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Factors controlling permeability of the blood–brain barrier

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Abstract

As the primary protective barrier for neurons in the brain, the blood–brain barrier (BBB) exists between the blood microcirculation system and the brain parenchyma. The normal BBB integrity is essential in protecting the brain from systemic toxins and maintaining the necessary level of nutrients and ions for neuronal function. This integrity is mediated by structural BBB components, such as tight junction proteins, integrins, annexins, and agrin, of a multicellular system including endothelial cells, astrocytes, pericytes, etc. BBB dysfunction is a significant contributor to the pathogeneses of a variety of brain disorders. Many signaling factors have been identified to be able to control BBB permeability through regulating the structural components. Among those signaling factors are inflammatory mediators, free radicals, vascular endothelial growth factor, matrix metalloproteinases, microRNAs, etc. In this review, we provide a summary of recent progress regarding these structural components and signaling factors, relating to their roles in various brain disorders. Attention is also devoted to recent research regarding impact of pharmacological agents such as isoflurane on BBB permeability and how iron ion passes across BBB. Hopefully, a better understanding of the factors controlling BBB permeability helps develop novel pharmacological interventions of BBB hyperpermeability under pathological conditions.

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References

  1. Daneman R, Prat A (2015) The blood–brain barrier. Cold Spring Harb Perspect Biol 7(1):a020412. doi:10.1101/cshperspect.a020412

    Article  PubMed  Google Scholar 

  2. Obermeier B, Daneman R, Ransohoff RM (2013) Development, maintenance and disruption of the blood–brain barrier. Nat Med 19(12):1584–1596. doi:10.1038/nm.3407

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  3. Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ (2010) Structure and function of the blood–brain barrier. Neurobiol Dis 37(1):13–25. doi:10.1016/j.nbd.2009.07.030

    Article  PubMed  CAS  Google Scholar 

  4. Persidsky Y, Ramirez SH, Haorah J, Kanmogne GD (2006) Blood–brain barrier: structural components and function under physiologic and pathologic conditions. J Neuroimmune Pharmacol 1(3):223–236. doi:10.1007/s11481-006-9025-3

    Article  PubMed  Google Scholar 

  5. Janzer RC, Raff MC (1987) Astrocytes induce blood–brain barrier properties in endothelial cells. Nature 325(6101):253–257. doi:10.1038/325253a0

    Article  PubMed  CAS  Google Scholar 

  6. Willis CL, Nolan CC, Reith SN, Lister T, Prior MJ, Guerin CJ, Mavroudis G, Ray DE (2004) Focal astrocyte loss is followed by microvascular damage, with subsequent repair of the blood–brain barrier in the apparent absence of direct astrocytic contact. Glia 45(4):325–337. doi:10.1002/glia.10333

    Article  PubMed  Google Scholar 

  7. 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. doi:10.1002/glia.22857

    Google Scholar 

  8. Armulik A, Genove G, Betsholtz C (2011) Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev Cell 21(2):193–215. doi:10.1016/j.devcel.2011.07.001

    Article  PubMed  CAS  Google Scholar 

  9. Winkler EA, Bell RD, Zlokovic BV (2011) Central nervous system pericytes in health and disease. Nat Neurosci 14(11):1398–1405. doi:10.1038/nn.2946

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  10. Spindler KR, Hsu TH (2012) Viral disruption of the blood–brain barrier. Trends Microbiol 20(6):282–290. doi:10.1016/j.tim.2012.03.009

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  11. Bai Y, Zhu X, Chao J, Zhang Y, Qian C, Li P, Liu D, Han B, Zhao L, Zhang J, Buch S, Teng G, Hu G, Yao H (2015) Pericytes contribute to the disruption of the cerebral endothelial barrier via increasing VEGF expression: implications for stroke. PLoS One 10(4):e0124362. doi:10.1371/journal.pone.0124362

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Zlokovic BV (2008) The blood–brain barrier in health and chronic neurodegenerative disorders. Neuron 57(2):178–201. doi:10.1016/j.neuron.2008.01.003

    Article  PubMed  CAS  Google Scholar 

  13. O’Shea E, Urrutia A, Green AR, Colado MI (2014) Current preclinical studies on neuroinflammation and changes in blood–brain barrier integrity by MDMA and methamphetamine. Neuropharmacology 87:125–134. doi:10.1016/j.neuropharm.2014.02.015

    Article  PubMed  CAS  Google Scholar 

  14. Correale J, Villa A (2007) The blood–brain-barrier in multiple sclerosis: functional roles and therapeutic targeting. Autoimmunity 40(2):148–160. doi:10.1080/08916930601183522

    Article  PubMed  CAS  Google Scholar 

  15. Miyazaki K, Ohta Y, Nagai M, Morimoto N, Kurata T, Takehisa Y, Ikeda Y, Matsuura T, Abe K (2011) Disruption of neurovascular unit prior to motor neuron degeneration in amyotrophic lateral sclerosis. J Neurosci Res 89(5):718–728. doi:10.1002/jnr.22594

    Article  PubMed  CAS  Google Scholar 

  16. Garbuzova-Davis S, Hernandez-Ontiveros DG, Rodrigues MC, Haller E, Frisina-Deyo A, Mirtyl S, Sallot S, Saporta S, Borlongan CV, Sanberg PR (2012) Impaired blood–brain/spinal cord barrier in ALS patients. Brain Res 1469:114–128. doi:10.1016/j.brainres.2012.05.056

    Article  PubMed  CAS  Google Scholar 

  17. Sandoval KE, Witt KA (2008) Blood–brain barrier tight junction permeability and ischemic stroke. Neurobiol Dis 32(2):200–219. doi:10.1016/j.nbd.2008.08.005

    Article  PubMed  CAS  Google Scholar 

  18. Kratzer I, Chip S, Vexler ZS (2014) Barrier mechanisms in neonatal stroke. Front Neurosci 8:359. doi:10.3389/fnins.2014.00359

    Article  PubMed  PubMed Central  Google Scholar 

  19. Kahles T, Luedike P, Endres M, Galla HJ, Steinmetz H, Busse R, Neumann-Haefelin T, Brandes RP (2007) NADPH oxidase plays a central role in blood–brain barrier damage in experimental stroke. Stroke 38(11):3000–3006. doi:10.1161/strokeaha.107.489765

    Article  PubMed  CAS  Google Scholar 

  20. Liu J, Jin X, Liu KJ, Liu W (2012) Matrix metalloproteinase-2-mediated occludin degradation and caveolin-1-mediated claudin-5 redistribution contribute to blood–brain barrier damage in early ischemic stroke stage. J Neurosci 32(9):3044–3057. doi:10.1523/jneurosci.6409-11.2012

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  21. Wolburg H, Neuhaus J, Kniesel U, Krauss B, Schmid EM, Ocalan M, Farrell C, Risau W (1994) Modulation of tight junction structure in blood–brain barrier endothelial cells. Effects of tissue culture, second messengers and cocultured astrocytes. J Cell Sci 107(Pt 5):1347–1357

    PubMed  CAS  Google Scholar 

  22. Hawkins BT, Davis TP (2005) The blood–brain barrier/neurovascular unit in health and disease. Pharmacol Rev 57(2):173–185. doi:10.1124/pr.57.2.4

    Article  PubMed  CAS  Google Scholar 

  23. Dobrogowska DH, Vorbrodt AW (2004) Immunogold localization of tight junctional proteins in normal and osmotically-affected rat blood–brain barrier. J Mol Histol 35(5):529–539

    Article  PubMed  CAS  Google Scholar 

  24. Wen H, Watry DD, Marcondes MC, Fox HS (2004) Selective decrease in paracellular conductance of tight junctions: role of the first extracellular domain of claudin-5. Mol Cell Biol 24(19):8408–8417. doi:10.1128/mcb.24.19.8408-8417.2004

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  25. Nitta T, Hata M, Gotoh S, Seo Y, Sasaki H, Hashimoto N, Furuse M, Tsukita S (2003) Size-selective loosening of the blood–brain barrier in claudin-5-deficient mice. J Cell Biol 161(3):653–660. doi:10.1083/jcb.200302070

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  26. Yan J, Zhang Z, Shi H (2012) HIF-1 is involved in high glucose-induced paracellular permeability of brain endothelial cells. Cell Mol Life Sci 69(1):115–128. doi:10.1007/s00018-011-0731-5

    Article  PubMed  CAS  Google Scholar 

  27. Pfeiffer F, Schafer J, Lyck R, Makrides V, Brunner S, Schaeren-Wiemers N, Deutsch U, Engelhardt B (2011) Claudin-1 induced sealing of blood–brain barrier tight junctions ameliorates chronic experimental autoimmune encephalomyelitis. Acta Neuropathol 122(5):601–614. doi:10.1007/s00401-011-0883-2

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  28. Lopez-Ramirez MA, Wu D, Pryce G, Simpson JE, Reijerkerk A, King-Robson J, Kay O, de Vries HE, Hirst MC, Sharrack B, Baker D, Male DK, Michael GJ, Romero IA (2014) MicroRNA-155 negatively affects blood–brain barrier function during neuroinflammation. FASEB J 28(6):2551–2565. doi:10.1096/fj.13-248880

    Article  PubMed  CAS  Google Scholar 

  29. Liebner S, Fischmann A, Rascher G, Duffner F, Grote EH, Kalbacher H, Wolburg H (2000) Claudin-1 and claudin-5 expression and tight junction morphology are altered in blood vessels of human glioblastoma multiforme. Acta Neuropathol 100(3):323–331

    Article  PubMed  CAS  Google Scholar 

  30. Fletcher NF, Wilson GK, Murray J, Hu K, Lewis A, Reynolds GM, Stamataki Z, Meredith LW, Rowe IA, Luo G, Lopez-Ramirez MA, Baumert TF, Weksler B, Couraud PO, Kim KS, Romero IA, Jopling C, Morgello S, Balfe P, McKeating JA (2012) Hepatitis C virus infects the endothelial cells of the blood–brain barrier. Gastroenterology 142(3):634–643.e636. doi:10.1053/j.gastro.2011.11.028

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  31. Tietz S, Engelhardt B (2015) Brain barriers: crosstalk between complex tight junctions and adherens junctions. J Cell Biol 209(4):493–506. doi:10.1083/jcb.201412147

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  32. Hynes RO (2002) Integrins: bidirectional, allosteric signaling machines. Cell 110(6):673–687

    Article  PubMed  CAS  Google Scholar 

  33. Giancotti FG, Ruoslahti E (1999) Integrin signaling. Science 285(5430):1028–1032

    Article  PubMed  CAS  Google Scholar 

  34. Huber JD, Egleton RD, Davis TP (2001) Molecular physiology and pathophysiology of tight junctions in the blood–brain barrier. Trends Neurosci 24(12):719–725

    Article  PubMed  CAS  Google Scholar 

  35. del Zoppo GJ, Milner R (2006) Integrin-matrix interactions in the cerebral microvasculature. Arterioscler Thromb Vasc Biol 26(9):1966–1975. doi:10.1161/01.ATV.0000232525.65682.a2

    Article  PubMed  CAS  Google Scholar 

  36. Proctor JM, Zang K, Wang D, Wang R, Reichardt LF (2005) Vascular development of the brain requires beta8 integrin expression in the neuroepithelium. J Neurosci 25(43):9940–9948. doi:10.1523/JNEUROSCI.3467-05.2005

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  37. Milner R, Huang X, Wu J, Nishimura S, Pytela R, Sheppard D, ffrench-Constant C (1999) Distinct roles for astrocyte alphavbeta5 and alphavbeta8 integrins in adhesion and migration. J Cell Sci 112(Pt 23):4271–4279

    PubMed  CAS  Google Scholar 

  38. Nguyen HL, Lee YJ, Shin J, Lee E, Park SO, McCarty JH, Oh SP (2011) TGF-beta signaling in endothelial cells, but not neuroepithelial cells, is essential for cerebral vascular development. Lab Invest 91(11):1554–1563. doi:10.1038/labinvest.2011.124

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  39. Arnold TD, Niaudet C, Pang MF, Siegenthaler J, Gaengel K, Jung B, Ferrero GM, Mukouyama YS, Fuxe J, Akhurst R, Betsholtz C, Sheppard D, Reichardt LF (2014) Excessive vascular sprouting underlies cerebral hemorrhage in mice lacking alphaVbeta8-TGFbeta signaling in the brain. Development 141(23):4489–4499. doi:10.1242/dev.107193

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  40. Wang J, Milner R (2006) Fibronectin promotes brain capillary endothelial cell survival and proliferation through alpha5beta1 and alphavbeta3 integrins via MAP kinase signalling. J Neurochem 96(1):148–159. doi:10.1111/j.1471-4159.2005.03521.x

    Article  PubMed  CAS  Google Scholar 

  41. Osada T, Gu YH, Kanazawa M, Tsubota Y, Hawkins BT, Spatz M, Milner R, del Zoppo GJ (2011) Interendothelial claudin-5 expression depends on cerebral endothelial cell-matrix adhesion by beta(1)-integrins. J Cereb Blood Flow Metab 31(10):1972–1985. doi:10.1038/jcbfm.2011.99

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  42. Milner R, Campbell IL (2002) Developmental regulation of beta1 integrins during angiogenesis in the central nervous system. Mol Cell Neurosci 20(4):616–626

    Article  PubMed  CAS  Google Scholar 

  43. Randi AM, Hogg N (1994) I domain of beta 2 integrin lymphocyte function-associated antigen-1 contains a binding site for ligand intercellular adhesion molecule-1. J Biol Chem 269(17):12395–12398

    PubMed  CAS  Google Scholar 

  44. Hermand P, Huet M, Callebaut I, Gane P, Ihanus E, Gahmberg CG, Cartron JP, Bailly P (2000) Binding sites of leukocyte beta 2 integrins (LFA-1, Mac-1) on the human ICAM-4/LW blood group protein. J Biol Chem 275(34):26002–26010. doi:10.1074/jbc.M002823200

    Article  PubMed  CAS  Google Scholar 

  45. Gorina R, Lyck R, Vestweber D, Engelhardt B (2014) beta2 integrin-mediated crawling on endothelial ICAM-1 and ICAM-2 is a prerequisite for transcellular neutrophil diapedesis across the inflamed blood–brain barrier. J Immunol 192(1):324–337. doi:10.4049/jimmunol.1300858

    Article  PubMed  CAS  Google Scholar 

  46. Hogg N, Patzak I, Willenbrock F (2011) The insider’s guide to leukocyte integrin signalling and function. Nat Rev Immunol 11(6):416–426. doi:10.1038/nri2986

    Article  PubMed  CAS  Google Scholar 

  47. Engelhardt B, Laschinger M, Schulz M, Samulowitz U, Vestweber D, Hoch G (1998) The development of experimental autoimmune encephalomyelitis in the mouse requires alpha4-integrin but not alpha4beta7-integrin. J Clin Invest 102(12):2096–2105. doi:10.1172/jci4271

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  48. Engelhardt B, Ransohoff RM (2012) Capture, crawl, cross: the T cell code to breach the blood–brain barriers. Trends Immunol 33(12):579–589. doi:10.1016/j.it.2012.07.004

    Article  PubMed  CAS  Google Scholar 

  49. Laschinger M, Engelhardt B (2000) Interaction of alpha4-integrin with VCAM-1 is involved in adhesion of encephalitogenic T cell blasts to brain endothelium but not in their transendothelial migration in vitro. J Neuroimmunol 102(1):32–43

    Article  PubMed  CAS  Google Scholar 

  50. Engelhardt B (2006) Molecular mechanisms involved in T cell migration across the blood–brain barrier. J Neural Transm 113(4):477–485. doi:10.1007/s00702-005-0409-y

    Article  PubMed  CAS  Google Scholar 

  51. Kawamoto E, Nakahashi S, Okamoto T, Imai H, Shimaoka M (2012) Anti-integrin therapy for multiple sclerosis. Autoimmune Dis 2012:357101. doi:10.1155/2012/357101

    PubMed  PubMed Central  Google Scholar 

  52. Haarmann A, Nowak E, Deiss A, van der Pol S, Monoranu CM, Kooij G, Muller N, van der Valk P, Stoll G, de Vries HE, Berberich-Siebelt F, Buttmann M (2015) Soluble VCAM-1 impairs human brain endothelial barrier integrity via integrin alpha-4-transduced outside-in signalling. Acta Neuropathol 129(5):639–652. doi:10.1007/s00401-015-1417-0

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  53. Chen W, Guo Y, Yang W, Zheng P, Zeng J, Tong W (2015) Protective effect of ginsenoside Rb1 on integrity of blood–brain barrier following cerebral ischemia. Exp Brain Res. doi:10.1007/s00221-015-4352-3

    Google Scholar 

  54. Wagner S, Tagaya M, Koziol JA, Quaranta V, del Zoppo GJ (1997) Rapid disruption of an astrocyte interaction with the extracellular matrix mediated by integrin alpha 6 beta 4 during focal cerebral ischemia/reperfusion. Stroke 28(4):858–865

    Article  PubMed  CAS  Google Scholar 

  55. Tagaya M, Haring HP, Stuiver I, Wagner S, Abumiya T, Lucero J, Lee P, Copeland BR, Seiffert D, del Zoppo GJ (2001) Rapid loss of microvascular integrin expression during focal brain ischemia reflects neuron injury. J Cereb Blood Flow Metab 21(7):835–846. doi:10.1097/00004647-200107000-00009

    Article  PubMed  CAS  Google Scholar 

  56. Haring HP, Akamine BS, Habermann R, Koziol JA, Del Zoppo GJ (1996) Distribution of integrin-like immunoreactivity on primate brain microvasculature. J Neuropathol Exp Neurol 55(2):236–245

    Article  PubMed  CAS  Google Scholar 

  57. Rice GP, Hartung HP, Calabresi PA (2005) Anti-alpha4 integrin therapy for multiple sclerosis: mechanisms and rationale. Neurology 64(8):1336–1342. doi:10.1212/01.WNL.0000158329.30470.D0

    Article  PubMed  CAS  Google Scholar 

  58. von Andrian UH, Engelhardt B (2003) Alpha4 integrins as therapeutic targets in autoimmune disease. N Engl J Med 348(1):68–72. doi:10.1056/NEJMe020157

    Article  Google Scholar 

  59. Schlaepfer DD, Haigler HT (1987) Characterization of Ca2+-dependent phospholipid binding and phosphorylation of lipocortin I. J Biol Chem 262(14):6931–6937

    PubMed  CAS  Google Scholar 

  60. Lim LH, Solito E, Russo-Marie F, Flower RJ, Perretti M (1998) Promoting detachment of neutrophils adherent to murine postcapillary venules to control inflammation: effect of lipocortin 1. Proc Natl Acad Sci USA 95(24):14535–14539

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  61. Solito E, de Coupade C, Parente L, Flower RJ, Russo-Marie F (1998) Human annexin 1 is highly expressed during the differentiation of the epithelial cell line A 549: involvement of nuclear factor interleukin 6 in phorbol ester induction of annexin 1. Cell Growth Differ 9(4):327–336

    PubMed  CAS  Google Scholar 

  62. McNeil AK, Rescher U, Gerke V, McNeil PL (2006) Requirement for annexin A1 in plasma membrane repair. J Biol Chem 281(46):35202–35207. doi:10.1074/jbc.M606406200

    Article  PubMed  CAS  Google Scholar 

  63. de Coupade C, Gillet R, Bennoun M, Briand P, Russo-Marie F, Solito E (2000) Annexin 1 expression and phosphorylation are upregulated during liver regeneration and transformation in antithrombin III SV40 T large antigen transgenic mice. Hepatology 31(2):371–380. doi:10.1002/hep.510310217

    Article  PubMed  Google Scholar 

  64. Solito E, de Coupade C, Canaider S, Goulding NJ, Perretti M (2001) Transfection of annexin 1 in monocytic cells produces a high degree of spontaneous and stimulated apoptosis associated with caspase-3 activation. Br J Pharmacol 133(2):217–228. doi:10.1038/sj.bjp.0704054

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  65. Solito E, McArthur S, Christian H, Gavins F, Buckingham JC, Gillies GE (2008) Annexin A1 in the brain—undiscovered roles? Trends Pharmacol Sci 29(3):135–142. doi:10.1016/j.tips.2007.12.003

    Article  PubMed  CAS  Google Scholar 

  66. Eberhard DA, Brown MD, VandenBerg SR (1994) Alterations of annexin expression in pathological neuronal and glial reactions. Immunohistochemical localization of annexins I, II (p36 and p11 subunits), IV, and VI in the human hippocampus. Am J Pathol 145(3):640–649

    PubMed  CAS  PubMed Central  Google Scholar 

  67. Herbert SP, Odell AF, Ponnambalam S, Walker JH (2007) The confluence-dependent interaction of cytosolic phospholipase A2-alpha with annexin A1 regulates endothelial cell prostaglandin E2 generation. J Biol Chem 282(47):34468–34478. doi:10.1074/jbc.M701541200

    Article  PubMed  CAS  Google Scholar 

  68. Smith T, Flower RJ, Buckingham JC (1993) Lipocortins 1, 2 and 5 in the central nervous system and pituitary gland of the rat: selective induction by dexamethasone of lipocortin 1 in the anterior pituitary gland. Mol Neuropharmacol 3(1):45–55

    CAS  Google Scholar 

  69. Johnson MD, Kamso-Pratt JM, Whetsell WO Jr, Pepinsky RB (1989) Lipocortin-1 immunoreactivity in the normal human central nervous system and lesions with astrocytosis. Am J Clin Pathol 92(4):424–429

    PubMed  CAS  Google Scholar 

  70. McKanna JA, Zhang MZ (1997) Immunohistochemical localization of lipocortin 1 in rat brain is sensitive to pH, freezing, and dehydration. J Histochem Cytochem 45(4):527–538

    Article  PubMed  CAS  Google Scholar 

  71. Dreier R, Schmid KW, Gerke V, Riehemann K (1998) Differential expression of annexins I, II and IV in human tissues: an immunohistochemical study. Histochem Cell Biol 110(2):137–148

    Article  PubMed  CAS  Google Scholar 

  72. Young KA, Hirst WD, Solito E, Wilkin GP (1999) De novo expression of lipocortin-1 in reactive microglia and astrocytes in kainic acid lesioned rat cerebellum. Glia 26(4):333–343

    Article  PubMed  CAS  Google Scholar 

  73. Gavins FN, Dalli J, Flower RJ, Granger DN, Perretti M (2007) Activation of the annexin 1 counter-regulatory circuit affords protection in the mouse brain microcirculation. FASEB J 21(8):1751–1758. doi:10.1096/fj.06-7842com

    Article  PubMed  CAS  Google Scholar 

  74. Dominguez R (2010) Structural insights into de novo actin polymerization. Curr Opin Struct Biol 20(2):217–225. doi:10.1016/j.sbi.2009.12.012

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  75. Cristante E, McArthur S, Mauro C, Maggioli E, Romero IA, Wylezinska-Arridge M, Couraud PO, Lopez-Tremoleda J, Christian HC, Weksler BB, Malaspina A, Solito E (2013) Identification of an essential endogenous regulator of blood–brain barrier integrity, and its pathological and therapeutic implications. Proc Natl Acad Sci USA 110(3):832–841. doi:10.1073/pnas.1209362110

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  76. Terry S, Nie M, Matter K, Balda MS (2010) Rho signaling and tight junction functions. Physiology 25(1):16–26. doi:10.1152/physiol.00034.2009

    Article  PubMed  CAS  Google Scholar 

  77. Su SC, Maxwell SA, Bayless KJ (2010) Annexin 2 regulates endothelial morphogenesis by controlling AKT activation and junctional integrity. J Biol Chem 285(52):40624–40634. doi:10.1074/jbc.M110.157271

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  78. Baumer S, Keller L, Holtmann A, Funke R, August B, Gamp A, Wolburg H, Wolburg-Buchholz K, Deutsch U, Vestweber D (2006) Vascular endothelial cell-specific phosphotyrosine phosphatase (VE-PTP) activity is required for blood vessel development. Blood 107(12):4754–4762. doi:10.1182/blood-2006-01-0141

    Article  PubMed  CAS  Google Scholar 

  79. Dominguez MG, Hughes VC, Pan L, Simmons M, Daly C, Anderson K, Noguera-Troise I, Murphy AJ, Valenzuela DM, Davis S, Thurston G, Yancopoulos GD, Gale NW (2007) Vascular endothelial tyrosine phosphatase (VE-PTP)-null mice undergo vasculogenesis but die embryonically because of defects in angiogenesis. Proc Natl Acad Sci USA 104(9):3243–3248. doi:10.1073/pnas.0611510104

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  80. Nawroth R, Poell G, Ranft A, Kloep S, Samulowitz U, Fachinger G, Golding M, Shima DT, Deutsch U, Vestweber D (2002) VE-PTP and VE-cadherin ectodomains interact to facilitate regulation of phosphorylation and cell contacts. EMBO J 21(18):4885–4895

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  81. Nottebaum AF, Cagna G, Winderlich M, Gamp AC, Linnepe R, Polaschegg C, Filippova K, Lyck R, Engelhardt B, Kamenyeva O, Bixel MG, Butz S, Vestweber D (2008) VE-PTP maintains the endothelial barrier via plakoglobin and becomes dissociated from VE-cadherin by leukocytes and by VEGF. J Exp Med 205(12):2929–2945. doi:10.1084/jem.20080406

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  82. Broermann A, Winderlich M, Block H, Frye M, Rossaint J, Zarbock A, Cagna G, Linnepe R, Schulte D, Nottebaum AF, Vestweber D (2011) Dissociation of VE-PTP from VE-cadherin is required for leukocyte extravasation and for VEGF-induced vascular permeability in vivo. J Exp Med 208(12):2393–2401. doi:10.1084/jem.20110525

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  83. Gloor SM, Weber A, Adachi N, Frei K (1997) Interleukin-1 modulates protein tyrosine phosphatase activity and permeability of brain endothelial cells. Biochem Biophys Res Commun 239(3):804–809. doi:10.1006/bbrc.1997.7557

    Article  PubMed  CAS  Google Scholar 

  84. Iovino F, Molema G, Bijlsma JJ (2014) Platelet endothelial cell adhesion molecule-1, a putative receptor for the adhesion of Streptococcus pneumoniae to the vascular endothelium of the blood–brain barrier. Infect Immun 82(9):3555–3566. doi:10.1128/iai.00046-14

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Wong D, Prameya R, Dorovini-Zis K (2007) Adhesion and migration of polymorphonuclear leukocytes across human brain microvessel endothelial cells are differentially regulated by endothelial cell adhesion molecules and modulate monolayer permeability. J Neuroimmunol 184(1–2):136–148. doi:10.1016/j.jneuroim.2006.12.003

    Article  PubMed  CAS  Google Scholar 

  86. DiMaio TA, Sheibani N (2008) PECAM-1 isoform-specific functions in PECAM-1-deficient brain microvascular endothelial cells. Microvasc Res 75(2):188–201. doi:10.1016/j.mvr.2007.10.001

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  87. Graesser D, Solowiej A, Bruckner M, Osterweil E, Juedes A, Davis S, Ruddle NH, Engelhardt B, Madri JA (2002) Altered vascular permeability and early onset of experimental autoimmune encephalomyelitis in PECAM-1-deficient mice. J Clin Invest 109(3):383–392. doi:10.1172/jci13595

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  88. Winger RC, Koblinski JE, Kanda T, Ransohoff RM, Muller WA (2014) Rapid remodeling of tight junctions during paracellular diapedesis in a human model of the blood–brain barrier. J Immunol 193(5):2427–2437. doi:10.4049/jimmunol.1400700

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  89. Chaitanya GV, Cromer W, Wells S, Jennings M, Mathis JM, Minagar A, Alexander JS (2012) Metabolic modulation of cytokine-induced brain endothelial adhesion molecule expression. Microcirculation 19(2):155–165. doi:10.1111/j.1549-8719.2011.00141.x

    Article  PubMed  CAS  Google Scholar 

  90. Tilling T, Korte D, Hoheisel D, Galla HJ (1998) Basement membrane proteins influence brain capillary endothelial barrier function in vitro. J Neurochem 71(3):1151–1157

    Article  PubMed  CAS  Google Scholar 

  91. Hawkins RA, O’Kane RL, Simpson IA, Vina JR (2006) Structure of the blood–brain barrier and its role in the transport of amino acids. J Nutr 136(1 Suppl):218S–226S

    PubMed  CAS  Google Scholar 

  92. van Horssen J, Bo L, Vos CM, Virtanen I, de Vries HE (2005) Basement membrane proteins in multiple sclerosis-associated inflammatory cuffs: potential role in influx and transport of leukocytes. J Neuropathol Exp Neurol 64(8):722–729

    Article  PubMed  Google Scholar 

  93. Hallmann R, Horn N, Selg M, Wendler O, Pausch F, Sorokin LM (2005) Expression and function of laminins in the embryonic and mature vasculature. Physiol Rev 85(3):979–1000. doi:10.1152/physrev.00014.2004

    Article  PubMed  CAS  Google Scholar 

  94. Sorokin L, Girg W, Gopfert T, Hallmann R, Deutzmann R (1994) Expression of novel 400-kDa laminin chains by mouse and bovine endothelial cells. Eur J Biochem 223(2):603–610

    Article  PubMed  CAS  Google Scholar 

  95. Sixt M, Engelhardt B, Pausch F, Hallmann R, Wendler O, Sorokin LM (2001) Endothelial cell laminin isoforms, laminins 8 and 10, play decisive roles in T cell recruitment across the blood–brain barrier in experimental autoimmune encephalomyelitis. J Cell Biol 153(5):933–946

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  96. Armulik A, Genove G, Mae 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(7323):557–561. doi:10.1038/nature09522

    Article  PubMed  CAS  Google Scholar 

  97. Smyth N, Vatansever HS, Murray P, Meyer M, Frie C, Paulsson M, Edgar D (1999) Absence of basement membranes after targeting the LAMC1 gene results in embryonic lethality due to failure of endoderm differentiation. J Cell Biol 144(1):151–160

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  98. Yao Y, Chen ZL, Norris EH, Strickland S (2014) Astrocytic laminin regulates pericyte differentiation and maintains blood brain barrier integrity. Nat Commun 5:3413. doi:10.1038/ncomms4413

    PubMed  PubMed Central  Google Scholar 

  99. Hamann GF, Burggraf D, Martens HK, Liebetrau M, Jager G, Wunderlich N, DeGeorgia M, Krieger DW (2004) Mild to moderate hypothermia prevents microvascular basal lamina antigen loss in experimental focal cerebral ischemia. Stroke 35(3):764–769. doi:10.1161/01.str.0000116866.60794.21

    Article  PubMed  Google Scholar 

  100. Cai Y, Liu X, Chen W, Wang Z, Xu G, Zeng Y, Ma Y (2015) TGF-beta1 prevents blood–brain barrier damage and hemorrhagic transformation after thrombolysis in rats. Exp Neurol 266:120–126. doi:10.1016/j.expneurol.2015.02.013

    Article  PubMed  CAS  Google Scholar 

  101. Poschl E, Schlotzer-Schrehardt U, Brachvogel B, Saito K, Ninomiya Y, Mayer U (2004) Collagen IV is essential for basement membrane stability but dispensable for initiation of its assembly during early development. Development 131(7):1619–1628. doi:10.1242/dev.01037

    Article  PubMed  CAS  Google Scholar 

  102. George EL, Georges-Labouesse EN, Patel-King RS, Rayburn H, Hynes RO (1993) Defects in mesoderm, neural tube and vascular development in mouse embryos lacking fibronectin. Development 119(4):1079–1091

    PubMed  CAS  Google Scholar 

  103. Hamann GF, Liebetrau M, Martens H, Burggraf D, Kloss CU, Bultemeier G, Wunderlich N, Jager G, Pfefferkorn T (2002) Microvascular basal lamina injury after experimental focal cerebral ischemia and reperfusion in the rat. J Cereb Blood Flow Metab 22(5):526–533. doi:10.1097/00004647-200205000-00004

    Article  PubMed  Google Scholar 

  104. Trinkl A, Vosko MR, Wunderlich N, Dichgans M, Hamann GF (2006) Pravastatin reduces microvascular basal lamina damage following focal cerebral ischemia and reperfusion. Eur J Neurosci 24(2):520–526. doi:10.1111/j.1460-9568.2006.04920.x

    Article  PubMed  Google Scholar 

  105. Wang CX, Shuaib A (2007) Critical role of microvasculature basal lamina in ischemic brain injury. Prog Neurobiol 83(3):140–148. doi:10.1016/j.pneurobio.2007.07.006

    Article  PubMed  CAS  Google Scholar 

  106. Kroger S, Mann S (1996) Biochemical and functional characterization of basal lamina-bound agrin in the chick central nervous system. Eur J Neurosci 8(3):500–509

    Article  PubMed  CAS  Google Scholar 

  107. Barber AJ, Lieth E (1997) Agrin accumulates in the brain microvascular basal lamina during development of the blood–brain barrier. Dev Dyn 208(1):62–74. doi:10.1002/(SICI)1097-0177(199701)208:1<62:AID-AJA6>3.0.CO;2-#

  108. Rascher G, Fischmann A, Kroger S, Duffner F, Grote EH, Wolburg H (2002) Extracellular matrix and the blood–brain barrier in glioblastoma multiforme: spatial segregation of tenascin and agrin. Acta Neuropathol 104(1):85–91. doi:10.1007/s00401-002-0524-x

    Article  PubMed  CAS  Google Scholar 

  109. Berzin TM, Zipser BD, Rafii MS, Kuo-Leblanc V, Yancopoulos GD, Glass DJ, Fallon JR, Stopa EG (2000) Agrin and microvascular damage in Alzheimer’s disease. Neurobiol Aging 21(2):349–355

    Article  PubMed  CAS  Google Scholar 

  110. Baumann E, Preston E, Slinn J, Stanimirovic D (2009) Post-ischemic hypothermia attenuates loss of the vascular basement membrane proteins, agrin and SPARC, and the blood–brain barrier disruption after global cerebral ischemia. Brain Res 1269:185–197. doi:10.1016/j.brainres.2009.02.062

    Article  PubMed  CAS  Google Scholar 

  111. Donahue JE, Berzin TM, Rafii MS, Glass DJ, Yancopoulos GD, Fallon JR, Stopa EG (1999) Agrin in Alzheimer’s disease: altered solubility and abnormal distribution within microvasculature and brain parenchyma. Proc Natl Acad Sci USA 96(11):6468–6472

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  112. Rauch SM, Huen K, Miller MC, Chaudry H, Lau M, Sanes JR, Johanson CE, Stopa EG, Burgess RW (2011) Changes in brain beta-amyloid deposition and aquaporin 4 levels in response to altered agrin expression in mice. J Neuropathol Exp Neurol 70(12):1124–1137. doi:10.1097/NEN.0b013e31823b0b12

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  113. Steiner E, Enzmann GU, Lyck R, Lin S, Ruegg MA, Kroger S, Engelhardt B (2014) The heparan sulfate proteoglycan agrin contributes to barrier properties of mouse brain endothelial cells by stabilizing adherens junctions. Cell Tissue Res 358(2):465–479. doi:10.1007/s00441-014-1969-7

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  114. de Vries HE, Kuiper J, de Boer AG, Van Berkel TJ, Breimer DD (1997) The blood–brain barrier in neuroinflammatory diseases. Pharmacol Rev 49(2):143–155

    PubMed  Google Scholar 

  115. Xanthos DN, Sandkuhler J (2014) Neurogenic neuroinflammation: inflammatory CNS reactions in response to neuronal activity. Nat Rev Neurosci 15(1):43–53. doi:10.1038/nrn3617

    Article  PubMed  CAS  Google Scholar 

  116. Erickson MA, Dohi K, Banks WA (2012) Neuroinflammation: a common pathway in CNS diseases as mediated at the blood–brain barrier. Neuroimmunomodulation 19(2):121–130. doi:10.1159/000330247

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  117. Carvey PM, Zhao CH, Hendey B, Lum H, Trachtenberg J, Desai BS, Snyder J, Zhu YG, Ling ZD (2005) 6-Hydroxydopamine-induced alterations in blood–brain barrier permeability. Eur J Neurosci 22(5):1158–1168. doi:10.1111/j.1460-9568.2005.04281.x

    Article  PubMed  CAS  Google Scholar 

  118. Minagar A, Alexander JS (2003) Blood–brain barrier disruption in multiple sclerosis. Mult Scler 9(6):540–549

    Article  PubMed  CAS  Google Scholar 

  119. de Vries HE, Blom-Roosemalen MC, van Oosten M, de Boer AG, van Berkel TJ, Breimer DD, Kuiper J (1996) The influence of cytokines on the integrity of the blood–brain barrier in vitro. J Neuroimmunol 64(1):37–43

    Article  PubMed  Google Scholar 

  120. Schnell L, Fearn S, Schwab ME, Perry VH, Anthony DC (1999) Cytokine-induced acute inflammation in the brain and spinal cord. J Neuropathol Exp Neurol 58(3):245–254

    Article  PubMed  CAS  Google Scholar 

  121. Wei EP, Ellison MD, Kontos HA, Povlishock JT (1986) O2 radicals in arachidonate-induced increased blood–brain barrier permeability to proteins. Am J Physiol 251(4 Pt 2):H693–699

    PubMed  CAS  Google Scholar 

  122. Lopez-Ramirez MA, Fischer R, Torres-Badillo CC, Davies HA, Logan K, Pfizenmaier K, Male DK, Sharrack B, Romero IA (2012) Role of caspases in cytokine-induced barrier breakdown in human brain endothelial cells. J Immunol 189(6):3130–3139. doi:10.4049/jimmunol.1103460

    Article  PubMed  CAS  Google Scholar 

  123. Benveniste EN (1992) Inflammatory cytokines within the central nervous system: sources, function, and mechanism of action. Am J Physiol 263(1 Pt 1):C1–16

    PubMed  CAS  Google Scholar 

  124. Quagliarello VJ, Wispelwey B, Long WJ Jr, Scheld WM (1991) Recombinant human interleukin-1 induces meningitis and blood–brain barrier injury in the rat. Characterization and comparison with tumor necrosis factor. J Clin Invest 87(4):1360–1366. doi:10.1172/jci115140

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  125. Wang Y, Jin S, Sonobe Y, Cheng Y, Horiuchi H, Parajuli B, Kawanokuchi J, Mizuno T, Takeuchi H, Suzumura A (2014) Interleukin-1beta induces blood–brain barrier disruption by downregulating Sonic hedgehog in astrocytes. PLoS One 9(10):e110024. doi:10.1371/journal.pone.0110024

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Rochfort KD, Collins LE, Murphy RP, Cummins PM (2014) Downregulation of blood–brain barrier phenotype by proinflammatory cytokines involves NADPH oxidase-dependent ROS generation: consequences for interendothelial adherens and tight junctions. PLoS One 9(7):e101815. doi:10.1371/journal.pone.0101815

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Mark KS, Miller DW (1999) Increased permeability of primary cultured brain microvessel endothelial cell monolayers following TNF-alpha exposure. Life Sci 64(21):1941–1953

    Article  PubMed  CAS  Google Scholar 

  128. Nishioku T, Matsumoto J, Dohgu S, Sumi N, Miyao K, Takata F, Shuto H, Yamauchi A, Kataoka Y (2010) Tumor necrosis factor-alpha mediates the blood–brain barrier dysfunction induced by activated microglia in mouse brain microvascular endothelial cells. J Pharmacol Sci 112(2):251–254

    Article  PubMed  CAS  Google Scholar 

  129. Gu X, Wei ZZ, Espinera A, Lee JH, Ji X, Wei L, Dix TA, Yu SP (2015) Pharmacologically induced hypothermia attenuates traumatic brain injury in neonatal rats. Exp Neurol 267:135–142. doi:10.1016/j.expneurol.2015.02.029

    Article  PubMed  CAS  Google Scholar 

  130. Yang Y, Salayandia VM, Thompson JF, Yang LY, Estrada EY, Yang Y (2015) Attenuation of acute stroke injury in rat brain by minocycline promotes blood–brain barrier remodeling and alternative microglia/macrophage activation during recovery. J Neuroinflamm 12(1):26. doi:10.1186/s12974-015-0245-4

    Article  CAS  Google Scholar 

  131. Larochelle C, Alvarez JI, Prat A (2011) How do immune cells overcome the blood–brain barrier in multiple sclerosis? FEBS Lett 585(23):3770–3780. doi:10.1016/j.febslet.2011.04.066

    Article  PubMed  CAS  Google Scholar 

  132. Rosenberg GA, Prestopnik J, Adair JC, Huisa BN, Knoefel J, Caprihan A, Gasparovic C, Thompson J, Erhardt EB, Schrader R (2015) Validation of biomarkers in subcortical ischaemic vascular disease of the Binswanger type: approach to targeted treatment trials. J Neurol Neurosurg Psychiatry. doi:10.1136/jnnp-2014-309421

    PubMed  PubMed Central  Google Scholar 

  133. Nomura DK, Morrison BE, Blankman JL, Long JZ, Kinsey SG, Marcondes MC, Ward AM, Hahn YK, Lichtman AH, Conti B, Cravatt BF (2011) Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation. Science 334(6057):809–813. doi:10.1126/science.1209200

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  134. Jaworowicz DJ Jr, Korytko PJ, Singh Lakhman S, Boje KM (1998) Nitric oxide and prostaglandin E2 formation parallels blood–brain barrier disruption in an experimental rat model of bacterial meningitis. Brain Res Bull 46(6):541–546

    Article  PubMed  CAS  Google Scholar 

  135. Dalvi S, Nguyen HH, On N, Mitchell RW, Aukema HM, Miller DW, Hatch GM (2015) Exogenous arachidonic acid mediates permeability of human brain microvessel endothelial cells through prostaglandin E activation of EP and EP receptors. J Neurochem. doi:10.1111/jnc.13117

    PubMed  Google Scholar 

  136. Candelario-Jalil E, Taheri S, Yang Y, Sood R, Grossetete M, Estrada EY, Fiebich BL, Rosenberg GA (2007) Cyclooxygenase inhibition limits blood–brain barrier disruption following intracerebral injection of tumor necrosis factor-alpha in the rat. J Pharmacol Exp Ther 323(2):488–498. doi:10.1124/jpet.107.127035

    Article  PubMed  CAS  Google Scholar 

  137. Black KL, Hoff JT (1985) Leukotrienes increase blood–brain barrier permeability following intraparenchymal injections in rats. Ann Neurol 18(3):349–351. doi:10.1002/ana.410180313

    Article  PubMed  CAS  Google Scholar 

  138. Abbott NJ (2000) Inflammatory mediators and modulation of blood–brain barrier permeability. Cell Mol Neurobiol 20(2):131–147

    Article  PubMed  CAS  Google Scholar 

  139. Easton AS, Fraser PA (1998) Arachidonic acid increases cerebral microvascular permeability by free radicals in single pial microvessels of the anaesthetized rat. J Physiol 507(Pt 2):541–547

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  140. Lee H, Pienaar IS (2014) Disruption of the blood–brain barrier in Parkinson’s disease: curse or route to a cure? Front Biosci 19:272–280

    Article  CAS  Google Scholar 

  141. Chung YC, Kim YS, Bok E, Yune TY, Maeng S, Jin BK (2013) MMP-3 contributes to nigrostriatal dopaminergic neuronal loss, BBB damage, and neuroinflammation in an MPTP mouse model of Parkinson’s disease. Mediators Inflamm 2013:370526. doi:10.1155/2013/370526

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  142. Duran-Vilaregut J, del Valle J, Manich G, Camins A, Pallas M, Vilaplana J, Pelegri C (2011) Role of matrix metalloproteinase-9 (MMP-9) in striatal blood–brain barrier disruption in a 3-nitropropionic acid model of Huntington’s disease. Neuropathol Appl Neurobiol 37(5):525–537. doi:10.1111/j.1365-2990.2010.01157.x

    Article  PubMed  CAS  Google Scholar 

  143. Goncalves FM, Martins-Oliveira A, Lacchini R, Belo VA, Speciali JG, Dach F, Tanus-Santos JE (2013) Matrix metalloproteinase (MMP)-2 gene polymorphisms affect circulating MMP-2 levels in patients with migraine with aura. Gene 512(1):35–40. doi:10.1016/j.gene.2012.09.109

    Article  PubMed  CAS  Google Scholar 

  144. Martins-Oliveira A, Speciali JG, Dach F, Marcaccini AM, Goncalves FM, Gerlach RF, Tanus-Santos JE (2009) Different circulating metalloproteinases profiles in women with migraine with and without aura. Clin Chim Acta 408(1–2):60–64. doi:10.1016/j.cca.2009.07.008

    Article  PubMed  CAS  Google Scholar 

  145. Gupta VK (2009) CSD, BBB and MMP-9 elevations: animal experiments versus clinical phenomena in migraine. Expert Rev Neurother 9(11):1595–1614. doi:10.1586/ern.09.103

    Article  PubMed  CAS  Google Scholar 

  146. Wan W, Cao L, Liu L, Zhang C, Kalionis B, Tai X, Li Y, Xia S (2015) Abeta oligomer-induced leakage in an in vitro blood–brain barrier model is associated with up-regulation of RAGE and metalloproteinases, and down-regulation of tight junction scaffold proteins. J Neurochem 134(2):382–393. doi:10.1111/jnc.13122

    Article  PubMed  CAS  Google Scholar 

  147. Louboutin JP, Reyes BA, Agrawal L, Van Bockstaele EJ, Strayer DS (2011) HIV-1 gp120 upregulates matrix metalloproteinases and their inhibitors in a rat model of HIV encephalopathy. Eur J Neurosci 34(12):2015–2023. doi:10.1111/j.1460-9568.2011.07908.x

    Article  PubMed  Google Scholar 

  148. Gasche Y, Fujimura M, Morita-Fujimura Y, Copin JC, Kawase M, Massengale J, Chan PH (1999) Early appearance of activated matrix metalloproteinase-9 after focal cerebral ischemia in mice: a possible role in blood–brain barrier dysfunction. J Cereb Blood Flow Metab 19(9):1020–1028. doi:10.1097/00004647-199909000-00010

    Article  PubMed  CAS  Google Scholar 

  149. Guilfoyle MR, Carpenter KL, Helmy A, Pickard JD, Menon DK, Hutchinson PJ (2015) Matrix metalloproteinase expression in contusional traumatic brain injury: a paired microdialysis study. J Neurotrauma. doi:10.1089/neu.2014.3764

    PubMed  PubMed Central  Google Scholar 

  150. Wu K, Fukuda K, Xing F, Zhang Y, Sharma S, Liu Y, Chan MD, Zhou X, Qasem SA, Pochampally R, Mo YY, Watabe K (2015) Roles of the cyclooxygenase 2 matrix metalloproteinase 1 pathway in brain metastasis of breast cancer. J Biol Chem 290(15):9842–9854. doi:10.1074/jbc.M114.602185

    Article  PubMed  CAS  Google Scholar 

  151. Xu L, Cao F, Xu F, He B, Dong Z (2015) Bexarotene reduces blood–brain barrier permeability in cerebral ischemia-reperfusion injured rats. PLoS One 10(4):e0122744. doi:10.1371/journal.pone.0122744

    Article  PubMed  PubMed Central  Google Scholar 

  152. Takata F, Dohgu S, Matsumoto J, Takahashi H, Machida T, Wakigawa T, Harada E, Miyaji H, Koga M, Nishioku T, Yamauchi A, Kataoka Y (2011) Brain pericytes among cells constituting the blood–brain barrier are highly sensitive to tumor necrosis factor-alpha, releasing matrix metalloproteinase-9 and migrating in vitro. J Neuroinflamm 106(8):106. doi:10.1186/1742-2094-8-106

    Article  CAS  Google Scholar 

  153. Machida T, Takata F, Matsumoto J, Takenoshita H, Kimura I, Yamauchi A, Dohgu S, Kataoka Y (2015) Brain pericytes are the most thrombin-sensitive matrix metalloproteinase-9-releasing cell type constituting the blood–brain barrier in vitro. Neurosci Lett. doi:10.1016/j.neulet.2015.05.028

    PubMed  Google Scholar 

  154. Halliday MR, Rege SV, Ma Q, Zhao Z, Miller CA, Winkler EA, Zlokovic BV (2015) Accelerated pericyte degeneration and blood–brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer’s disease. J Cereb Blood Flow Metab. doi:10.1038/jcbfm.2015.44

    PubMed  Google Scholar 

  155. Bezerra FJ, Brown M, Alarcon W, Karki K, Knight RA, Keenan KA, Nagaraja TN (2014) Rate and extent of leakage of a magnetic resonance contrast agent tend to be lower under isoflurane anesthesia in comparison to halothane in a rat model of embolic stroke. Neurol Res 36(9):847–850. doi:10.1179/1743132814Y.0000000341

    Article  PubMed  CAS  Google Scholar 

  156. Takeuchi S, Nagatani K, Otani N, Nawashiro H, Sugawara T, Wada K, Mori K (2015) Hydrogen improves neurological function through attenuation of blood–brain barrier disruption in spontaneously hypertensive stroke-prone rats. BMC Neurosci 16(1):22. doi:10.1186/s12868-015-0165-3

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  157. Geng Y, Li E, Mu Q, Zhang Y, Wei X, Li H, Cheng L, Zhang B (2015) Hydrogen sulfide inhalation decreases early blood–brain barrier permeability and brain edema induced by cardiac arrest and resuscitation. J Cereb Blood Flow Metab 35(3):494–500. doi:10.1038/jcbfm.2014.223

    Article  PubMed  CAS  Google Scholar 

  158. Allahtavakoli M, Amin F, Esmaeeli-Nadimi A, Shamsizadeh A, Kazemi-Arababadi M, Kennedy D (2015) Ascorbic acid reduces the adverse effects of delayed administration of tissue plasminogen activator in a rat stroke model. Basic Clin Pharmacol Toxicol. doi:10.1111/bcpt.12413

    PubMed  Google Scholar 

  159. Wang MD, Wang Y, Xia YP, Dai JW, Gao L, Wang SQ, Wang HJ, Mao L, Li M, Yu SM, Tu Y, He QW, Zhang GP, Wang L, Xu GZ, Xu HB, Zhu LQ, Hu B (2015) High serum MiR-130a levels are associated with severe perihematomal edema and predict adverse outcome in acute ICH. Mol Neurobiol. doi:10.1007/s12035-015-9099-0

    Google Scholar 

  160. Wu J, Zhao D, Wu S, Wang D (2015) Ang-(1–7) exerts protective role in blood–brain barrier damage by the balance of TIMP-1/MMP-9. Eur J Pharmacol 748:30–36. doi:10.1016/j.ejphar.2014.12.007

    Article  PubMed  CAS  Google Scholar 

  161. Wang T, Chen X, Wang Z, Zhang M, Meng H, Gao Y, Luo B, Tao L, Chen Y (2015) Poloxamer-188 can attenuate blood–brain barrier damage to exert neuroprotective effect in mice intracerebral hemorrhage model. J Mol Neurosci 55(1):240–250. doi:10.1007/s12031-014-0313-8

    Article  PubMed  CAS  Google Scholar 

  162. Reuter B, Rodemer C, Grudzenski S, Meairs S, Bugert P, Hennerici MG, Fatar M (2015) Effect of simvastatin on MMPs and TIMPs in human brain endothelial cells and experimental stroke. Transl Stroke Res 6(2):156–159. doi:10.1007/s12975-014-0381-7

    Article  PubMed  CAS  Google Scholar 

  163. Wei H, Wang S, Zhen L, Yang Q, Wu Z, Lei X, Lv J, Xiong L, Xue R (2015) Resveratrol attenuates the blood–brain barrier dysfunction by regulation of the MMP-9/TIMP-1 balance after cerebral ischemia reperfusion in rats. J Mol Neurosci 55(4):872–879. doi:10.1007/s12031-014-0441-1

    Article  PubMed  CAS  Google Scholar 

  164. Abdul-Muneer PM, Schuetz H, Wang F, Skotak M, Jones J, Gorantla S, Zimmerman MC, Chandra N, Haorah J (2013) Induction of oxidative and nitrosative damage leads to cerebrovascular inflammation in an animal model of mild traumatic brain injury induced by primary blast. Free Radic Biol Med 60:282–291. doi:10.1016/j.freeradbiomed.2013.02.029

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  165. Floyd RA (1999) Neuroinflammatory processes are important in neurodegenerative diseases: an hypothesis to explain the increased formation of reactive oxygen and nitrogen species as major factors involved in neurodegenerative disease development. Free Radic Biol Med 26(9–10):1346–1355

    Article  PubMed  CAS  Google Scholar 

  166. Jian Liu K, Rosenberg GA (2005) Matrix metalloproteinases and free radicals in cerebral ischemia. Free Radic Biol Med 39(1):71–80. doi:10.1016/j.freeradbiomed.2005.03.033

    Article  PubMed  CAS  Google Scholar 

  167. Rosenberg GA (2012) Neurological diseases in relation to the blood–brain barrier. J Cereb Blood Flow Metab 32(7):1139–1151. doi:10.1038/jcbfm.2011.197

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  168. Zhao Z, Hu J, Gao X, Liang H, Liu Z (2014) Activation of AMPK attenuates lipopolysaccharide-impaired integrity and function of blood–brain barrier in human brain microvascular endothelial cells. Exp Mol Pathol 97(3):386–392. doi:10.1016/j.yexmp.2014.09.006

    Article  PubMed  CAS  Google Scholar 

  169. Minami T, Okazaki J, Kawabata A, Kawaki H, Okazaki Y, Tohno Y (1998) Roles of nitric oxide and prostaglandins in the increased permeability of the blood–brain barrier caused by lipopolysaccharide. Environ Toxicol Pharmacol 5(1):35–41

    Article  PubMed  CAS  Google Scholar 

  170. 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(13):3666–3676. doi:10.1096/fj.07-8329com

    Article  PubMed  CAS  Google Scholar 

  171. Haorah J, Ramirez SH, Schall K, Smith D, Pandya R, Persidsky Y (2007) Oxidative stress activates protein tyrosine kinase and matrix metalloproteinases leading to blood–brain barrier dysfunction. J Neurochem 101(2):566–576. doi:10.1111/j.1471-4159.2006.04393.x

    Article  PubMed  CAS  Google Scholar 

  172. Coisne C, Engelhardt B (2011) Tight junctions in brain barriers during central nervous system inflammation. Antioxid Redox Signal 15(5):1285–1303. doi:10.1089/ars.2011.3929

    Article  PubMed  CAS  Google Scholar 

  173. Wang GH, Jiang ZL, Li YC, Li X, Shi H, Gao YQ, Vosler PS, Chen J (2011) Free-radical scavenger edaravone treatment confers neuroprotection against traumatic brain injury in rats. J Neurotrauma 28(10):2123–2134. doi:10.1089/neu.2011.1939

    Article  PubMed  PubMed Central  Google Scholar 

  174. Gelati M, Corsini E, Dufour A, Massa G, Giombini S, Solero CL, Salmaggi A (2000) High-dose methylprednisolone reduces cytokine-induced adhesion molecules on human brain endothelium. Can J Neurol Sci 27(3):241–244

    Article  PubMed  CAS  Google Scholar 

  175. Schweingruber N, Reichardt SD, Luhder F, Reichardt HM (2012) Mechanisms of glucocorticoids in the control of neuroinflammation. J Neuroendocrinol 24(1):174–182. doi:10.1111/j.1365-2826.2011.02161.x

    Article  PubMed  CAS  Google Scholar 

  176. Dietrich JB (2004) Endothelial cells of the blood–brain barrier: a target for glucocorticoids and estrogens? Front Biosci 9:684–693

    Article  PubMed  CAS  Google Scholar 

  177. Ding R, Feng L, He L, Chen Y, Wen P, Fu Z, Lin C, Yang S, Deng X, Zeng J, Sun G (2015) Peroxynitrite decomposition catalyst prevents matrix metalloproteinase-9 activation and neurovascular injury after hemoglobin injection into the caudate nucleus of rats. Neuroscience 297:182–193. doi:10.1016/j.neuroscience.2015.03.065

    Article  PubMed  CAS  Google Scholar 

  178. Rosenstein JM, Mani N, Silverman WF, Krum JM (1998) Patterns of brain angiogenesis after vascular endothelial growth factor administration in vitro and in vivo. Proc Natl Acad Sci USA 95(12):7086–7091

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  179. Schoch HJ, Fischer S, Marti HH (2002) Hypoxia-induced vascular endothelial growth factor expression causes vascular leakage in the brain. Brain 125(Pt 11):2549–2557

    Article  PubMed  Google Scholar 

  180. 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 USA 106(6):1977–1982. doi:10.1073/pnas.0808698106

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  181. Engelhardt S, Patkar S, Ogunshola OO (2014) Cell-specific blood–brain barrier regulation in health and disease: a focus on hypoxia. Br J Pharmacol 171(5):1210–1230. doi:10.1111/bph.12489

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  182. Zhang ZG, Zhang L, Jiang Q, Zhang R, Davies K, Powers C, Bruggen N, Chopp M (2000) VEGF enhances angiogenesis and promotes blood–brain barrier leakage in the ischemic brain. J Clin Invest 106(7):829–838. doi:10.1172/JCI9369

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  183. Li YN, Pan R, Qin XJ, Yang WL, Qi Z, Liu W, Liu KJ (2014) Ischemic neurons activate astrocytes to disrupt endothelial barrier via increasing VEGF expression. J Neurochem 129(1):120–129. doi:10.1111/jnc.12611

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  184. Zhao LN, Yang ZH, Liu YH, Ying HQ, Zhang H, Xue YX (2011) Vascular endothelial growth factor increases permeability of the blood–tumor barrier via caveolae-mediated transcellular pathway. J Mol Neurosci 44(2):122–129. doi:10.1007/s12031-010-9487-x

    Article  PubMed  CAS  Google Scholar 

  185. Wang W, Merrill MJ, Borchardt RT (1996) Vascular endothelial growth factor affects permeability of brain microvessel endothelial cells in vitro. Am J Physiol 271(6 Pt 1):C1973–1980

    PubMed  CAS  Google Scholar 

  186. Zhao L, Zhang MM, Ng KY (1998) Effects of vascular permeability factor on the permeability of cultured endothelial cells from brain capillaries. J Cardiovasc Pharmacol 32(1):1–4

    Article  PubMed  CAS  Google Scholar 

  187. Mayhan WG (1999) VEGF increases permeability of the blood–brain barrier via a nitric oxide synthase/cGMP-dependent pathway. Am J Physiol 276(5 Pt 1):C1148–1153

    PubMed  CAS  Google Scholar 

  188. Dvorak HF, Brown LF, Detmar M, Dvorak AM (1995) Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol 146(5):1029–1039

    PubMed  CAS  PubMed Central  Google Scholar 

  189. 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(4):697–709. doi:10.1038/sj.jcbfm.9600375

    PubMed  CAS  Google Scholar 

  190. Chen W, Jadhav V, Tang J, Zhang JH (2008) HIF-1alpha inhibition ameliorates neonatal brain injury in a rat pup hypoxic-ischemic model. Neurobiol Dis 31(3):433–441. doi:10.1016/j.nbd.2008.05.020

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  191. Yeh WL, Lu DY, Lin CJ, Liou HC, Fu WM (2007) Inhibition of hypoxia-induced increase of blood–brain barrier permeability by YC-1 through the antagonism of HIF-1alpha accumulation and VEGF expression. Mol Pharmacol 72(2):440–449. doi:10.1124/mol.107.036418

    Article  PubMed  CAS  Google Scholar 

  192. Chen C, Ostrowski RP, Zhou C, Tang J, Zhang JH (2010) Suppression of hypoxia-inducible factor-1alpha and its downstream genes reduces acute hyperglycemia-enhanced hemorrhagic transformation in a rat model of cerebral ischemia. J Neurosci Res 88(9):2046–2055. doi:10.1002/jnr.22361

    PubMed  CAS  Google Scholar 

  193. Jalal FY, Yang Y, Thompson JF, Roitbak T, Rosenberg GA (2015) Hypoxia-induced neuroinflammatory white-matter injury reduced by minocycline in SHR/SP. J Cereb Blood Flow Metab. doi:10.1038/jcbfm.2015.21

    PubMed  Google Scholar 

  194. Reijerkerk A, Lopez-Ramirez MA, van Het Hof B, Drexhage JA, Kamphuis WW, Kooij G, Vos JB, van der Pouw Kraan TC, van Zonneveld AJ, Horrevoets AJ, Prat A, Romero IA, de Vries HE (2013) MicroRNAs regulate human brain endothelial cell-barrier function in inflammation: implications for multiple sclerosis. J Neurosci 33(16):6857–6863. doi:10.1523/JNEUROSCI.3965-12.2013

    Article  PubMed  CAS  Google Scholar 

  195. Kalani A, Kamat PK, Familtseva A, Chaturvedi P, Muradashvili N, Narayanan N, Tyagi SC, Tyagi N (2014) Role of microRNA29b in blood–brain barrier dysfunction during hyperhomocysteinemia: an epigenetic mechanism. J Cereb Blood Flow Metab 34(7):1212–1222. doi:10.1038/jcbfm.2014.74

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  196. Deng X, Zhong Y, Gu L, Shen W, Guo J (2013) MiR-21 involve in ERK-mediated upregulation of MMP9 in the rat hippocampus following cerebral ischemia. Brain Res Bull 94:56–62. doi:10.1016/j.brainresbull.2013.02.007

    Article  PubMed  CAS  Google Scholar 

  197. Yin KJ, Deng Z, Hamblin M, Xiang Y, Huang H, Zhang J, Jiang X, Wang Y, Chen YE (2010) Peroxisome proliferator-activated receptor delta regulation of miR-15a in ischemia-induced cerebral vascular endothelial injury. J Neurosci 30(18):6398–6408. doi:10.1523/JNEUROSCI.0780-10.2010

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  198. Eadon MT, Jacob A, Cunningham PN, Quigg RJ, Garcia JG, Alexander JJ (2014) Transcriptional profiling reveals that C5a alters microRNA in brain endothelial cells. Immunology 143(3):363–373. doi:10.1111/imm.12314

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  199. Rom S, Dykstra H, Zuluaga-Ramirez V, Reichenbach NL, Persidsky Y (2015) miR-98 and let-7g* protect the blood–brain barrier under neuroinflammatory conditions. J Cereb Blood Flow Metab. doi:10.1038/jcbfm.2015.154

    PubMed Central  Google Scholar 

  200. Zhu J, Jiang Y, Wu L, Lu T, Xu G, Liu X (2012) Suppression of local inflammation contributes to the neuroprotective effect of ginsenoside Rb1 in rats with cerebral ischemia. Neuroscience 202:342–351. doi:10.1016/j.neuroscience.2011.11.070

    Article  PubMed  CAS  Google Scholar 

  201. Chi OZ, Anwar M, Sinha AK, Wei HM, Klein SL, Weiss HR (1992) Effects of isoflurane on transport across the blood–brain barrier. Anesthesiology 76(3):426–431

    Article  PubMed  CAS  Google Scholar 

  202. Tetrault S, Chever O, Sik A, Amzica F (2008) Opening of the blood–brain barrier during isoflurane anaesthesia. Eur J Neurosci 28(7):1330–1341. doi:10.1111/j.1460-9568.2008.06443.x

    Article  PubMed  Google Scholar 

  203. Cao Y, Ni C, Li Z, Li L, Liu Y, Wang C, Zhong Y, Cui D, Guo X (2015) Isoflurane anesthesia results in reversible ultrastructure and occludin tight junction protein expression changes in hippocampal blood–brain barrier in aged rats. Neurosci Lett 587:51–56. doi:10.1016/j.neulet.2014.12.018

    Article  PubMed  CAS  Google Scholar 

  204. Zhao J, Hao J, Fei X, Wang X, Hou Y, Deng C (2014) Isoflurane inhibits occludin expression via up-regulation of hypoxia-inducible factor 1alpha. Brain Res 1562:1–10. doi:10.1016/j.brainres.2014.03.025

    Article  PubMed  CAS  Google Scholar 

  205. Dittmar MS, Petermichl W, Schlachetzki F, Graf BM, Gruber M (2012) Isoflurane induces endothelial apoptosis of the post-hypoxic blood–brain barrier in a transdifferentiated human umbilical vein endothelial cell model. PLoS One 7(6):e38260. doi:10.1371/journal.pone.0038260

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  206. Thal SC, Luh C, Schaible EV, Timaru-Kast R, Hedrich J, Luhmann HJ, Engelhard K, Zehendner CM (2012) Volatile anesthetics influence blood–brain barrier integrity by modulation of tight junction protein expression in traumatic brain injury. PLoS One 7(12):e50752. doi:10.1371/journal.pone.0050752

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  207. Acharya NK, Goldwaser EL, Forsberg MM, Godsey GA, Johnson CA, Sarkar A, DeMarshall C, Kosciuk MC, Dash JM, Hale CP, Leonard DM, Appelt DM, Nagele RG (2015) Sevoflurane and Isoflurane induce structural changes in brain vascular endothelial cells and increase blood–brain barrier permeability: possible link to postoperative delirium and cognitive decline. Brain Res. doi:10.1016/j.brainres.2015.04.054

    PubMed  Google Scholar 

  208. Fischer S, Renz D, Schaper W, Karliczek GF (1995) In vitro effects of fentanyl, methohexital, and thiopental on brain endothelial permeability. Anesthesiology 82(2):451–458

    Article  PubMed  CAS  Google Scholar 

  209. Ke Y, Qian ZM (2007) Brain iron metabolism: neurobiology and neurochemistry. Prog Neurobiol 83(3):149–173. doi:10.1016/j.pneurobio.2007.07.009

    Article  PubMed  CAS  Google Scholar 

  210. Bradbury MW (1997) Transport of iron in the blood–brain-cerebrospinal fluid system. J Neurochem 69(2):443–454

    Article  PubMed  CAS  Google Scholar 

  211. Qian ZM, Tang PL, Wang Q (1997) Iron crosses the endosomal membrane by a carrier-mediated process. Prog Biophys Mol Biol 67(1):1–15

    Article  PubMed  CAS  Google Scholar 

  212. Moos T, Rosengren Nielsen T, Skjorringe T, Morgan EH (2007) Iron trafficking inside the brain. J Neurochem 103(5):1730–1740. doi:10.1111/j.1471-4159.2007.04976.x

    Article  PubMed  CAS  Google Scholar 

  213. De Domenico I, Ward DM, di Patti MC, Jeong SY, David S, Musci G, Kaplan J (2007) Ferroxidase activity is required for the stability of cell surface ferroportin in cells expressing GPI-ceruloplasmin. EMBO J 26(12):2823–2831. doi:10.1038/sj.emboj.7601735

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  214. McCarthy RC, Kosman DJ (2014) Glial cell ceruloplasmin and hepcidin differentially regulate iron efflux from brain microvascular endothelial cells. PLoS One 9(2):e89003. doi:10.1371/journal.pone.0089003

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  215. Nicolas G, Chauvet C, Viatte L, Danan JL, Bigard X, Devaux I, Beaumont C, Kahn A, Vaulont S (2002) The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest 110(7):1037–1044. doi:10.1172/JCI15686

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  216. da Fonseca AC, Matias D, Garcia C, Amaral R, Geraldo LH, Freitas C, Lima FR (2014) The impact of microglial activation on blood–brain barrier in brain diseases. Front Cell Neurosci 8:362. doi:10.3389/fncel.2014.00362

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  217. Baby N, Patnala R, Ling EA, Dheen ST (2014) Nanomedicine and its application in treatment of microglia-mediated neuroinflammation. Curr Med Chem 21(37):4215–4226

    Article  PubMed  CAS  Google Scholar 

  218. Alvarez JI, Dodelet-Devillers A, Kebir H, Ifergan I, Fabre PJ, Terouz S, Sabbagh M, Wosik K, Bourbonniere L, Bernard M, van Horssen J, de Vries HE, Charron F, Prat A (2011) The Hedgehog pathway promotes blood–brain barrier integrity and CNS immune quiescence. Science 334(6063):1727–1731. doi:10.1126/science.1206936

    Article  PubMed  CAS  Google Scholar 

  219. Ilhan A, Akyol O, Gurel A, Armutcu F, Iraz M, Oztas E (2004) Protective effects of caffeic acid phenethyl ester against experimental allergic encephalomyelitis-induced oxidative stress in rats. Free Radic Biol Med 37(3):386–394. doi:10.1016/j.freeradbiomed.2004.04.022

    Article  PubMed  CAS  Google Scholar 

  220. Zhao J, Pati S, Redell JB, Zhang M, Moore AN, Dash PK (2012) Caffeic Acid phenethyl ester protects blood–brain barrier integrity and reduces contusion volume in rodent models of traumatic brain injury. J Neurotrauma 29(6):1209–1218. doi:10.1089/neu.2011.1858

    Article  PubMed  PubMed Central  Google Scholar 

  221. Manschot SM, Brands AM, van der Grond J, Kessels RP, Algra A, Kappelle LJ, Biessels GJ (2006) Brain magnetic resonance imaging correlates of impaired cognition in patients with type 2 diabetes. Diabetes 55(4):1106–1113. pii: 55/4/1106

  222. Starr JM, Wardlaw J, Ferguson K, MacLullich A, Deary IJ, Marshall I (2003) Increased blood–brain barrier permeability in type II diabetes demonstrated by gadolinium magnetic resonance imaging. J Neurol Neurosurg Psychiatry 74(1):70–76

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  223. Mooradian AD, Haas MJ, Batejko O, Hovsepyan M, Feman SS (2005) Statins ameliorate endothelial barrier permeability changes in the cerebral tissue of streptozotocin-induced diabetic rats. Diabetes 54(10):2977–2982. pii: 54/10/2977

  224. Hink U, Li H, Mollnau H, Oelze M, Matheis E, Hartmann M, Skatchkov M, Thaiss F, Stahl RA, Warnholtz A, Meinertz T, Griendling K, Harrison DG, Forstermann U, Munzel T (2001) Mechanisms underlying endothelial dysfunction in diabetes mellitus. Circ Res 88(2):E14–22

    Article  PubMed  CAS  Google Scholar 

  225. Kook SY, Seok Hong H, Moon M, Mook-Jung I (2013) Disruption of blood–brain barrier in Alzheimer disease pathogenesis. TissueBarriers 1(2):e23993. doi:10.4161/tisb.23993

    Article  Google Scholar 

  226. Wan W, Chen H, Li Y (2014) The potential mechanisms of Abeta-receptor for advanced glycation end-products interaction disrupting tight junctions of the blood–brain barrier in Alzheimer’s disease. Int J Neurosci 124(2):75–81. doi:10.3109/00207454.2013.825258

    Article  PubMed  CAS  Google Scholar 

  227. Carrano A, Hoozemans JJ, van der Vies SM, Rozemuller AJ, van Horssen J, de Vries HE (2011) Amyloid Beta induces oxidative stress-mediated blood–brain barrier changes in capillary amyloid angiopathy. Antioxid Redox Signal 15(5):1167–1178. doi:10.1089/ars.2011.3895

    Article  PubMed  CAS  Google Scholar 

  228. Kahles T, Brandes RP (2012) NADPH oxidases as therapeutic targets in ischemic stroke. Cell Mol Life Sci 69(14):2345–2363. doi:10.1007/s00018-012-1011-8

    Article  PubMed  CAS  Google Scholar 

  229. Ransohoff RM (2007) Natalizumab for multiple sclerosis. N Engl J Med 356(25):2622–2629. doi:10.1056/NEJMct071462

    Article  PubMed  CAS  Google Scholar 

  230. Wang WX, Danaher RJ, Miller CS, Berger JR, Nubia VG, Wilfred BS, Neltner JH, Norris CM, Nelson PT (2014) Expression of miR-15/107 family microRNAs in human tissues and cultured rat brain cells. Genomics Proteomics Bioinform 12(1):19–30. doi:10.1016/j.gpb.2013.10.003

    Article  CAS  Google Scholar 

  231. Ge X, Han Z, Chen F, Wang H, Zhang B, Jiang R, Lei P, Zhang J (2015) MiR-21 alleviates secondary blood–brain barrier damage after traumatic brain injury in rats. Brain Res 1603:150–157. doi:10.1016/j.brainres.2015.01.009

    Article  PubMed  CAS  Google Scholar 

  232. Smirnova L, Grafe A, Seiler A, Schumacher S, Nitsch R, Wulczyn FG (2005) Regulation of miRNA expression during neural cell specification. Eur J Neurosci 21(6):1469–1477. doi:10.1111/j.1460-9568.2005.03978.x

    Article  PubMed  Google Scholar 

  233. Junker A, Krumbholz M, Eisele S, Mohan H, Augstein F, Bittner R, Lassmann H, Wekerle H, Hohlfeld R, Meinl E (2009) MicroRNA profiling of multiple sclerosis lesions identifies modulators of the regulatory protein CD47. Brain 132(Pt 12):3342–3352. doi:10.1093/brain/awp300

    Article  PubMed  Google Scholar 

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Acknowledgments

This work was supported in part by the University of Kansas Center for Research and National Natural Science Foundation of China (31520103908 and 31528013). Mohammed M. A. Almutairi was supported by a scholarship from King Saud University (Riyadh, Saudi Arabia).

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, 1251 Wescoe Hall Drive, Malott Hall 5044, Lawrence, KS, 66045, USA

    Mohammed M. A. Almutairi, Chen Gong & Honglian Shi

  2. Department of Anesthesiology, School of Medicine, University of Kansas, Kansas City, KS, 66160, USA

    Yuexian G. Xu

  3. Laboratory of Molecular Iron Metabolism, College of Life Science, Hebei Normal University, Shijiazhuang, 050016, China

    Yanzhong Chang

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  1. Mohammed M. A. Almutairi
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  5. Honglian Shi
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Correspondence to Honglian Shi.

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Almutairi, M.M.A., Gong, C., Xu, Y.G. et al. Factors controlling permeability of the blood–brain barrier. Cell. Mol. Life Sci. 73, 57–77 (2016). https://doi.org/10.1007/s00018-015-2050-8

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