transcriptional complexes in hippocampal neurons: Clinical implications for the role of S100B in excitotoxic brain injury.Neuroscience 2004; 127(4): 913-20.
30. Sedaghat F, Notopoulos A. S100 protein family and its application in clinical practice. Hippokratia 2008; 12(4): 198-204.
31. Michetti F, Corvino V, Geloso MC,Lattanzi W, Bernardini C, Serpero L, et al. The S100B protein in biological fluids: More than a lifelong biomarker of brain distress. J Neurochem 2012; 120(5): 644-59.
32. Gazzolo D, Monego G, Corvino V, Bruschettini M, Bruschettini P, Zelano G, et al. Human milk contains S100B protein. Biochim Biophys Acta 2003;1619(2): 209-12.
33. Kleindienst A, Hesse F, Bullock MR, Buchfelder M. The neurotrophic protein S100B: Value as a marker of braindamage and possible therapeutic implications. Prog Brain Res 2007; 161:317-25.
34. Heidari K, Asadollahi S, Jamshidian M,Abrishamchi SN, Nouroozi M. Prediction of neuropsychological outcome after mild traumatic brain injury using clinical parameters, serum S100B protein and findings on computed tomography. Brain Inj 2015; 29(1): 33-40.
35. Nylen K, Ost M, Csajbok LZ, Nilsson I, Hall C, Blennow K, et al. Serum levels of S100B, S100A1B and S100BB are allrelated to outcome after severe traumatic brain injury. Acta Neurochir (Wien) 2008; 150(3): 221-7.
36. Biberthaler P, Linsenmeier U, Pfeifer KJ,Kroetz M, Mussack T, Kanz KG, et al.Serum S-100B concentration provides additional information fot the indication of computed tomography in patients after minor head injury: A prospective multicenter study. Shock 2006; 25(5):446-53.
37. Vos PE, Lamers KJ, Hendriks JC, van Haaren M, Beems T, Zimmerman C, et al. Glial and neuronal proteins in serumpredict outcome after severe traumatic brain injury. Neurology 2004; 62(8):1303-10.
38. Welch RD, Ellis M, Lewis LM, Ayaz SI,Mika VH, Millis, et al. Modeling the kinetics of serum glial fibrillary acidicprotein, ubiquitin carboxyl-terminal hydrolase-l1, and s100b concentrations in patients with traumatic brain injury. J Neurotrauma 2017; 34(11): 1957-71.
39. Thelin EP, Nelson DW, Bellander BM. A review of the clinical utility of serum S100B protein levels in the assessment of
traumatic brain injury. Acta Neurochir (Wien) 2017; 159(2): 209-25.
40. Jagoda AS, Bazarian JJ, Bruns JJ Jr, Cantrill SV, Gean AD, Howard PK, et al. Clinical policy: neuroimaging and decisionmaking in adult mild traumatic brain injury in the acute setting. Ann Emerg Med 2008; 52(6): 714-48.
41. Unden J, Ingebrigtsen T, Romner B.Scandinavian guidelines for initial management of minimal, mild and moderate head injuries in adults: An evidence and consensus-based update.BMC Med 2013; 11: 50.
42. Lippi G, Cervellin G. Protein S100B:From cancer diagnostics to the evaluation of mild traumatic brain injury. Clin Chem
Lab Med 2016; 54(5): 703-5.
43. Lin J, Blake M, Tang C, Zimmer D,Rustandi RR, Weber DJ, et al. Inhibition of p53 transcriptional activity by the S100B calcium-binding protein. J Biol Chem 2001; 276(37): 35037-41.
44. Stranjalis G, Korfias S, Psachoulia C,Boviatsis E, Kouyialis A, Protopappa D, et al. Serum S-100B as an indicator ofearly postoperative deterioration after meningioma surgery. Clin Chem 2005;51(1): 202-7.
45. Ilhan-Mutlu A, Wagner L, Preusser M.Circulating biomarkers of CNS tumors:an update. Biomark Med 2013; 7(2): 267-
46. Ortiz-Munoz B, Menendez-Lopez A,Yaya-Tur R, Arribas-Alpuente L,Maiquez-Richart J, Bordes-Monmeneu M. S100 protein in tumours of the central nervous system. Rev Neurol 2003;36(11): 1011-5.
47. Song WS, Guo LB, Hong ZY, Li JJ, Wu J. Serum S100 protein and radiationinduced brain injury in astrocytoma patients. Di Yi Jun Yi Da Xue Xue Bao 2005; 25(6): 723-5.
48. Gartner W, Ilhan A, Neziri D, Base W, Weissel M, Wohrer A, et al. Elevated blood markers 1 year beforemanifestation of malignant glioma. Neuro Oncol 2010; 12(9): 1004-8.
49. Vos MJ, Postma TJ, Martens F,Uitdehaag BM, Blankenstein MA, Vandertop WP, et al. Serum levels of S- 100B protein and neuron-specific enolase in glioma patients: A pilot study.Anticancer Res 2004; 24(4): 2511-4.
50. Jauch EC, Lindsell C, Broderick J, Fagan SC, Tilley BC, Levine SR. Association of serial biochemical markers with acute ischemic stroke: The National Institute of Neurological Disorders and Stroke recombinant tissue plasminogen activator Stroke Study. Stroke 2006; 37(10): 2508-13.
51. Missler U, Wiesmann M, Friedrich C, Kaps M. S-100 protein and neuronspecific enolase concentrations in blood as indicators of infarction volume and prognosis in acute ischemic stroke. Stroke 1997; 28(10): 1956-60.
52. Nash DL, Bellolio MF, Stead LG. S100 as a marker of acute brain ischemia: A systematic review. Neurocrit Care 2008; 8(2): 301-7.
53. Kartal AG, Yilmaz S, Yaka E, Pekdemir M, Sarisoy HT, Cekmen MB, et al.Diagnostic value of S100B protein in thedifferential diagnosis of acute vertigo in the emergency department. Acad Emerg Med 2014; 21(7): 736-41.
54. Purrucker JC, Herrmann O, Lutsch JK,Zorn M, Schwaninger M, Bruckner T, et al. Serum protein S100beta is a diagnostic biomarker for distinguishing posterior circulation stroke from vertigo ofnonvascular causes. Eur Neurol 2014;
72(5-6): 278-84.
55. Ishibashi H, Funakoshi Y. Serum S-100B protein levels in left-and right-hemisphere strokes. J Clin Neurosci 2008; 15(5):520-5.
56. Foerch C, Singer OC, Neumann-Haefelin T, du Mesnil de Rochemont R, Steinmetz H, Sitzer M. Evaluation of serum S100B as a surrogate marker for long-term outcome and infarct volume in acute middle cerebral artery infarction. Arch Neurol 2005; 62(7): 1130-4.
57. Foerch C, Otto B, Singer OC, Neumann-Haefelin T, Yan B, Berkefeld J, et al. Serum S100B predicts a malignant courseof infarction in patients with acute middle cerebral artery occlusion. Stroke 2004;35(9): 2160-4.
58. Delgado P, Alvarez Sabin J, Santamarina E, Molina CA, Quintana M, Rosell A, et al. Plasma S100B level after acute spontaneous intracerebral hemorrhage. Stroke 2006; 37(11): 2837-9.
59. Weglewski A, Ryglewicz D, Mular A, Jurynczyk J. Changes of protein S100B serum concentration during ischemic and
hemorrhagic stroke in relation to the volume of stroke lesion. Neurol Neurochir Pol 2005; 39(4): 310-7.
60. Raabe A, Kopetsch O, Woszczyk A,Lang J, Gerlach R, Zimmermann M, et al. S-100B protein as a serum marker of secondary neurological complications in neurocritical care patients. Neurol Res 2004; 26(4): 440-5.
61. Chong ZZ. S100B raises the alert in subarachnoid hemorrhage. Rev Neurosci 2016; 27(7): 745-59.
62. Kellermann I, Kleindienst A, Hore N,Buchfelder M, Brandner S. Early CSF and serum S100B concentrations for outcome prediction in traumatic brain injury and subarachnoid hemorrhage. Clin Neurol Neurosurg 2016; 145: 79-83.
63. Fisher CM, Kistler JP, Davis JM.Relation of cerebral vasospasm to subarachnoid hemorrhage visualized by computerized tomographic scanning.Neurosurgery 1980; 6(1): 1-9.
64. Teasdale GM, Drake CG, Hunt W,Kassell N, Sano K, Pertuiset B, et al. A universal subarachnoid hemorrhage scale: Report of a committee of the World Federation of Neurosurgical Societies. JNeurol Neurosurg Psychiatry 1988;51(11): 1457.
65. Moritz S, Warnat J, Bele S, Graf BM,Woertgen C. The prognostic value of NSE and S100B from serum and cerebrospinal fluid in patients withspontaneous subarachnoid hemorrha ge.Neurosurg Anesthesiol 2010; 22(1): 21-31.
66. Sanchez-Pena P, Pereira AR, Sourour NA, Biondi A, Lejean L, Colonne C, et al. S100B as an additional prognostic marker in subarachnoid aneurysmal hemorrhage. Crit Care Med 2008; 36(8):2267-73.
67. Weiss N, Sanchez-Pena P, Roche S,Beaudeux JL, Colonne C, Coriat P, et al.Prognosis value of plasma S100B protein levels after subarachnoid aneurysmal hemorrhage. Anesthesiology 2006; 104(4): 658-66.
68. Amiri M, Astrand R, Romner B. Can S100B predict cerebral vasospasms in patients suffering from subarachnoid hemorrhage? Front Neurol 2013; 4: 65
How to Cite
Rezaei O, Pakdaman H, Gharehgozli K, Simani L, Vahedian-Azimi A, Asadi S, Sahraei Z, Hajiesmaeili M. S100 B: A new concept in neurocritical care. Curr J Neurol. 16(2):83-89.
Review Article(s)