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Elucidating the novel biomarker and therapeutic potentials of High-mobility group box 1 in Subarachnoid hemorrhage: A review

Department of Medicine, Princefield University, P. O. Box MA 128, Ho-Volta Region, Ghana West Africa

Subarachnoid hemorrhage (SAH) frequently arises after an aneurysm in a cerebral artery ruptures, resulting into bleeding as well as clot formation. High-mobility group box 1 (HMGB1) is an extremely preserved, universal protein secreted in the nuclei of all cell varieties. This review explores the biomarker as well as therapeutic potentials of HMBG1 in SAH especially during the occurrence of cerebral vasospasms. Plasma HMGB1 levels have proven to be very useful prognosticators of effective outcome as well as death after SAH. Correspondingly, higher HMGB1 levels in the cerebrospinal fluid (CSF) of SAH patients correlated well with poor outcome; signifying that, CSF level of HMGB1 is a novel predictor of outcome following SAH. Nonetheless, the degree of angiographic vasospasm does not always correlate with the degree of neurological deficits in SAH patients. HMGB1 stimulated cerebral vasospasm, augmented gene as well as protein secretory levels of receptor for advance glycation end product (RAGE) in neurons following SAH; which means that, silencing HMGB1 during SAH could be of therapeutic value. Compounds like resveratrol, glycyrrhizin, rhinacanthin, purpurogallin, 4′-O-β-D-Glucosyl-5-O-Methylvisamminol (4OGOMV) as well as receptor-interacting serine/threonine-protein kinase 3 (RIPK3) gene are capable of interacting with HMGB1 resulting in therapeutic benefits following SAH.
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Keywords CSF; HMGB1; Plasma; Prognosis; SAH; Vasospasm

Citation: Seidu A. Richard. Elucidating the novel biomarker and therapeutic potentials of High-mobility group box 1 in Subarachnoid hemorrhage: A review. AIMS Neuroscience, 2019, 6(4): 316-332. doi: 10.3934/Neuroscience.2019.4.316


  • 1. Sobey CG, Faraci FM (1998) Subarachnoid haemorrhage: what happens to the cerebral arteries? Clin Exp Pharmacol Physiol 25: 867–876.    
  • 2. Singer RJ, Ogilvy CS, Rordorf G (2013) Aneurysmal subarachnoid hemorrhage: Epidemiology, risk factors, and pathogenesis. UpToDate.
  • 3. Worthington JM, Goumas C, Jalaludin B, et al. (2017) Decreasing risk of fatal subarachnoid hemorrhage and other epidemiological trends in the era of coiling implementation in Australia. Front Neurol 8: 424.    
  • 4. Cook DA (1995) Mechanisms of cerebral vasospasm in subarachnoid haemorrhage. Pharmacol Ther 66: 259–284.    
  • 5. Smith R, Clower B, Grotendorst G, et al. (1985) Arterial wall changes in early human vasospasm. Neurosurgery 16: 171–176.    
  • 6. Dhandapani S, Singh A, Singla N, et al. (2018) Has Outcome of subarachnoid hemorrhage changed with improvements in neurosurgical services? Study of 2000 patients over 2 decades from India. Stroke 49: 2890–2895.
  • 7. Weir B (1995) The pathophysiology of cerebral vasospasm. Brit J Neurosurg 9: 375–390.    
  • 8. Wang D, Liu K, Wake H, et al. (2017) Anti-high mobility group box-1 (HMGB1) antibody inhibits hemorrhage-induced brain injury and improved neurological deficits in rats. Sci Rep 7: 46243.    
  • 9. Hendrix P, Foreman PM, Harrigan MR, et al. (2017) Impact of high-mobility group box 1 polymorphism on delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. World Neurosurg 101: 325–330.    
  • 10. Seidu RA, Wu M, Su Z, et al. (2017) Paradoxical role of high mobility group box 1 in glioma: A suppressor or a promoter? Oncol Rev 11: 325.
  • 11. Sokół B, Woźniak A, Jankowski R, et al. (2015) HMGB1 level in cerebrospinal fluid as a marker of treatment outcome in patients with acute hydrocephalus following aneurysmal subarachnoid hemorrhage. J Stroke Cerebrovasc Dis 24: 1897–1904.    
  • 12. Richard SA, Jiang Y, Xiang LH, et al. (2017) Post-translational modifications of high mobility group box 1 and cancer. Am J Transl Res 9: 5181–5196.
  • 13. Richard SA, Xiang LH, Yun JX, et al. (2017) Carcinogenic and therapeutic role of High-Mobility Group Box 1 in Cancer: Is it a cancer facilitator, a cancer inhibitor or both? World Cancer Res J 4: e919.
  • 14. Su Z, Ni P, She P, et al. (2017) Bio-HMGB1 from breast cancer contributes to M-MDSC differentiation from bone marrow progenitor cells and facilitates conversion of monocytes into MDSC-like cells. Cancer Immunol Immunother 66: 391–401.    
  • 15. Ieong C, Sun H, Wang Q, et al. (2018) Glycyrrhizin suppresses the expressions of HMGB1 and ameliorates inflammative effect after acute subarachnoid hemorrhage in rat model. J Clin Neurosci 47: 278–284.    
  • 16. Andersson U, Tracey KJ (2011) HMGB1 is a therapeutic target for sterile inflammation and infection. Annu Rev Immunol 29: 139–162.    
  • 17. Richard SA (2018) High-mobility group box 1 is a promising diagnostic and therapeutic monitoring biomarker in Cancers: A review. AIMS Molecular Science 5: 183–241.    
  • 18. Festoff BW, Sajja RK, van Dreden P, et al. (2016) HMGB1 and thrombin mediate the blood- brain barrier dysfunction acting as biomarkers of neuroinflammation and progression to neurodegeneration in Alzheimer's disease. J Neuroinflammation 13: 194.    
  • 19. Nakahara T, Tsuruta R, Kaneko T, et al. (2009) High-mobility group box 1 protein in CSF of patients with subarachnoid hemorrhage. Neurocrit Care 11: 362–368.    
  • 20. King MD, Laird MD, Ramesh SS, et al. (2010) Elucidating novel mechanisms of brain injury following subarachnoid hemorrhage: An emerging role for neuroproteomics. Neurosurg Focus 28: E10.
  • 21. Richard SA (2018) Myeloid-derived suppressor cells in cancer: A review on the pathogenesis and therapeutic potentials. Open Cancer Immunol J 7.
  • 22. Richard SA, Min W, Su Z, et al. (2017) Epochal neuroinflammatory role of high mobility group box 1 in central nervous system diseases. AIMS Molecular Science 4: 185–218.    
  • 23. Sun Q, Wu W, Hu YC, et al. (2014) Early release of high-mobility group box 1 (HMGB1) from neurons in experimental subarachnoid hemorrhage in vivo and in vitro. J Neuroinflammation 11: 106.    
  • 24. Wang L, Zhang Z, Liang L, et al. (2019) Anti-high mobility group box-1 antibody attenuated vascular smooth muscle cell phenotypic switching and vascular remodelling after subarachnoid haemorrhage in rats. Neurosci Lett 708: 134338.    
  • 25. Chang CZ, Wu SC, Kwan AL, et al. (2015) 4′-O-β-d-glucosyl-5-O-methylvisamminol, an active ingredient of Saposhnikovia divaricata, attenuates high-mobility group box 1 and subarachnoid hemorrhage-induced vasospasm in a rat model. Behav Brain Funct 11: 28.    
  • 26. Wolfson RK, Chiang ET, Garcia JG (2011) HMGB1 induces human lung endothelial cell cytoskeletal rearrangement and barrier disruption. Microvasc Res 81: 189–197.    
  • 27. Richard SA, Sackey M, Su Z, et al. (2017) Pivotal neuroinflammatory and therapeutic role of high mobility group box 1 in ischemic stroke. Biosci Rep 37.
  • 28. Furlani D, Donndorf P, Westien I, et al. (2012) HMGB‐1 induces c‐kit+ cell microvascular rolling and adhesion via both toll‐like receptor‐2 and toll‐like receptor‐4 of endothelial cells. J Cell Mol Med 16: 1094–1105.    
  • 29. Bae JS, Rezaie AR (2013) Thrombin inhibits HMGB1-mediated proinflammatory signaling responses when endothelial protein C receptor is occupied by its natural ligand. BMB Rep 46: 544–549.    
  • 30. Bustin M (1999) Regulation of DNA-dependent activities by the functional motifs of the high-mobility-group chromosomal proteins. Mol Cell Biol 19: 5237–5246.    
  • 31. Chaudhry S, Hafez A, Rezai Jahromi B, et al. (2018) Role of damage associated molecular pattern molecules (DAMPs) in aneurysmal subarachnoid hemorrhage (aSAH). Int J Mol Sci 19: E2035.    
  • 32. Zhu XD, Chen JS, Zhou F, et al. (2012) Relationship between plasma high mobility group box-1 protein levels and clinical outcomes of aneurysmal subarachnoid hemorrhage. J Neuroinflammation 9: 194.
  • 33. Murakami K, Koide M, Dumont TM, et al. (2011) Subarachnoid hemorrhage induces gliosis and increased expression of the pro-inflammatory cytokine high mobility group box 1 protein. Transl Stroke Res 2: 72–79.    
  • 34. Scaffidi P, Misteli T, Bianchi ME (2002) Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418: 191.    
  • 35. Friedrich V, Flores R, Sehba FA (2012) Cell death starts early after subarachnoid hemorrhage. Neurosci Lett 512: 6–11.    
  • 36. Kim JB, Choi JS, Yu YM, et al. (2006) HMGB1, a novel cytokine-like mediator linking acute neuronal death and delayed neuroinflammation in the postischemic brain. J Neurosci 26: 6413–6421.    
  • 37. Haruma J, Teshigawara K, Hishikawa T, et al. (2016) Anti-high mobility group box-1 (HMGB1) antibody attenuates delayed cerebral vasospasm and brain injury after subarachnoid hemorrhage in rats. Sci Rep 6: 37755.    
  • 38. Dorsch N, King M (1994) A review of cerebral vasospasm in aneurysmal subarachnoid haemorrhage Part I: Incidence and effects. J Clin Neurosci 1: 19–26.    
  • 39. Greenhalgh AD, Brough D, Robinson EM, et al. (2012) Interleukin-1 receptor antagonist is beneficial after subarachnoid haemorrhage in rat by blocking haem-driven inflammatory pathology. Dis Model Mech 5: 823–833.    
  • 40. Munakata A, Naraoka M, Katagai T, et al. (2016) Role of cyclooxygenase-2 in relation to nitric oxide and endothelin-1 on pathogenesis of cerebral vasospasm after subarachnoid hemorrhage in rabbit. Transl Stroke Res 7: 220–227.    
  • 41. Zhao XD, Mao HY, Lv J, et al. (2016) Expression of high-mobility group box-1 (HMGB1) in the basilar artery after experimental subarachnoid hemorrhage. J Clin Neurosci 27: 161–165.    
  • 42. Mu SW, Dang Y, Wang SS, et al. (2018) The role of high mobility group box 1 protein in acute cerebrovascular diseases. Biomed Rep 9: 191–197.
  • 43. Li H, Wu W, Sun Q, et al. (2014) Expression and cell distribution of receptor for advanced glycation end-products in the rat cortex following experimental subarachnoid hemorrhage. Brain Res 1543: 315–323.    
  • 44. Chang CZ, Lin CL, Wu SC, et al. (2014) Purpurogallin, a natural phenol, attenuates high-mobility group box 1 in subarachnoid hemorrhage induced vasospasm in a rat model. Int J Vasc Med 2014: 254270.
  • 45. Camelo S, Iglesias AH, Hwang D, et al. (2005) Transcriptional therapy with the histone deacetylase inhibitor trichostatin A ameliorates experimental autoimmune encephalomyelitis. J Neuroimmunol 164: 10–21.    
  • 46. Kiiski H, Långsjö J, Tenhunen J, et al. (2017) Time-courses of plasma IL-6 and HMGB-1 reflect initial severity of clinical presentation but do not predict poor neurologic outcome following subarachnoid hemorrhage. Eneurologicalsci 6: 55–62.    
  • 47. Umahara T, Uchihara T, Hirokawa K, et al. (2018) Time-dependent and lesion-dependent HMGB1-selective localization in brains of patients with cerebrovascular diseases. Histol Histopathol 33: 215–222.
  • 48. Sabri M, Kawashima A, Ai J, et al. (2008) Neuronal and astrocytic apoptosis after subarachnoid hemorrhage: a possible cause for poor prognosis. Brain Res 1238: 163–171.    
  • 49. Mann KG, Jenny RJ, Krishnaswamy S (1988) Cofactor proteins in the assembly and expression of blood clotting enzyme complexes. Annu Rev Biochem 57: 915–956.    
  • 50. Coughlin SR (2000) Thrombin signalling and protease-activated receptors. Nature 407: 258.    
  • 51. Steinhoff M, Buddenkotte J, Shpacovitch V, et al. (2005) Proteinase-activated receptors: transducers of proteinase-mediated signaling in inflammation and immune response. Endocr Rev 26: 1–43.
  • 52. Kassis I, Grigoriadis N, Gowda-Kurkalli B, et al. (2008) Neuroprotection and immunomodulation with mesenchymal stem cells in chronic experimental autoimmune encephalomyelitis. Arch Neurol 65: 753–761.
  • 53. Louboutin JP, Strayer DS (2013) Relationship between the chemokine receptor CCR5 and microglia in neurological disorders: consequences of targeting CCR5 on neuroinflammation, neuronal death and regeneration in a model of epilepsy. CNS Neurol Disord Drug Targets 12: 815–829.    
  • 54. Ito T, Kawahara K, Okamoto K, et al. (2008) Proteolytic cleavage of high mobility group box 1 protein by thrombin-thrombomodulin complexes. Arterioscler Thromb Vasc Biol 28: 1825–1830.    
  • 55. Abeyama K, Stern DM, Ito Y, et al. (2005) The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism. J Clin Invest 115: 1267–1274.    
  • 56. Esmon C (2005) Do-all receptor takes on coagulation, inflammation. Nat Med 11: 475–477.    
  • 57. Birukova AA, Birukov KG, Smurova K, et al. (2004) Novel role of microtubules in thrombin-induced endothelial barrier dysfunction. FASEB J 18: 1879–1890.    
  • 58. Nawaz MI, Mohammad G (2015) Role of high-mobility group box-1 protein in disruption of vascular barriers and regulation of leukocyte–endothelial interactions. J Recept Signal Transduct Res 35: 340–345.    
  • 59. An JY, Pang HG, Huang TQ, et al. (2018) AG490 ameliorates early brain injury via inhibition of JAK2/STAT3‑mediated regulation of HMGB1 in subarachnoid hemorrhage. Exp Ther Med 15: 1330–1338.
  • 60. Liu H, Yao YM, Yu Y, et al. (2007) Role of Janus kinase/signal transducer and activator of transcription pathway in regulation of expression and inflammation-promoting activity of high mobility group box protein 1 in rat peritoneal macrophages. Shock 27: 55–60.    
  • 61. You W-C, Wang C-x, Pan Y-x, et al. (2013) Activation of nuclear factor-κB in the brain after experimental subarachnoid hemorrhage and its potential role in delayed brain injury. PLoS One 8: e60290.    
  • 62. Zheng VZ, Wong GKC (2017) Neuroinflammation responses after subarachnoid hemorrhage: A review. J Clin Neurosci 42: 7–11.    
  • 63. Lu B, Antoine DJ, Kwan K, et al. (2014) JAK/STAT1 signaling promotes HMGB1 hyperacetylation and nuclear translocation. Proc Natl Acad Sci U S A 111: 3068–3073.    
  • 64. Lumpkins K, Bochicchio GV, Zagol B, et al. (2008) Plasma levels of the beta chemokine regulated upon activation, normal T cell expressed, and secreted (RANTES) correlate with severe brain injury. J Trauma 64: 358–361.    
  • 65. Sugawara T, Fujimura M, Noshita N, et al. (2004) Neuronal death/survival signaling pathways in cerebral ischemia. NeuroRx 1: 17–25.    
  • 66. Sun Q, Dai Y, Zhang X, et al. (2013) Expression and cell distribution of myeloid differentiation primary response protein 88 in the cerebral cortex following experimental subarachnoid hemorrhage in rats: a pilot study. Brain Res 1520: 134–144.    
  • 67. Jiang Y, Liu D-W, Han X-Y, et al. (2012) Neuroprotective effects of anti-tumor necrosis factor-alpha antibody on apoptosis following subarachnoid hemorrhage in a rat model. J Clin Neurosci 19: 866–872.    
  • 68. Chang CZ, Wu SC, Kwan AL, et al. (2016) Rhinacanthin-C, a fat-soluble extract from Rhinacanthus nasutus, modulates high-mobility group box 1-related neuro-inflammation and subarachnoid hemorrhage-induced brain apoptosis in a rat model. World Neurosurg 86: 349–360.    
  • 69. Horii H, Suzuki R, Sakagami H, et al. (2013) New biological activities of Rhinacanthins from the root of Rhinacanthus nasutus. Anticancer Res 33: 453–459.
  • 70. Ali MS, Starke RM, Jabbour PM, et al. (2013) TNF-α induces phenotypic modulation in cerebral vascular smooth muscle cells: implications for cerebral aneurysm pathology. J Cereb Blood Flow Metab 33: 1564–1573.    
  • 71. van Beijnum JR, Buurman WA, Griffioen AW (2008) Convergence and amplification of toll-like receptor (TLR) and receptor for advanced glycation end products (RAGE) signaling pathways via high mobility group B1 (HMGB1). Angiogenesis 11: 91–99.    
  • 72. Hildmann C, Riester D, Schwienhorst A (2007) Histone deacetylases-an important class of cellular regulators with a variety of functions. Appl Microbiol Biotechnol 75: 487–497.    
  • 73. Zhou C, Yamaguchi M, Kusaka G, et al. (2004) Caspase inhibitors prevent endothelial apoptosis and cerebral vasospasm in dog model of experimental subarachnoid hemorrhage. J Cereb Blood Flow Metab 24: 419–431.    
  • 74. Salmivirta M, Rauvala H, Elenius K, et al. (1992) Neurite growth-promoting protein (amphoterin, p30) binds syndecan. Exp Cell Res 200: 444–451.    
  • 75. Huttunen H, Rauvala H (2004) Amphoterin as an extracellular regulator of cell motility: from discovery to disease. J Intern Med 255: 351–366.    
  • 76. Wang K, Li W, Yu Q, et al. (2017) High mobility group box 1 mediates Interferon‐γ‐Induced phenotypic modulation of vascular smooth muscle cells. J Cell Biochem 118: 518–529.    
  • 77. Wang HL, Peng LP, Chen WJ, et al. (2014) HMGB1 enhances smooth muscle cell proliferation and migration in pulmonary artery remodeling. Int J Clin Exp Pathol 7: 3836–3844.
  • 78. Lotze MT, Tracey KJ (2005) High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nat Rev Immunol 5: 331–342.    
  • 79. Macdonald RL (2014) Delayed neurological deterioration after subarachnoid haemorrhage. Nat Rev Neurol 10: 44–58.
  • 80. Zhang H, Jiang L, Guo Z, et al. (2017) PPARβ/δ, a novel regulator for vascular smooth muscle cells phenotypic modulation and vascular remodeling after subarachnoid hemorrhage in rats. Sci Rep 7: 45234.    
  • 81. Yang J, Wang W, Dong M, et al. (2015) Effect of nucleoprotein factor-kB (NF-κB) in endothelial cells during high blood flow-associated pulmonary vascular remodeling on vasoactive substances adrenomedullin and prostacyclin. Int J Clin Exp Med 8: 13842–13847.
  • 82. Zhang XS, Li W, Wu Q, et al. (2016) Resveratrol attenuates acute inflammatory injury in experimental subarachnoid hemorrhage in rats via inhibition of TLR4 pathway. Int J Mol Sci 17: E1331.    
  • 83. Richard SA (2019) The therapeutic potential of resveratrol in gliomas. Adv Biosci Clin Med 7: 44–59.    
  • 84. Jing CH, Wang L, Liu PP, et al. (2012) Autophagy activation is associated with neuroprotection against apoptosis via a mitochondrial pathway in a rat model of subarachnoid hemorrhage. Neuroscience 213: 144–153.    
  • 85. Kim MK, Yang DH, Jung M, et al. (2011) Simultaneous determination of chromones and coumarins in Radix Saposhnikoviae by high performance liquid chromatography with diode array and tandem mass detectors. J Chromatogr A 1218: 6319–6330.    
  • 86. Li Z, Ni K, Du G (2007) Simultaneous analysis of six effective components in the anti-Alzheimer's disease effective component group of Xiao-Xu-Ming Decoction. Se pu= Chinese J Chromatogr 25: 80–83.
  • 87. Takizawa T, Tada T, Kitazawa K, et al. (2001) Inflammatory cytokine cascade released by leukocytes in cerebrospinal fluid after subarachnoid hemorrhage. Neurol Res 23: 724–730.    
  • 88. Chen T, Pan H, Li J, et al. (2018) Inhibiting of RIPK3 attenuates early brain injury following subarachnoid hemorrhage: Possibly through alleviating necroptosis. Biomed Pharmacother 107: 563–570.    
  • 89. Lee JM, Yoshida M, Kim MS, et al. (2018) Involvement of alveolar epithelial cell necroptosis in idiopathic pulmonary fibrosis pathogenesis. Am J Respir Cell Mol Biol 59: 215–224.    
  • 90. Cho E, Lee JK, Park E, et al. (2018) Antitumor activity of HPA3P through RIPK3-dependent regulated necrotic cell death in colon cancer. Oncotarget 9: 7902–7917.
  • 91. Xiong X, Gu L, Wang Y, et al. (2016) Glycyrrhizin protects against focal cerebral ischemia via inhibition of T cell activity and HMGB1-mediated mechanisms. J Neuroinflammation 13: 241.    
  • 92. Richard SA, Min W, Su Z, et al. (2017) High mobility group box 1 and traumatic brain injury. J Behav Brain Sci 7: 50–61.    
  • 93. Zhang J, Wu Y, Weng Z, et al. (2014) Glycyrrhizin protects brain against ischemia–reperfusion injury in mice through HMGB1-TLR4-IL-17A signaling pathway. Brain Res 1582: 176–186.    
  • 94. Sun Q, Wang F, Li W, et al. (2013) Glycyrrhizic acid confers neuroprotection after subarachnoid hemorrhage via inhibition of high mobility group box-1 protein: A hypothesis for novel therapy of subarachnoid hemorrhage. Med Hypotheses 81: 681–685.    


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