Journal of Neuroimmune Pharmacology

, Volume 14, Issue 2, pp 157–172 | Cite as

Mechanisms of Blood-Brain Barrier Disruption in Herpes Simplex Encephalitis

  • Hui Liu
  • Ke Qiu
  • Qiang He
  • Qiang LeiEmail author
  • Wei LuEmail author


Herpes simplex encephalitis (HSE) is often caused by infection with herpes simplex virus 1 (HSV-1), a neurotropic double-stranded DNA virus. HSE infection always impacts the temporal and frontal lobes or limbic system, leading to edema, hemorrhage, and necrotic changes in the brain parenchyma. Additionally, patients often exhibit severe complications following antiviral treatment, including dementia and epilepsy. HSE is further associated with disruptions to the blood-brain barrier (BBB), which consists of microvascular endothelial cells, tight junctions, astrocytes, pericytes, and basement membranes. Following an HSV-1 infection, changes in BBB integrity and permeability can result in increased movement of viruses, immune cells, and/or cytokines into the brain parenchyma. This leads to an enhanced inflammatory response in the central nervous system and further damage to the brain. Thus, it is important to protect the BBB from pathogens to reduce brain damage from HSE. Here, we discuss HSE and the normal structure and function of the BBB. We also discuss growing evidence indicating an association between BBB breakdown and the pathogenesis of HSE, as well as future research directions and potential new therapeutic targets.

Graphical Abstract

During herpes simplex encephalitis, the functions and structures of each composition of BBB have been altered by different factors, thus the permeability and integrity of BBB have been broken. The review aim to explore the potential mechanisms and factors in the process, probe the next research targets and new therapeutic targets.


Herpes simplex encephalitis Blood-brain barrier Tight junctions Microglia Immune response 



tight junctions


adhesion junction


basal membrane


blood-brain barrier


central nervous system


experimental autoimmune encephalomyelitis


endothelial cells


extracellular molecules


Golgi apparatus


Herpes simplex encephalitis


herpes simplex virus 1


intracellular adhesion molecule




interleukin 1-beta


inducible nitric oxide synthase


Membrane metalloprotease


nuclear factor kappa B


protein kinase C


transendothelial electric resistance


tumor necrosis factor alpha


transforming growth factor-beta


vascular endothelial growth factor


zonula occluden.



This study was supported by the National Natural Science Foundation (Grant 81571181) of China P.R. HL carried out the literature review and drafted the manuscript. KQ and QH helped to draft the manuscript. QL conceived of, designed, and coordinated the study. WL contributed to and finalized the draft. All authors read and approved the final manuscript.


This study was supported by the National Natural Science Foundation (Grant 81571181) of China P.R.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

This article does not contain any studies with human participants or animals performed by any of the authors.


  1. Abbott NJ (2002) Astrocyte-endothelial interactions and blood-brain barrier permeability. J Anat 200:629–638Google Scholar
  2. Abbott NJ, Patabendige AAK, Dolman DEM, Yusof SR, Begley DJ (2010) Structure and function of the blood–brain barrier. Neurobiol Dis 37:13–25Google Scholar
  3. Adamson P, Etienne S, Couraud PO, Calder V, Greenwood J (1999) Lymphocyte migration through brain endothelial cell monolayers involves signaling through endothelial ICAM-1 via a rho-dependent pathway. J Immunol 162:2964–2973Google Scholar
  4. Albert S, Lossinsky MJM, Wisniewski RPAH (1995) Intercellular adhesion molecule-I (ICAM-I) upregulation in human brain tumors as an expression of increased blood-brain barrier permeability. Brain Pathol 5:339–344Google Scholar
  5. Almutairi MMA, Gong C, Xu YG, Chang Y, Shi H (2016) Factors controlling permeability of the blood–brain barrier. Cell Mol Life Sci 73:57–77Google Scholar
  6. Alvarez JI, Katayama T, Prat A (2013) Glial influence on the blood brain barrier. Glia 61:1939–1958Google Scholar
  7. Aravalli RN, Hu S, Rowen TN, Gekker G, Lokensgard JR (2006) Differential apoptotic signaling in primary glial cells infected with herpes simplex virus 1. J Neurovirol 12:501–510Google Scholar
  8. Argaw AT, Zhang Y, Snyder BJ, Zhao ML, Kopp N, Lee SC, Raine CS, Brosnan CF, John GR (2006) IL-1beta regulates blood-brain barrier permeability via reactivation of the hypoxia-angiogenesis program. J Immunol 177:5574–5584Google Scholar
  9. Argaw AT, Gurfein BT, Zhang Y, Zameer A, John GR (2009) VEGF-mediated disruption of endothelial CLN-5 promotes blood-brain barrier breakdown. Proc Natl Acad Sci 106:1977–1982Google Scholar
  10. Argaw AT, Asp L, Zhang J, Navrazhina K, Pham T, Mariani JN, Mahase S, Dutta DJ, Seto J, Kramer EG, Ferrara N, Sofroniew MV, John GR (2012) Astrocyte-derived VEGF-A drives blood-brain barrier disruption in CNS inflammatory disease. J Clin Investig 122:2454–2468Google Scholar
  11. Armien AG, Hu S, Little MR, Robinson N, Lokensgard JR, Low WC, Cheeran MC (2010) Chronic cortical and subcortical pathology with associated neurological deficits ensuing experimental herpes encephalitis. Brain Pathol 20:738–750Google Scholar
  12. Armulik A, Genové G, Mäe M, Nisancioglu MH, Wallgard E, Niaudet C, He L, Norlin J, Lindblom P, Strittmatter K, Johansson BR, Betsholtz C (2010) Pericytes regulate the blood–brain barrier. Nature 468:557–561Google Scholar
  13. Ashley SL, Pretto CD, Stier MT, Kadiyala P, Castro-Jorge L, Hsu T, Doherty R, Carnahan KE, Castro MG, Lowenstein PR, Spindler KR (2017) Matrix metalloproteinase activity in infections by an encephalitic virus, mouse adenovirus type 1. J Virol 91:e1412–e1416Google Scholar
  14. Banisadr G, Queraud-Lesaux F, Boutterin MC, Pelaprat D, Zalc B, Rostene W, Haour F, Parsadaniantz SM (2002) Distribution, cellular localization and functional role of CCR2 chemokine receptors in adult rat brain. J Neurochem 81:257–269Google Scholar
  15. Bataveljić D, Nikolić L, Milosević M, Todorović N, Andjus PR (2012) Changes in the astrocytic aquaporin-4 and inwardly rectifying potassium channel expression in the brain of the amyotrophic lateral sclerosis SOD1G93A rat model. Glia 60:1991–2003Google Scholar
  16. Bedard K, Krause KH (2007) The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87:245–313Google Scholar
  17. Block ML, Hong J (2005) Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism. Prog Neurobiol 76:77–98Google Scholar
  18. Bradshaw MJ, Venkatesan A (2016) Herpes simplex Virus-1 encephalitis in adults: pathophysiology, diagnosis, and management. Neurotherapeutics 13:493–508Google Scholar
  19. Brankin B, Hart MN, Cosby SL, Fabry Z, Allen IV (1995) Adhesion molecule expression and lymphocyte adhesion to cerebral endothelium: effects of measles virus and herpes simplex 1 virus. J Neuroimmunol 56:1–8Google Scholar
  20. Broux B, Gowing E, Prat A (2015) Glial regulation of the blood-brain barrier in health and disease. Semin Immunopathol 37:577–590Google Scholar
  21. Burda JE, Sofroniew MV (2014) Reactive gliosis and the multicellular response to CNS damage and disease. Neuron 81:229–248Google Scholar
  22. Carpen O, Pallai P, Staunton DE, Springer TA (1992) Association of intercellular adhesion molecule-1 (ICAM-1) with actin-containing cytoskeleton and alpha-actinin. J Cell Biol 118:1223–1234Google Scholar
  23. Carvey PM, Hendey B, Monahan AJ (2009) The blood-brain barrier in neurodegenerative disease: a rhetorical perspective. J Neurochem 111:291–314Google Scholar
  24. Chang CY, Li JR, Chen WY, Ou YC, Lai CY, Hu YH, Wu CC, Chang CJ, Chen CJ (2015) Disruption of in vitro endothelial barrier integrity by Japanese encephalitis virus-infected astrocytes. Glia 63:1915–1932Google Scholar
  25. Chapouly C, Tadesse Argaw A, Horng S, Castro K, Zhang J, Asp L, Loo H, Laitman BM, Mariani JN, Straus Farber R, Zaslavsky E, Nudelman G, Raine CS, John GR (2015) Astrocytic TYMP and VEGFA drive blood–brain barrier opening in inflammatory central nervous system lesions. Brain 138:1548–1567Google Scholar
  26. Chen Y, McCarron RM, Golech S, Bembry J, Ford B, Lenz FA, Azzam N, Spatz M (2003) ET-1- and NO-mediated signal transduction pathway in human brain capillary endothelial cells. Am J Physiol Cell Physiol 284:C243–C249Google Scholar
  27. Chen CJ, Ou YC, Li JR, Chang CY, Pan HC, Lai CY, Liao SL, Raung SL, Chang CJ (2014) Infection of pericytes in vitro by Japanese encephalitis virus disrupts the integrity of the endothelial barrier. J Virol 88:1150–1161Google Scholar
  28. Chu H, Xiang J, Wu P, Su J, Ding H (2014) The role of aquaporin 4 in apoptosis after intracerebral hemorrhage. J Neuroinflammation 11:1–12Google Scholar
  29. Clayton A, Evans RA, Pettit E, Hallett M, Williams JD, Steadman R (1998) Cellular activation through the ligation of intercellular adhesion molecule-1. J Cell Sci 111(Pt 4):443–453Google Scholar
  30. Croen KD (1993) Evidence for an antiviral effect of nitric oxide. J Clin Invest 91:2446–2452Google Scholar
  31. Cummins PM (2011) Occludin: one protein, many forms. Mol Cell Biol 32:242–250Google Scholar
  32. Daneman R, Prat A (2015) The blood–brain barrier. Cold Spring Harb Perspect Biol 7:a20412Google Scholar
  33. Davis LE, Johnson RT (1979) An explanation for the localization of herpes simplex encephalitis? Ann Neurol 5:2–5Google Scholar
  34. Deng, S, Liu, H, Qiu, K, You, H, Lei, Q, Lu, W (2017) Role of the Golgi apparatus in the blood-brain barrier: Golgi protection may be a targeted therapy for neurological diseases. Mol Neurobiol 1-14Google Scholar
  35. Derakhshan M (2006) Human herpesvirus 1 protein US3 induces an inhibition of mitochondrial electron transport. J Gen Virol 87:2155–2159Google Scholar
  36. Di Cara G, Marabeti M, Musso R, Riili I, Cancemi P, Pucci Minafra I (2018) New insights into the occurrence of matrix metalloproteases −2 and −9 in a cohort of breast Cancer patients and proteomic correlations. Cells 7:89Google Scholar
  37. Dietrich JB (2002) The adhesion molecule ICAM-1 and its regulation in relation with the blood-brain barrier. J Neuroimmunol 128:58–68Google Scholar
  38. DiMauro S, Davidzon G (2009) Mitochondrial DNA and disease. Ann Med 37:222–232Google Scholar
  39. Ding R, Chen Y, Yang S, Deng X, Fu Z, Feng L, Cai Y, Du M, Zhou Y, Tang Y (2014) Blood–brain barrier disruption induced by hemoglobin in vivo: involvement of up-regulation of nitric oxide synthase and peroxynitrite formation. Brain Res 1571:25–38Google Scholar
  40. Dobbie MS, Hurst RD, Klein NJ, Surtees RA (1999) Upregulation of intercellular adhesion molecule-1 expression on human endothelial cells by tumour necrosis factor-a in an in vitro model of the blood – brain barrier. Brain Res 830:330–336Google Scholar
  41. Dohgu S, Takata F, Yamauchi A, Nakagawa S, Egawa T, Naito M, Tsuruo T, Sawada Y, Niwa M, Kataoka Y (2005) Brain pericytes contribute to the induction and up-regulation of blood–brain barrier functions through transforming growth factor-β production. Brain Res 1038:208–215Google Scholar
  42. Duguay BA, Smiley JR (2013) Mitochondrial nucleases ENDOG and EXOG participate in mitochondrial DNA depletion initiated by herpes simplex virus 1 UL12.5. J Virol 87:11787–11797Google Scholar
  43. Elias BC, Suzuki T, Seth A, Giorgianni F, Kale G, Shen L, Turner JR, Naren A, Desiderio DM, Rao R (2008) Phosphorylation of Tyr-398 and Tyr-402 in Occludin prevents its interaction with ZO-1 and destabilizes its assembly at the tight junctions. J Biol Chem 284:1559–1569Google Scholar
  44. Esiri MM (1982) Herpes simplex encephalitis. An immunohistological study of the distribution of viral antigen within the brain. J Neurol Sci 54:209–226Google Scholar
  45. Etienne-Manneville S, Manneville JB, Adamson P, Wilbourn B, Greenwood J, Couraud PO (2000) ICAM-1-coupled cytoskeletal rearrangements and transendothelial lymphocyte migration involve intracellular calcium signaling in brain endothelial cell lines. J Immunol 165:3375–3383Google Scholar
  46. Fan J, Hu Z, Zeng L, Lu W, Tang X, Zhang J, Li T (2008) Golgi apparatus and neurodegenerative diseases. Int J Dev Neurosci 26:523–534Google Scholar
  47. Fanning AS (2002) Isolation and functional characterization of the actin-binding region in the tight junction protein ZO-1. FASEB J 16:1835–1837Google Scholar
  48. Fanning AS, Jameson BJ, Jesaitis LA, Anderson JM (1998) The tight junction protein ZO-1 establishes a link between the transmembrane protein occludin and the actin cytoskeleton. J Biol Chem 273:29745–29753Google Scholar
  49. Feldman LTEA (2002) Spontaneous molecular reactivation of herpes simplex virus type 1 latency in mice. Proc Natl Acad Sci U S A 99:978–983Google Scholar
  50. Feng S, Cen J, Huang Y, Shen H, Yao L, Wang Y, Chen Z (2011) Matrix metalloproteinase-2 and -9 secreted by leukemic cells increase the permeability of blood-brain barrier by disrupting tight junction proteins. PLoS One 6:e20599Google Scholar
  51. Fujii S, Akaike T, Maeda H (1999) Role of nitric oxide in pathogenesis of herpes simplex virus encephalitis in rats. Virology 256:203–212Google Scholar
  52. Fukumura D, Gohongi T, Kadambi A, Izumi Y, Ang J, Yun CO, Buerk DG, Huang PL, Jain RK (2001) Predominant role of endothelial nitric oxide synthase in vascular endothelial growth factor-induced angiogenesis and vascular permeability. Proc Natl Acad Sci U S A 98:2604–2609Google Scholar
  53. Furr SR, Chauhan VS, Moerdyk-Schauwecker MJ, Marriott I (2011) A role for DNA-dependent activator of interferon regulatory factor in the recognition of herpes simplex virus type 1 by glial cells. J Neuroinflammation 8:99–111Google Scholar
  54. Fuyuko Takata SDJM, Eriko Harada HMMK (2011) Brain pericytes among cells constituting the blood-brain barrier are highly sensitive to tumor necrosis factor-a, releasing matrix metalloproteinase-9 and migrating in vitro. J Neuroinflammation 8:106–118Google Scholar
  55. Galdiero S, Valiante S, Falanga A, Cigliano L, Iachetta G, Busiello RA, La Marca V, Galdiero M, Lombardi A (2015) Peptide gH625 enters into neuron and astrocyte cell lines and crosses the blood–brain barrier in rats. Int J Nanomedicine 10:1885–1898Google Scholar
  56. Garcia JG, Davis HW, Patterson CE (1995) Regulation of endothelial cell gap formation and barrier dysfunction: role of myosin light chain phosphorylation. J Cell Physiol 163:510–522Google Scholar
  57. Gonzalez-Mariscal, L, ABPN (2003). Tight junction proteins. Prog Biophys Mol Biol 81, 1–44Google Scholar
  58. Hamann GF, Okada Y, Fitridge R, Del ZG (1995) Microvascular basal lamina antigens disappear during cerebral ischemia and reperfusion. Stroke 26:2120–2126Google Scholar
  59. Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10:1387–1394Google Scholar
  60. Haseloff RF, Dithmer S, Winkler L, Wolburg H, Blasig IE (2015) Transmembrane proteins of the tight junctions at the blood–brain barrier: structural and functional aspects. Semin Cell Dev Biol 38:16–25Google Scholar
  61. Hayashi K, Nakao S, Nakaoke R, Nakagawa S, Kitagawa N, Niwa M (2004) Effects of hypoxia on endothelial/pericytic co-culture model of the blood–brain barrier. Regul Pept 123:77–83Google Scholar
  62. Hill J, Rom S, Ramirez SH, Persidsky Y (2014) Emerging roles of Pericytes in the regulation of the neurovascular unit in health and disease. J NeuroImmune Pharmacol 9:591–605Google Scholar
  63. Hirase T, Kawashima S, Wong EYM, Ueyama T, Rikitake Y, Tsukita S, Yokoyama M, Staddon JM (2001) Regulation of tight junction permeability and Occludin phosphorylation by RhoA-p160ROCK-dependent and -independent mechanisms. J Biol Chem 276:10423–10431Google Scholar
  64. Hjalmarsson A, Blomqvist P, Skoldenberg B (2007) Herpes simplex encephalitis in Sweden, 1990-2001: incidence, morbidity, and mortality. Clin Infect Dis 45:875–880Google Scholar
  65. Hsieh HL, Wang HH, Wu WB, Chu PJ, Yang CM (2010) Transforming growth factor-beta1 induces matrix metalloproteinase-9 and cell migration in astrocytes: roles of ROS-dependent ERK- and JNK-NF-kappaB pathways. J Neuroinflammation 7:88–105Google Scholar
  66. Hu S, Sheng WS, Schachtele SJ, Lokensgard JR (2011) Reactive oxygen species drive herpes simplex virus (HSV)-1-induced proinflammatory cytokine production by murine microglia. J Neuroinflammation 8:123–132Google Scholar
  67. Huang J, Han S, Sun Q, Zhao Y, Liu J, Yuan X, Mao W, Peng B, Liu W, Yin J, He X (2017) Kv1.3 channel blocker (ImKTx88) maintains blood–brain barrier in experimental autoimmune encephalomyelitis. Cell Biosci 7:31–44Google Scholar
  68. Jennische E, Eriksson CE, Lange S, Trybala E, Bergström T (2015) The anterior commissure is a pathway for contralateral spread of herpes simplex virus type 1 after olfactory tract infection. J Neurovirol 21:129–147Google Scholar
  69. Jung JS, Bhat RV, Preston GM, Guggino WB, Baraban JM, Agre P (1994) Molecular characterization of an aquaporin cDNA from brain: candidate osmoreceptor and regulator of water balance. Proc Natl Acad Sci U S A 91:13052–13056Google Scholar
  70. Kettenmann H, Hanisch UK, Noda M, Verkhratsky A (2011) Physiology of microglia. Physiol Rev 91:461–553Google Scholar
  71. Kiening KL, Landeghem F, Schreiber S, Thomale UW, Deimling AV (2002) Decreased hemispheric Aquaporin-4 is linked to evolving brain edema following controlled cortical impact injury in rats. Neurosci Lett 324:105–108Google Scholar
  72. Kim YC, Bang D, Lee K, Lee S (2000) The effect of herpesvirus infection on the expression of cell adhesion molecules on cultured human dermal microvascular endothelial cells. J Dermatol Sci 24:38–47Google Scholar
  73. Ko A, Kim JY, Hyun H, Kim J (2015a) Endothelial NOS activation induces the blood–brain barrier disruption via ER stress following status epilepticus. Brain Res 1622:163–173Google Scholar
  74. Ko A, Kim JY, Hyun H, Kim J (2015b) Endothelial NOS activation induces the blood–brain barrier disruption via ER stress following status epilepticus. Brain Res 1622:163–173Google Scholar
  75. Kolb SA, Lahrtz F, Paul R, Leppert D, Nadal D, Pfister HW, Fontana A (1998) Matrix metalloproteinases and tissue inhibitors of metalloproteinases in viral meningitis: upregulation of MMP-9 and TIMP-1 in cerebrospinal fluid. J Neuroimmunol 84:143–150Google Scholar
  76. Kreutzberg GW (1996) Microglia: a sensor for pathological events in the CNS. Trends Neurosci 19:312–318Google Scholar
  77. Kumaraswamy GK, Fu MM, Docherty JJ (2006) Innate and adaptive host response during the initial phase of herpes simplex virus encephalitis in the neonatal mouse. J Neurovirol 12:365–374Google Scholar
  78. Lai C, Kuo K, Leo JM (2005) Critical role of actin in modulating BBB permeability. Brain Res Rev 50:7–13Google Scholar
  79. Lee C, Wu C, Chiang Y, Chen Y, Chang K, Chuang C, Lee I (2018) Carbon monoxide releasing molecule-2 attenuates Pseudomonas aeruginosa-induced ROS-dependent ICAM-1 expression in human pulmonary alveolar epithelial cells. Redox Biol 18:93–103Google Scholar
  80. Leuzinger H, Ziegler U, Schraner EM, Fraefel C, Glauser DL, Heid I, Ackermann M, Mueller M, Wild P (2005) Herpes simplex virus 1 envelopment follows two diverse pathways. J Virol 79:13047–13059Google Scholar
  81. Lewandowski G, Hobbs MV (1998) Evidence for deficiencies in intracerebral cytokine production, adhesion molecule induction, and T cell recruitment in herpes simplex virus type-2 infected mice. J Neuroimmunol 81:58–65Google Scholar
  82. Li T, You H, Zhang J, Mo X, He W, Chen Y, Tang X, Jiang Z, Tu R, Zeng L, Lu W, Hu Z (2014) Study of GOLPH3: a potential stress-inducible protein from Golgi apparatus. Mol Neurobiol 49:1449–1459Google Scholar
  83. Li W, Qi K, Wang Z, Gu M, Chen G, Guo F, Wang Z (2015) Golgi phosphoprotein 3 regulates metastasis of prostate cancer via matrix metalloproteinase 9. Int J Clin Exp Pathol 8:3691–3700Google Scholar
  84. Li T, You H, Mo X, He W, Tang X, Jiang Z, Chen S, Chen Y, Zhang J, Hu Z (2016) GOLPH3 mediated Golgi stress response in modulating N2A cell death upon oxygen-glucose deprivation and Reoxygenation injury. Mol Neurobiol 53:1377–1385Google Scholar
  85. Lima GK, Zolini GP, Mansur DS, Freire Lima BH, Wischhoff U, Astigarraga RG, Dias MF, Silva MDGA, Béla SR, Do Valle Antonelli LR, Arantes RM, Gazzinelli RT, Báfica A, Kroon EG, Campos MA (2010) Toll-like receptor (TLR) 2 and TLR9 expressed in trigeminal ganglia are critical to viral control during herpes simplex virus 1 infection. Am J Pathol 177:2433–2445Google Scholar
  86. Lind L, Studahl M, Persson Berg L, Eriksson K (2017) CXCL11 production in cerebrospinal fluid distinguishes herpes simplex meningitis from herpes simplex encephalitis. J Neuroinflammation 14:134Google Scholar
  87. Liu B, Hong JS (2003) Role of microglia in inflammation-mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention. J Pharmacol Exp Ther 304:1–7Google Scholar
  88. Lokensgard JR, Hu S, Sheng W, VanOijen M, Cox D, Cheeran MC, Peterson PK (2001) Robust expression of TNF-alpha, IL-1beta, RANTES, and IP-10 by human microglial cells during nonproductive infection with herpes simplex virus. J Neuro-Oncol 7:208–219Google Scholar
  89. Lokensgard JR, Cheeran MC, Hu S, Gekker G, Peterson PK (2002) Glial cell responses to herpesvirus infections: role in defense and immunopathogenesis. J Infect Dis 186(Suppl 2):S171–S179Google Scholar
  90. Lundberg P, Ramakrishna C, Brown J, Tyszka JM, Hamamura M, Hinton DR, Kovats S, Nalcioglu O, Weinberg K, Openshaw H, Cantin EM (2008a) The immune response to herpes simplex virus type 1 infection in susceptible mice is a major cause of central nervous system pathology resulting in fatal encephalitis. J Virol 82:7078–7088Google Scholar
  91. Lundberg P, Ramakrishna C, Brown J, Tyszka JM, Hamamura M, Hinton DR, Kovats S, Nalcioglu O, Weinberg K, Openshaw H, Cantin EM (2008b) The immune response to herpes simplex virus type 1 infection in susceptible mice is a major cause of central nervous system pathology resulting in fatal encephalitis. J Virol 82:7078–7088Google Scholar
  92. Manley GT, Fujimura M, Ma T, Noshita N, Filiz F, Bollen AW, Chan P, Verkman AS (2000) Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke. Nat Med 6:159–163Google Scholar
  93. Mantovani A (1999) The chemokine system: redundancy for robust outputs. Immunol Today 20:254–257Google Scholar
  94. Maragakis NJ, Rothstein JD (2006) Mechanisms of disease: astrocytes in neurodegenerative disease. Nat Clin Pract Neurol 2:679–689Google Scholar
  95. Margolis TP, Imai Y, Yang L, Vallas V, Krause PR (2007) Herpes simplex virus type 2 (HSV-2) establishes latent infection in a different population of ganglionic neurons than HSV-1: role of latency-associated transcripts. J Virol 81:1872–1878Google Scholar
  96. Mark KS, Burroughs AR, Brown RC, Huber JD, Davis TP (2004) Nitric oxide mediates hypoxia-induced changes in paracellular permeability of cerebral microvasculature. AJP: Heart and Circulatory Physiology 286:174H–180HGoogle Scholar
  97. Marques CP, Cheeran MC, Palmquist JM, Hu S, Lokensgard JR (2008a) Microglia are the major cellular source of iNOS during experimental herpes encephalitis. J Neurovirol 14:229–238Google Scholar
  98. Marques CP, Cheeran MC, Palmquist JM, Hu S, Lokensgard JR (2008b) Prolonged microglial cell activation and lymphocyte infiltration following experimental herpes Encephalitis1. J Immunol 181:6417–6426Google Scholar
  99. Martínez-Torres FJ, Wagner S, Haas J, Kehm R, Sellner J, Hacke W, Meyding-Lamadé U (2004) Increased presence of matrix metalloproteinases 2 and 9 in short- and long-term experimental herpes simplex virus encephalitis. Neurosci Lett 368:274–278Google Scholar
  100. Mathiisen TM, Lehre KP, Danbolt NC, Ottersen OP (2010) The perivascular astroglial sheath provides a complete covering of the brain microvessels: an electron microscopic 3D reconstruction. Glia 58:1094–1103Google Scholar
  101. Mettenleiter TC (2004) Budding events in herpesvirus morphogenesis. Virus Res 106:167–180Google Scholar
  102. Meyding-Lamade U, Haas J, Lamade W, Stingele K, Kehm R, Fath A, Heinrich K, Storch HB, Wildemann B (1998) Herpes simplex virus encephalitis: long-term comparative study of viral load and the expression of immunologic nitric oxide synthase in mouse brain tissue. Neurosci Lett 244:9–12Google Scholar
  103. Meyding-Lamade U, Lamade W, Kehm R, Oberlinner C, Fath A, Wildemann B, Haas J, Hacke W (1999a) Herpes simplex virus encephalitis: chronic progressive cerebral MRI changes despite good clinical recovery and low viral load - an experimental mouse study. Eur J Neurol 6:531–538Google Scholar
  104. Meyding-Lamade UK, Lamade WR, Wildemann BT, Sartor K, Hacke W (1999b) Herpes simplex virus encephalitis: chronic progressive cerebral magnetic resonance imaging abnormalities in patients despite good clinical recovery. Clin Infect Dis 28:148–149Google Scholar
  105. Meyding-Lamade U, Seyfer S, Haas J, Dvorak F, Kehm R, Lamade W, Hacke W, Wildemann B (2002) Experimental herpes simplex virus encephalitis: inhibition of the expression of inducible nitric oxide synthase in mouse brain tissue. Neurosci Lett 318:21–24Google Scholar
  106. Milatovic D, Zhang Y, Olson SJ, Montine KS, Roberts LN, Morrow JD, Montine TJ, Dermody TS, Valyi-Nagy T (2002) Herpes simplex virus type 1 encephalitis is associated with elevated levels of F2-isoprostanes and F4-neuroprostanes. J Neuro-Oncol 8:295–305Google Scholar
  107. Morita K, Sasaki H, Furuse M, Tsukita S (1999) Endothelial claudin: claudin-5/TMVCF constitutes tight junction strands in endothelial cells. J Cell Biol 147:185–194Google Scholar
  108. Murata T, Goshima F, Daikoku T, Inagaki-Ohara K, Takakuwa H (2000) Mitochondrial distribution and function in herpes simplex virus-infected cells. J Gen Virol 81:401–406Google Scholar
  109. Ozaki H, Ishii K, Arai H, Horiuchi H, Kawamoto T, Suzuki H, Kita T (2000) Junctional adhesion molecule (JAM) is phosphorylated by protein kinase C upon platelet activation. Biochem Biophys Res Commun 276:873–878Google Scholar
  110. Papadopoulos MC, Verkman AS (2005) Aquaporin-4 gene disruption in mice reduces brain swelling and mortality in pneumococcal meningitis. J Biol Chem 280:13906–13912Google Scholar
  111. Pirici I, Balsanu T, Bogdan C, Margaritescu C, Divan T, Vitalie V, Mogoanta L, Pirici D, Carare R, Muresanu D (2018) Inhibition of Aquaporin-4 improves the outcome of Ischaemic stroke and modulates brain Paravascular drainage pathways. Int J Mol Sci 19:46Google Scholar
  112. Polster BM, Fiskum G (2004) Mitochondrial mechanisms of neural cell apoptosis. J Neurochem 90:1281–1289Google Scholar
  113. Proescholdt MA, Jacobson S, Tresser N, Oldfield EH, Merrill MJ (2002) Vascular endothelial growth factor is expressed in multiple sclerosis plaques and can induce inflammatory lesions in experimental allergic encephalomyelitis rats. J Neuropathol Exp Neurol 61:914–925Google Scholar
  114. Rahman A, Anwar KN, Malik AB (2000) Protein kinase C-zeta mediates TNF-alpha-induced ICAM-1 gene transcription in endothelial cells. Am J Phys Cell Phys 279:C906–C914Google Scholar
  115. Read SJ, Kurtz JB (1999) Laboratory diagnosis of common viral infections of the central nervous system by using a single multiplex PCR screening assay. J Clin Microbiol 37:1352–1355Google Scholar
  116. Reinert LS, Lopušná K, Winther H, Sun C, Thomsen MK, Nandakumar R, Mogensen TH, Meyer M, Vægter C, Nyengaard JR, Fitzgerald KA, Paludan SR (2016) Sensing of HSV-1 by the cGAS–STING pathway in microglia orchestrates antiviral defence in the CNS. Nat Commun 7:1–12Google Scholar
  117. Roe K, Orillo B, Verma S (2014) West Nile virus-induced cell adhesion molecules on human brain microvascular endothelial cells regulate leukocyte adhesion and modulate permeability of the in vitro blood-brain barrier model. PLoS One 9:e102598Google Scholar
  118. Rosenberger J, Petrovics G, Buzas B (2001) Oxidative stress induces proorphanin FQ and proenkephalin gene expression in astrocytes through p38- and ERK-MAP kinases and NF-kappaB. J Neurochem 79:35–44Google Scholar
  119. Saffran HA, Pare JM, Corcoran JA, Weller SK, Smiley JR (2007) Herpes simplex virus eliminates host mitochondrial DNA. EMBO Rep 8:188–193Google Scholar
  120. Sangwung P, Greco TM, Wang Y, Ischiropoulos H, Sessa WC, Iwakiri Y (2012) Proteomic identification of S-nitrosylated Golgi proteins: new insights into endothelial cell regulation by eNOS-derived NO. PLoS One 7:e31564Google Scholar
  121. Saraya AW, Wacharapluesadee S, Petcharat S, Sittidetboripat N, Ghai S, Wilde H, Hemachudha T (2016) Normocellular CSF in herpes simplex encephalitis. BMC Res Notes 9:95Google Scholar
  122. Schmutzhard E (2001) Viral infections of the CNS with special emphasis on herpes simplex infections. J Neurol 248:469–477Google Scholar
  123. Schreibelt G, Kooij G, Reijerkerk A, van Doorn R, Gringhuis SI, van der Pol S, Weksler BB, Romero IA, Couraud PO, Piontek J, Blasig IE, Dijkstra CD, Ronken E, de Vries HE (2007) Reactive oxygen species alter brain endothelial tight junction dynamics via RhoA, PI3 kinase, and PKB signaling. FASEB J 21:3666–3676Google Scholar
  124. Sellner J, Dvorak F, Zhou Y, Haas J, Kehm R, Wildemann B, Meyding-Lamadè U (2005) Acute and long-term alteration of chemokine mRNA expression after anti-viral and anti-inflammatory treatment in herpes simplex virus encephalitis. Neurosci Lett 374:197–202Google Scholar
  125. Sellner J, Simon F, Meyding-Lamade U, Leib SL (2006) Herpes-simplex virus encephalitis is characterized by an early MMP-9 increase and collagen type IV degradation. Brain Res 1125:155–162Google Scholar
  126. Shen L, Black ED, Witkowski ED, Lencer WI, Guerriero V, Schneeberger EE, Turner JR (2006) Myosin light chain phosphorylation regulates barrier function by remodeling tight junction structure. J Cell Sci 119:2095–2106Google Scholar
  127. Shivkumar M, Milho R, May JS, Nicoll MP, Efstathiou S, Stevenson PG (2013) Herpes simplex virus 1 targets the murine olfactory Neuroepithelium for host entry. J Virol 87:10477–10488Google Scholar
  128. Shukla A, Dikshit M, Srimal RC (1995) Nitric oxide modulates blood-brain barrier permeability during infections with an inactivated bacterium. Neuroreport 6:1629–1632Google Scholar
  129. Simko JP, Caliendo AM, Hogle K, Versalovic J (2002) Differences in laboratory findings for cerebrospinal fluid specimens obtained from patients with meningitis or encephalitis due to herpes simplex virus (HSV) documented by detection of HSV DNA. Clin Infect Dis 35:414–419Google Scholar
  130. Sobel RA, Mitchell ME, Fondren G (1990) Intercellular adhesion molecule-1 (ICAM-1) in cellular immune reactions in the human central nervous system. Am J Pathol 136:1309–1316Google Scholar
  131. Sofroniew MV (2005) Reactive astrocytes in neural repair and protection. Neuroscientist 11:400–407Google Scholar
  132. Sofroniew MV (2009) Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci 32:638–647Google Scholar
  133. Sofroniew MV (2015) Astrogliosis. Cold Spring Harb Perspect Biol 7:a20420Google Scholar
  134. Sofroniew MV, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol 119:7–35Google Scholar
  135. Spindler KR, Hsu T (2012) Viral disruption of the blood–brain barrier. Trends Microbiol 20:282–290Google Scholar
  136. Stamatovic SM, Keep RF, Kunkel SL, Andjelkovic AV (2003) Potential role of MCP-1 in endothelial cell tight junction 'opening': signaling via rho and rho kinase. J Cell Sci 116:4615–4628Google Scholar
  137. Stamatovic SM, Dimitrijevic OB, Keep RF, Andjelkovic AV (2006) Protein kinase C -RhoA cross-talk in CCL2-induced alterations in brain endothelial permeability. J Biol Chem 281:8379–8388Google Scholar
  138. Stamatovic SM, Johnson AM, Keep RF, Andjelkovic AV (2016) Junctional proteins of the blood-brain barrier: new insights into function and dysfunction. Tissue Barriers 4:e1154641Google Scholar
  139. Steiner I (2011) Herpes simplex virus encephalitis: new infection or reactivation? Curr Opin Neurol 24:268–274Google Scholar
  140. Stroop WG, McKendall RR, Battles EJ, Schaefer DC, Jones B (1990) Spread of herpes simplex virus type 1 in the central nervous system during experimentally reactivated encephalitis. Microb Pathog 8:119–134Google Scholar
  141. Sutter E, de Oliveira AP, Tobler K, Schraner EM, Sonda S, Kaech A, Lucas MS, Ackermann M, Wild P (2012) Herpes simplex virus 1 induces de novo phospholipid synthesis. Virology 429:124–135Google Scholar
  142. Taskinen E, Koskiniemi ML, Vaheri A (1984) Herpes simplex virus encephalitis. Prolonged intrathecal IgG synthesis and cellular activity in the cerebrospinal fluid with transient impairment of blood-brain barrier. J Neurol Sci 63:331–338Google Scholar
  143. Thomsen LB, Burkhart A, Moos T (2015) A triple culture model of the blood-brain barrier using porcine brain endothelial cells, astrocytes and Pericytes. PLoS One 10:e134765Google Scholar
  144. Torres FM, Völcker D, Dörner N, Lenhard T, Nielsen S, Haas J, Kiening K, Meyding-Lamadé U (2007) Aquaporin 4 regulation during acute and long-term experimental herpes simplex virus encephalitis. J Neurovirol 13:38–46Google Scholar
  145. Uchida T, Mori M, Uzawa A, Masuda H, Muto M, Ohtani R, Kuwabara S (2017) Increased cerebrospinal fluid metalloproteinase-2 and interleukin-6 are associated with albumin quotient in neuromyelitis optica: their possible role on blood-brain barrier disruption. Mult Scler 23:1072–1084Google Scholar
  146. van Wetering S, van den Berk N, van Buul JD, Mul FPJ, Lommerse I, Mous R, Klooster JPT, Zwaginga JJ, Hordijk PL (2003) VCAM-1-mediated Rac signaling controls endothelial cell-cell contacts and leukocyte transmigration. Am J Physiol Cell Physiol 285:C343–C352Google Scholar
  147. Wang R, Ke Z, Wang F, Zhang W, Wang Y, Li S, Wang L (2015a) GOLPH3 overexpression is closely correlated with poor prognosis in human non-small cell lung Cancer and mediates its metastasis through upregulating MMP-2 and MMP-9. Cell Physiol Biochem 35:969–982Google Scholar
  148. Wang Y, Wang N, Cai B, Wang GY, Li J, Piao XX (2015b) In vitro model of the blood-brain barrier established by co-culture of primary cerebral microvascular endothelial and astrocyte cells. Neural Regen Res 10:2011–2017Google Scholar
  149. Whitley RJ (2006) Herpes simplex encephalitis: adolescents and adults. Antivir Res 71:141–148Google Scholar
  150. Wolburg H, Wolburg-Buchholz K, Kraus J, Rascher-Eggstein G, Liebner S, Hamm S, Duffner F, Grote EH, Risau W, Engelhardt B (2003) Localization of claudin-3 in tight junctions of the blood-brain barrier is selectively lost during experimental autoimmune encephalomyelitis and human glioblastoma multiforme. Acta Neuropathol 105:586–592Google Scholar
  151. Wong D, Dorovini-Zis K, Vincent SR (2004) Cytokines, nitric oxide, and cGMP modulate the permeability of an in vitro model of the human blood–brain barrier. Exp Neurol 190:446–455Google Scholar
  152. Wu M, Tsirka SE (2009) Endothelial NOS-deficient mice reveal dual roles for nitric oxide during experimental autoimmune encephalomyelitis. Glia 57:1204–1215Google Scholar
  153. Yamamoto M, Ramirez SH, Sato S, Kiyota T, Cerny RL, Kaibuchi K, Persidsky Y, Ikezu T (2008) Phosphorylation of Claudin-5 and Occludin by rho kinase in brain endothelial cells. Am J Pathol 172:521–533Google Scholar
  154. Yang Y, Estrada EY, Thompson JF, Liu W, Rosenberg GA (2007) Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. J Cereb Blood Flow Metab 27:697–709Google Scholar
  155. Yang Y, Zhang Y, Wang Z, Wang S, Gao M, Xu R, Liang C, Zhang H (2016) Attenuation of acute phase injury in rat intracranial hemorrhage by Cerebrolysin that inhibits brain edema and inflammatory response. Neurochem Res 41:748–757Google Scholar
  156. Yechiel Schlesinger, PTMG, Storch, AGA (1995) Herpes Simplex Virus Type 2 Meningitis in the Absence of Genital Lesions: Improved Recognition with Use of the Polymerase Chain Reaction Author(s): Yechiel Schlesinger, Pablo Tebas, Monique Gaudreault-Keener, Richard S. Buller and Gregory A. Storch Source: Clinical Infectious Diseases, Vol. 20, No. 4 (Apr., 1995), pp. 842–848 Published by: Oxford University Press Stable URL: Accessed: 31-12-2016 05:35 UTC. Oxford University Press 4, 842–848
  157. You H, Li T, Zhang J, Lei Q, Tao X, Xie P, Lu W (2014) Reduction in ischemic cerebral infarction is mediated through golgi phosphoprotein 3 and Akt/mTOR signaling following salvianolate administration. Curr Neurovasc Res 11:107–113Google Scholar
  158. Yu-ping ZHU, TSYL (2013) Astragalus polysaccharides suppress ICAM-1 and VCAM-1 expression in TNF- α -treated human vascular endothelial cells by blocking NF- κ B activation. Acta Pharmacol Sin, 1036-1042Google Scholar
  159. Zhang L, Liu H, Peng YM, Dai YY, Liu FY (2015) Vascular endothelial growth factor increases GEnC permeability by affecting the distributions of occludin, ZO-1 and tight juction assembly. Eur Rev Med Pharmacol Sci 19:2621–2627Google Scholar
  160. Zhang HT, Zhang P, Gao Y, Li CL, Wang HJ, Chen LC, Feng Y, Li RY, Li YL, Jiang CL (2016) Early VEGF inhibition attenuates blood-brain barrier disruption in ischemic rat brains by regulating the expression of MMPs. Mol Med Rep 15:57–64Google Scholar
  161. Zhang HT, Zhang P, Gao Y, Li CL, Wang HJ, Chen LC, Feng Y, Li RY, Li YL, Jiang CL (2017) Early VEGF inhibition attenuates blood-brain barrier disruption in ischemic rat brains by regulating the expression of MMPs. Mol Med Rep 15:57–64Google Scholar
  162. Zhou Y, Lu ZN, Guo YJ, Mei YW (2010) Favorable effects of MMP-9 knockdown in murine herpes simplex encephalitis using small interfering RNA. Neurol Res 32:801–809Google Scholar
  163. Zhou Y, Zeng Y, Zhou Q, Guan J, Lu Z (2016a) The effect of captopril on the expression of MMP-9 and the prognosis of neurological function in herpes simplex encephalitis mice. Neurol Res 38:733–739Google Scholar
  164. Zhou Y, Zeng Y, Zhou Q, Guan J, Lu Z (2016b) The effect of cyclin-dependent kinases inhibitor treatment on experimental herpes simplex encephalitis mice. Neurosci Lett 627:71–76Google Scholar

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Authors and Affiliations

  1. 1.Department of Neurology, The Second Xiangya HospitalCentral South UniversityChangshaPeople’s Republic of China

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