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The role of endogenous tissue-type plasminogen activator in neuronal survival after ischemic stroke: friend or foe?

  • Jiayi Zhu
  • Yan Wan
  • Hexiang Xu
  • Yulang Wu
  • Bo HuEmail author
  • Huijuan JinEmail author
Review

Abstract

Endogenous protease tissue-type plasminogen activator (tPA) has highly efficient fibrinolytic activity and its recombinant variants alteplase and tenecteplase are established as highly effective thrombolytic drugs for ischemic stroke. Endogenous tPA is constituted of five functional domains through which it interacts with a variety of substrates, binding proteins and receptors, thus having enzymatic and cytokine-like effects to act on all cell types of the brain. In the past 2 decades, numerous studies have explored the clinical relevance of endogenous tPA in neurological diseases, especially in ischemic stroke. tPA is released from many cells within the brain parenchyma exposed to ischemia conditions in vitro and in vivo, which is believed to control neuronal fate. Some studies proved that tPA could induce blood–brain barrier disruption, neural excitotoxicity and inflammation, while others indicated that tPA also has anti-excitotoxic, neurotrophic and anti-apoptotic effects on neurons. Therefore, more work is needed to elucidate how tPA mediates such opposing functions that may amplify tPA from a therapeutic means into a key therapeutic target in endogenous neuroprotection after stroke. In this review, we summarize the biological characteristics and pleiotropic functions of tPA in the brain. Then we focus on possible hypotheses about why and how endogenous tPA mediates ischemic neuronal death and survival. Finally, we analyze how endogenous tPA affects neuron fate in ischemic stroke in a comprehensive view.

Keywords

Endogenous tPA Ischemic stroke Neuronal survival Pleiotropic functions Signal 

Notes

Acknowledgements

This work was supported by the National Key R&D Program of China (2018YFC1312200 to Bo Hu) and National Natural Science Foundation of China (Grants: 81571119 and 81371311 to BH, and 81671147 to JHJ).

Compliance with ethical standards

Conflict of interest

The authors have no conflicts of interest to disclose.

References

  1. 1.
    Rha JH, Saver JL (2007) The impact of recanalization on ischemic stroke outcome: a meta-analysis. Stroke 38(3):967–973.  https://doi.org/10.1161/01.STR.0000258112.14918.24 CrossRefPubMedGoogle Scholar
  2. 2.
    Tabrizi P, Wang L, Seeds N, McComb JG, Yamada S, Griffin JH, Carmeliet P, Weiss MH, Zlokovic BV (1999) Tissue plasminogen activator (tPA) deficiency exacerbates cerebrovascular fibrin deposition and brain injury in a murine stroke model: studies in tPA-deficient mice and wild-type mice on a matched genetic background. Arterioscler Thromb Vasc Biol 19(11):2801–2806CrossRefPubMedGoogle Scholar
  3. 3.
    Kagitani H, Tagawa M, Hatanaka K, Ikari T, Saito A, Bando H, Okada K, Matsuo O (1985) Expression in E. coli of finger-domain lacking tissue-type plasminogen activator with high fibrin affinity. FEBS Lett 189(1):145–149CrossRefPubMedGoogle Scholar
  4. 4.
    Levin EG, Santell L, Osborn KG (1997) The expression of endothelial tissue plasminogen activator in vivo: a function defined by vessel size and anatomic location. J Cell Sci 110(Pt 2):139–148PubMedGoogle Scholar
  5. 5.
    Ringleb P, Schellinger PD, Hacke W, Europaischen S (2008) European Stroke Organisation 2008 guidelines for managing acute cerebral infarction or transient ischemic attack. Part 1. Der Nervenarzt 79(8):936–957.  https://doi.org/10.1007/s00115-008-2531-1 CrossRefPubMedGoogle Scholar
  6. 6.
    Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, Biller J, Brown M, Demaerschalk BM, Hoh B, Jauch EC, Kidwell CS, Leslie-Mazwi TM, Ovbiagele B, Scott PA, Sheth KN, Southerland AM, Summers DV, Tirschwell DL, American Heart Association Stroke C (2018) 2018 Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 49(3):e46–e110.  https://doi.org/10.1161/STR.0000000000000158 CrossRefPubMedGoogle Scholar
  7. 7.
    Flavin MP, Zhao G (2001) Tissue plasminogen activator protects hippocampal neurons from oxygen-glucose deprivation injury. J Neurosci Res 63(5):388–394.  https://doi.org/10.1002/1097-4547(20010301)63:5%3c388:AID-JNR1033%3e3.0.CO;2-T CrossRefPubMedGoogle Scholar
  8. 8.
    Siao CJ, Fernandez SR, Tsirka SE (2003) Cell type-specific roles for tissue plasminogen activator released by neurons or microglia after excitotoxic injury. J Neurosci 23(8):3234–3242CrossRefPubMedGoogle Scholar
  9. 9.
    Casse F, Bardou I, Danglot L, Briens A, Montagne A, Parcq J, Alahari A, Galli T, Vivien D, Docagne F (2012) Glutamate controls tPA recycling by astrocytes, which in turn influences glutamatergic signals. J Neurosci 32(15):5186–5199.  https://doi.org/10.1523/JNEUROSCI.5296-11.2012 CrossRefPubMedGoogle Scholar
  10. 10.
    Yepes M, Sandkvist M, Moore EG, Bugge TH, Strickland DK, Lawrence DA (2003) Tissue-type plasminogen activator induces opening of the blood–brain barrier via the LDL receptor-related protein. J Clin Investig 112(10):1533–1540.  https://doi.org/10.1172/JCI19212 CrossRefPubMedGoogle Scholar
  11. 11.
    Nicole O, Docagne F, Ali C, Margaill I, Carmeliet P, MacKenzie ET, Vivien D, Buisson A (2001) The proteolytic activity of tissue-plasminogen activator enhances NMDA receptor-mediated signaling. Nat Med 7(1):59–64.  https://doi.org/10.1038/83358 CrossRefPubMedGoogle Scholar
  12. 12.
    Zhang C, An J, Strickland DK, Yepes M (2009) The low-density lipoprotein receptor-related protein 1 mediates tissue-type plasminogen activator-induced microglial activation in the ischemic brain. Am J Pathol 174(2):586–594.  https://doi.org/10.2353/ajpath.2009.080661 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Haile WB, Wu J, Echeverry R, Wu F, An J, Yepes M (2012) Tissue-type plasminogen activator has a neuroprotective effect in the ischemic brain mediated by neuronal TNF-alpha. J Cereb Blood Flow Metab 32(1):57–69.  https://doi.org/10.1038/jcbfm.2011.106 CrossRefPubMedGoogle Scholar
  14. 14.
    Wu F, Echeverry R, Wu J, An J, Haile WB, Cooper DS, Catano M, Yepes M (2013) Tissue-type plasminogen activator protects neurons from excitotoxin-induced cell death via activation of the ERK1/2-CREB-ATF3 signaling pathway. Mol Cell Neurosci 52:9–19.  https://doi.org/10.1016/j.mcn.2012.10.001 CrossRefPubMedGoogle Scholar
  15. 15.
    Wu F, Wu J, Nicholson AD, Echeverry R, Haile WB, Catano M, An J, Lee AK, Duong D, Dammer EB, Seyfried NT, Tong FC, Votaw JR, Medcalf RL, Yepes M (2012) Tissue-type plasminogen activator regulates the neuronal uptake of glucose in the ischemic brain. J Neurosci 32(29):9848–9858.  https://doi.org/10.1523/JNEUROSCI.1241-12.2012 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Danglot G, Vinson D, Chapeville F (1986) Qualitative and quantitative distribution of plasminogen activators in organs from healthy adult mice. FEBS Lett 194(1):96–100CrossRefPubMedGoogle Scholar
  17. 17.
    Tachias K, Madison EL (1997) Converting tissue type plasminogen activator into a zymogen. Important role of Lys156. J Biol Chem 272(1):28–31CrossRefPubMedGoogle Scholar
  18. 18.
    Pennica D, Holmes WE, Kohr WJ, Harkins RN, Vehar GA, Ward CA, Bennett WF, Yelverton E, Seeburg PH, Heyneker HL, Goeddel DV, Collen D (1983) Cloning and expression of human tissue-type plasminogen activator cDNA in E. coli. Nature 301(5897):214–221CrossRefPubMedGoogle Scholar
  19. 19.
    Lamba D, Bauer M, Huber R, Fischer S, Rudolph R, Kohnert U, Bode W (1996) The 2.3 A crystal structure of the catalytic domain of recombinant two-chain human tissue-type plasminogen activator. J Mol Biol 258(1):117–135.  https://doi.org/10.1006/jmbi.1996.0238 CrossRefPubMedGoogle Scholar
  20. 20.
    Rijken DC, Hoylaerts M, Collen D (1982) Fibrinolytic properties of one-chain and two-chain human extrinsic (tissue-type) plasminogen activator. J Biol Chem 257(6):2920–2925PubMedGoogle Scholar
  21. 21.
    MacDonald ME, van Zonneveld AJ, Pannekoek H (1986) Functional analysis of the human tissue-type plasminogen activator protein: the light chain. Gene 42(1):59–67CrossRefPubMedGoogle Scholar
  22. 22.
    Andreasen PA, Riccio A, Welinder KG, Douglas R, Sartorio R, Nielsen LS, Oppenheimer C, Blasi F, Dano K (1986) Plasminogen activator inhibitor type-1: reactive center and amino-terminal heterogeneity determined by protein and cDNA sequencing. FEBS Lett 209(2):213–218CrossRefPubMedGoogle Scholar
  23. 23.
    Bu G, Williams S, Strickland DK, Schwartz AL (1992) Low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor is an hepatic receptor for tissue-type plasminogen activator. Proc Natl Acad Sci USA 89(16):7427–7431CrossRefPubMedGoogle Scholar
  24. 24.
    Vivien D, Gauberti M, Montagne A, Defer G, Touze E (2011) Impact of tissue plasminogen activator on the neurovascular unit: from clinical data to experimental evidence. J Cereb Blood Flow Metab 31(11):2119–2134.  https://doi.org/10.1038/jcbfm.2011.127 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Siao CJ, Tsirka SE (2002) Tissue plasminogen activator mediates microglial activation via its finger domain through annexin II. J Neurosci 22(9):3352–3358 (20026281) CrossRefPubMedGoogle Scholar
  26. 26.
    Pineda D, Ampurdanes C, Medina MG, Serratosa J, Tusell JM, Saura J, Planas AM, Navarro P (2012) Tissue plasminogen activator induces microglial inflammation via a noncatalytic molecular mechanism involving activation of mitogen-activated protein kinases and Akt signaling pathways and AnnexinA2 and Galectin-1 receptors. Glia 60(4):526–540.  https://doi.org/10.1002/glia.22284 CrossRefPubMedGoogle Scholar
  27. 27.
    Ling Q, Jacovina AT, Deora A, Febbraio M, Simantov R, Silverstein RL, Hempstead B, Mark WH, Hajjar KA (2004) Annexin II regulates fibrin homeostasis and neoangiogenesis in vivo. J Clin Investig 113(1):38–48.  https://doi.org/10.1172/JCI19684 CrossRefPubMedGoogle Scholar
  28. 28.
    Correa F, Gauberti M, Parcq J, Macrez R, Hommet Y, Obiang P, Hernangomez M, Montagne A, Liot G, Guaza C, Maubert E, Ali C, Vivien D, Docagne F (2011) Tissue plasminogen activator prevents white matter damage following stroke. J Exp Med 208(6):1229–1242.  https://doi.org/10.1084/jem.20101880 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Ortiz-Zapater E, Peiro S, Roda O, Corominas JM, Aguilar S, Ampurdanes C, Real FX, Navarro P (2007) Tissue plasminogen activator induces pancreatic cancer cell proliferation by a non-catalytic mechanism that requires extracellular signal-regulated kinase 1/2 activation through epidermal growth factor receptor and annexin A2. Am J Pathol 170(5):1573–1584.  https://doi.org/10.2353/ajpath.2007.060850 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Hajjar KA, Reynolds CM (1994) alpha-Fucose-mediated binding and degradation of tissue-type plasminogen activator by HepG2 cells. J Clin Investig 93(2):703–710.  https://doi.org/10.1172/JCI117023 CrossRefPubMedGoogle Scholar
  31. 31.
    van Zonneveld AJ, Veerman H, Pannekoek H (1986) On the interaction of the finger and the kringle-2 domain of tissue-type plasminogen activator with fibrin Inhibition of kringle-2 binding to fibrin by epsilon-amino caproic acid. J Biol Chem 261(30):14214–14218PubMedGoogle Scholar
  32. 32.
    Pohl G, Kallstrom M, Bergsdorf N, Wallen P, Jornvall H (1984) Tissue plasminogen activator: peptide analyses confirm an indirectly derived amino acid sequence, identify the active site serine residue, establish glycosylation sites, and localize variant differences. Biochemistry 23(16):3701–3707CrossRefPubMedGoogle Scholar
  33. 33.
    Hebert M, Lesept F, Vivien D, Macrez R (2016) The story of an exceptional serine protease, tissue-type plasminogen activator (tPA). Revue neurologique 172(3):186–197.  https://doi.org/10.1016/j.neurol.2015.10.002 CrossRefPubMedGoogle Scholar
  34. 34.
    Su EJ, Cao C, Fredriksson L, Nilsson I, Stefanitsch C, Stevenson TK, Zhao J, Ragsdale M, Sun YY, Yepes M, Kuan CY, Eriksson U, Strickland DK, Lawrence DA, Zhang L (2017) Microglial-mediated PDGF-CC activation increases cerebrovascular permeability during ischemic stroke. Acta Neuropathol 134(4):585–604.  https://doi.org/10.1007/s00401-017-1749-z CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Fredriksson L, Li H, Fieber C, Li X, Eriksson U (2004) Tissue plasminogen activator is a potent activator of PDGF-CC. EMBO J 23(19):3793–3802.  https://doi.org/10.1038/sj.emboj.7600397 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Bertrand T, Lesept F, Chevilley A, Lenoir S, Aimable M, Briens A, Hommet Y, Bardou I, Parcq J, Vivien D (2015) Conformations of tissue plasminogen activator (tPA) orchestrate neuronal survival by a crosstalk between EGFR and NMDAR. Cell Death Dis 6:e1924.  https://doi.org/10.1038/cddis.2015.296 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Lopez-Atalaya JP, Roussel BD, Levrat D, Parcq J, Nicole O, Hommet Y, Benchenane K, Castel H, Leprince J, Van To D, Bureau R, Rault S, Vaudry H, Petersen KU, Santos JS, Ali C, Vivien D (2008) Toward safer thrombolytic agents in stroke: molecular requirements for NMDA receptor-mediated neurotoxicity. J Cereb Blood Flow Metab 28(6):1212–1221.  https://doi.org/10.1038/jcbfm.2008.14 CrossRefPubMedGoogle Scholar
  38. 38.
    Parcq J, Bertrand T, Baron AF, Hommet Y, Angles-Cano E, Vivien D (2013) Molecular requirements for safer generation of thrombolytics by bioengineering the tissue-type plasminogen activator A chain. J Thromb Haemost JTH 11(3):539–546CrossRefPubMedGoogle Scholar
  39. 39.
    Kuiper J, Otter M, Rijken DC, van Berkel TJ (1988) Characterization of the interaction in vivo of tissue-type plasminogen activator with liver cells. J Biol Chem 263(34):18220–18224PubMedGoogle Scholar
  40. 40.
    Dunoyer-Geindre S, Kruithof EK (2011) Epigenetic control of tissue-type plasminogen activator synthesis in human endothelial cells. Cardiovasc Res 90(3):457–463.  https://doi.org/10.1093/cvr/cvr028 CrossRefPubMedGoogle Scholar
  41. 41.
    Yepes M (2015) Tissue-type plasminogen activator is a neuroprotectant in the central nervous system. Front Cell Neurosci 9:304.  https://doi.org/10.3389/fncel.2015.00304 CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Verstraete M, Bounameaux H, de Cock F, Van de Werf F, Collen D (1985) Pharmacokinetics and systemic fibrinogenolytic effects of recombinant human tissue-type plasminogen activator (rt-PA) in humans. J Pharmacol Exp Ther 235(2):506–512PubMedGoogle Scholar
  43. 43.
    Seeds NW, Williams BL, Bickford PC (1995) Tissue plasminogen activator induction in Purkinje neurons after cerebellar motor learning. Science 270(5244):1992–1994CrossRefPubMedGoogle Scholar
  44. 44.
    Salles FJ, Strickland S (2002) Localization and regulation of the tissue plasminogen activator-plasmin system in the hippocampus. J Neurosci 22(6):2125–2134CrossRefPubMedGoogle Scholar
  45. 45.
    Carroll PM, Tsirka SE, Richards WG, Frohman MA, Strickland S (1994) The mouse tissue plasminogen activator gene 5′ flanking region directs appropriate expression in development and a seizure-enhanced response in the CNS. Development 120(11):3173–3183PubMedGoogle Scholar
  46. 46.
    Aflalo ED, Sod-Moriah UA, Potashnik G, Har-Vardi I (2005) Expression of plasminogen activators in preimplantation rat embryos developed in vivo and in vitro. Reprod Biol Endocrinol RB&E 3:7.  https://doi.org/10.1186/1477-7827-3-7 CrossRefGoogle Scholar
  47. 47.
    Aflalo ED, Sod-Moriah UA, Potashnik G, Har-Vardi I (2004) Differences in the implantation rates of rat embryos developed in vivo and in vitro: possible role for plasminogen activators. Fertil Steril 81:780–785.  https://doi.org/10.1016/j.fertnstert.2003.10.014 CrossRefPubMedGoogle Scholar
  48. 48.
    Zhang X, Kidder GM, Zhang C, Khamsi F, Armstrong DT (1994) Expression of plasminogen activator genes and enzymatic activities in rat preimplantation embryos. J Reprod Fertil 101(1):235–240CrossRefPubMedGoogle Scholar
  49. 49.
    Dano K, Andreasen PA, Grondahl-Hansen J, Kristensen P, Nielsen LS, Skriver L (1985) Plasminogen activators, tissue degradation, and cancer. Adv Cancer Res 44:139–266CrossRefPubMedGoogle Scholar
  50. 50.
    Friedman GC, Seeds NW (1995) Tissue plasminogen activator mRNA expression in granule neurons coincides with their migration in the developing cerebellum. J Comp Neurol 360(4):658–670.  https://doi.org/10.1002/cne.903600410 CrossRefPubMedGoogle Scholar
  51. 51.
    Thewke DP, Seeds NW (1999) The expression of mRNAs for hepatocyte growth factor/scatter factor, its receptor c-met, and one of its activators tissue-type plasminogen activator show a systematic relationship in the developing and adult cerebral cortex and hippocampus. Brain Res 821(2):356–367CrossRefPubMedGoogle Scholar
  52. 52.
    Pawlak R, Nagai N, Urano T, Napiorkowska-Pawlak D, Ihara H, Takada Y, Collen D, Takada A (2002) Rapid, specific and active site-catalyzed effect of tissue-plasminogen activator on hippocampus-dependent learning in mice. Neuroscience 113(4):995–1001CrossRefPubMedGoogle Scholar
  53. 53.
    Ware JH, Dibenedetto AJ, Pittman RN (1995) Localization of tissue plasminogen activator mRNA in adult rat brain. Brain Res Bull 37(3):275–281CrossRefPubMedGoogle Scholar
  54. 54.
    Thewke DP, Seeds NW (1996) Expression of hepatocyte growth factor/scatter factor, its receptor, c-met, and tissue-type plasminogen activator during development of the murine olfactory system. J Neurosci 16(21):6933–6944CrossRefPubMedGoogle Scholar
  55. 55.
    Teesalu T, Kulla A, Simisker A, Siren V, Lawrence DA, Asser T, Vaheri A (2004) Tissue plasminogen activator and neuroserpin are widely expressed in the human central nervous system. Thromb Haemost 92(2):358–368.  https://doi.org/10.1160/TH02-12-0310 CrossRefPubMedGoogle Scholar
  56. 56.
    Sappino AP, Madani R, Huarte J, Belin D, Kiss JZ, Wohlwend A, Vassalli JD (1993) Extracellular proteolysis in the adult murine brain. J Clin Investig 92(2):679–685.  https://doi.org/10.1172/JCI116637 CrossRefPubMedGoogle Scholar
  57. 57.
    Louessard M, Lacroix A, Martineau M, Mondielli G, Montagne A, Lesept F, Lambolez B, Cauli B, Mothet JP, Vivien D, Maubert E (2016) Tissue plasminogen activator expression is restricted to subsets of excitatory pyramidal glutamatergic neurons. Mol Neurobiol 53(7):5000–5012.  https://doi.org/10.1007/s12035-015-9432-7 CrossRefPubMedGoogle Scholar
  58. 58.
    Chu P, Chen E, Bajnath A, Brumberg JC (2015) Cell type specificity of tissue plasminogen activator in the mouse barrel cortex. Data Brief 4:332–335.  https://doi.org/10.1016/j.dib.2015.06.008 CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Lochner JE, Honigman LS, Grant WF, Gessford SK, Hansen AB, Silverman MA, Scalettar BA (2006) Activity-dependent release of tissue plasminogen activator from the dendritic spines of hippocampal neurons revealed by live-cell imaging. J Neurobiol 66(6):564–577.  https://doi.org/10.1002/neu.20250 CrossRefPubMedGoogle Scholar
  60. 60.
    Carmeliet P, Schoonjans L, Kieckens L, Ream B, Degen J, Bronson R, De Vos R, van den Oord JJ, Collen D, Mulligan RC (1994) Physiological consequences of loss of plasminogen activator gene function in mice. Nature 368(6470):419–424.  https://doi.org/10.1038/368419a0 CrossRefPubMedGoogle Scholar
  61. 61.
    Pasquet N, Douceau S, Naveau M, Lesept F, Louessard M, Lebouvier L, Hommet Y, Vivien D, Bardou I (2018) Tissue-type plasminogen activator controlled corticogenesis through a mechanism dependent of NMDA receptors expressed on radial glial cells. Cereb Cortex.  https://doi.org/10.1093/cercor/bhy119 CrossRefPubMedGoogle Scholar
  62. 62.
    Galas L, Benard M, Lebon A, Komuro Y, Schapman D, Vaudry H, Vaudry D, Komuro H (2017) Postnatal migration of cerebellar interneurons. Brain Sci.  https://doi.org/10.3390/brainsci7060062 CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Seeds NW, Basham ME, Ferguson JE (2003) Absence of tissue plasminogen activator gene or activity impairs mouse cerebellar motor learning. J Neurosci 23(19):7368–7375CrossRefPubMedGoogle Scholar
  64. 64.
    Seeds NW, Basham ME, Haffke SP (1999) Neuronal migration is retarded in mice lacking the tissue plasminogen activator gene. Proc Natl Acad Sci USA 96(24):14118–14123CrossRefPubMedGoogle Scholar
  65. 65.
    Baranes D, Lederfein D, Huang YY, Chen M, Bailey CH, Kandel ER (1998) Tissue plasminogen activator contributes to the late phase of LTP and to synaptic growth in the hippocampal mossy fiber pathway. Neuron 21(4):813–825CrossRefPubMedGoogle Scholar
  66. 66.
    Madani R, Hulo S, Toni N, Madani H, Steimer T, Muller D, Vassalli JD (1999) Enhanced hippocampal long-term potentiation and learning by increased neuronal expression of tissue-type plasminogen activator in transgenic mice. EMBO J 18(11):3007–3012.  https://doi.org/10.1093/emboj/18.11.3007 CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Muller CM, Griesinger CB (1998) Tissue plasminogen activator mediates reverse occlusion plasticity in visual cortex. Nat Neurosci 1(1):47–53.  https://doi.org/10.1038/248 CrossRefPubMedGoogle Scholar
  68. 68.
    Rastogi A, Mintz EM (2017) Neural correlates of food anticipatory activity in mice subjected to once- or twice-daily feeding periods. Eur J Neurosci 46(7):2265–2275.  https://doi.org/10.1111/ejn.13671 CrossRefPubMedGoogle Scholar
  69. 69.
    Pothakos K, Robinson JK, Gravanis I, Marsteller DA, Dewey SL, Tsirka SE (2010) Decreased serotonin levels associated with behavioral disinhibition in tissue plasminogen activator deficient (tPA −/−) mice. Brain Res 1326:135–142.  https://doi.org/10.1016/j.brainres.2009.12.095 CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Pawlak R, Magarinos AM, Melchor J, McEwen B, Strickland S (2003) Tissue plasminogen activator in the amygdala is critical for stress-induced anxiety-like behavior. Nat Neurosci 6(2):168–174.  https://doi.org/10.1038/nn998 CrossRefPubMedGoogle Scholar
  71. 71.
    Mataga N, Mizuguchi Y, Hensch TK (2004) Experience-dependent pruning of dendritic spines in visual cortex by tissue plasminogen activator. Neuron 44(6):1031–1041.  https://doi.org/10.1016/j.neuron.2004.11.028 CrossRefPubMedGoogle Scholar
  72. 72.
    Wu F, Torre E, Cuellar-Giraldo D, Cheng L, Yi H, Bichler EK, Garcia PS, Yepes M (2015) Tissue-type plasminogen activator triggers the synaptic vesicle cycle in cerebral cortical neurons. J Cereb Blood Flow Metab 35(12):1966–1976.  https://doi.org/10.1038/jcbfm.2015.155 CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Jeanneret V, Wu F, Merino P, Torre E, Diaz A, Cheng L, Yepes M (2016) Tissue-type plasminogen activator (tPA) modulates the postsynaptic response of cerebral cortical neurons to the presynaptic release of glutamate. Front Mol Neurosci 9:121.  https://doi.org/10.3389/fnmol.2016.00121 CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Stefanitsch C, Lawrence AL, Olverling A, Nilsson I, Fredriksson L (2015) tPA deficiency in mice leads to rearrangement in the cerebrovascular tree and cerebroventricular malformations. Front Cell Neurosci 9:456.  https://doi.org/10.3389/fncel.2015.00456 CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Park L, Gallo EF, Anrather J, Wang G, Norris EH, Paul J, Strickland S, Iadecola C (2008) Key role of tissue plasminogen activator in neurovascular coupling. Proc Natl Acad Sci USA 105(3):1073–1078.  https://doi.org/10.1073/pnas.0708823105 CrossRefPubMedGoogle Scholar
  76. 76.
    Fredriksson L, Stevenson TK, Su EJ, Ragsdale M, Moore S, Craciun S, Schielke GP, Murphy GG, Lawrence DA (2015) Identification of a neurovascular signaling pathway regulating seizures in mice. Ann Clin Transl Neurol 2(7):722–738.  https://doi.org/10.1002/acn3.209 CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Sashindranath M, Samson AL, Downes CE, Crack PJ, Lawrence AJ, Li QX, Ng AQ, Jones NC, Farrugia JJ, Abdella E, Vassalli JD, Madani R, Medcalf RL (2011) Compartment- and context-specific changes in tissue-type plasminogen activator (tPA) activity following brain injury and pharmacological stimulation. Lab Investig J Tech Methods Pathol 91(7):1079–1091.  https://doi.org/10.1038/labinvest.2011.67 CrossRefGoogle Scholar
  78. 78.
    Echeverry R, Wu J, Haile WB, Guzman J, Yepes M (2010) Tissue-type plasminogen activator is a neuroprotectant in the mouse hippocampus. J Clin Investig 120(6):2194–2205.  https://doi.org/10.1172/JCI41722 CrossRefPubMedGoogle Scholar
  79. 79.
    Wang YF, Tsirka SE, Strickland S, Stieg PE, Soriano SG, Lipton SA (1998) Tissue plasminogen activator (tPA) increases neuronal damage after focal cerebral ischemia in wild-type and tPA-deficient mice. Nat Med 4(2):228–231CrossRefPubMedGoogle Scholar
  80. 80.
    Lemarchand E, Maubert E, Haelewyn B, Ali C, Rubio M, Vivien D (2016) Stressed neurons protect themselves by a tissue-type plasminogen activator-mediated EGFR-dependent mechanism. Cell Death Differ 23(1):123–131.  https://doi.org/10.1038/cdd.2015.76 CrossRefPubMedGoogle Scholar
  81. 81.
    Yepes M, Sandkvist M, Wong MK, Coleman TA, Smith E, Cohan SL, Lawrence DA (2000) Neuroserpin reduces cerebral infarct volume and protects neurons from ischemia-induced apoptosis. Blood 96(2):569–576PubMedGoogle Scholar
  82. 82.
    Zlokovic BV, Wang L, Sun N, Haffke S, Verrall S, Seeds NW, Fisher MJ, Schreiber SS (1995) Expression of tissue plasminogen activator in cerebral capillaries: possible fibrinolytic function of the blood–brain barrier. Neurosurgery 37(5):955–961CrossRefPubMedGoogle Scholar
  83. 83.
    Ahn MY, Zhang ZG, Tsang W, Chopp M (1999) Endogenous plasminogen activator expression after embolic focal cerebral ischemia in mice. Brain Res 837(1–2):169–176CrossRefPubMedGoogle Scholar
  84. 84.
    Osterwalder T, Contartese J, Stoeckli ET, Kuhn TB, Sonderegger P (1996) Neuroserpin, an axonally secreted serine protease inhibitor. EMBO J 15(12):2944–2953CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Sprengers ED, Kluft C (1987) Plasminogen activator inhibitors. Blood 69(2):381–387PubMedGoogle Scholar
  86. 86.
    Mayer EJ, Fujita T, Gardell SJ, Shebuski RJ, Reilly CF (1990) The pharmacokinetics of plasminogen activator inhibitor-1 in the rabbit. Blood 76(8):1514–1520PubMedGoogle Scholar
  87. 87.
    Kawano T, Morimoto K, Uemura Y (1968) Urokinase inhibitor in human placenta. Nature 217(5125):253–254CrossRefPubMedGoogle Scholar
  88. 88.
    Sprengers ED, Verheijen JH, Van Hinsbergh VW, Emeis JJ (1984) Evidence for the presence of two different fibrinolytic inhibitors in human endothelial cell conditioned medium. Biochem Biophys Acta 801(2):163–170CrossRefPubMedGoogle Scholar
  89. 89.
    Quax PH, van den Hoogen CM, Verheijen JH, Padro T, Zeheb R, Gelehrter TD, van Berkel TJ, Kuiper J, Emeis JJ (1990) Endotoxin induction of plasminogen activator and plasminogen activator inhibitor type 1 mRNA in rat tissues in vivo. J Biol Chem 265(26):15560–15563PubMedGoogle Scholar
  90. 90.
    Declerck PJ, Alessi MC, Verstreken M, Kruithof EK, Juhan-Vague I, Collen D (1988) Measurement of plasminogen activator inhibitor 1 in biologic fluids with a murine monoclonal antibody-based enzyme-linked immunosorbent assay. Blood 71(1):220–225PubMedGoogle Scholar
  91. 91.
    Kruithof EK, Nicolosa G, Bachmann F (1987) Plasminogen activator inhibitor 1: development of a radioimmunoassay and observations on its plasma concentration during venous occlusion and after platelet aggregation. Blood 70(5):1645–1653PubMedGoogle Scholar
  92. 92.
    Nagai N, De Mol M, Lijnen HR, Carmeliet P, Collen D (1999) Role of plasminogen system components in focal cerebral ischemic infarction: a gene targeting and gene transfer study in mice. Circulation 99(18):2440–2444CrossRefPubMedGoogle Scholar
  93. 93.
    Lindgren A, Lindoff C, Norrving B, Astedt B, Johansson BB (1996) Tissue plasminogen activator and plasminogen activator inhibitor-1 in stroke patients. Stroke 27(6):1066–1071CrossRefPubMedGoogle Scholar
  94. 94.
    Hino H, Akiyama H, Iseki E, Kato M, Kondo H, Ikeda K, Kosaka K (2001) Immunohistochemical localization of plasminogen activator inhibitor-1 in rat and human brain tissues. Neurosci Lett 297(2):105–108CrossRefPubMedGoogle Scholar
  95. 95.
    Kim JW, Lee SH, Ko HM, Kwon KJ, Cho KS, Choi CS, Park JH, Kim HY, Lee J, Han SH, Ignarro LJ, Cheong JH, Kim WK, Shin CY (2011) Biphasic regulation of tissue plasminogen activator activity in ischemic rat brain and in cultured neural cells: essential role of astrocyte-derived plasminogen activator inhibitor-1. Neurochem Int 58(3):423–433.  https://doi.org/10.1016/j.neuint.2010.12.020 CrossRefPubMedGoogle Scholar
  96. 96.
    Docagne F, Nicole O, Marti HH, MacKenzie ET, Buisson A, Vivien D (1999) Transforming growth factor-beta1 as a regulator of the serpins/t-PA axis in cerebral ischemia. FASEB J 13(11):1315–1324CrossRefPubMedGoogle Scholar
  97. 97.
    Hastings GA, Coleman TA, Haudenschild CC, Stefansson S, Smith EP, Barthlow R, Cherry S, Sandkvist M, Lawrence DA (1997) Neuroserpin, a brain-associated inhibitor of tissue plasminogen activator is localized primarily in neurons Implications for the regulation of motor learning and neuronal survival. J Biol Chem 272(52):33062–33067CrossRefPubMedGoogle Scholar
  98. 98.
    Barker-Carlson K, Lawrence DA, Schwartz BS (2002) Acyl-enzyme complexes between tissue-type plasminogen activator and neuroserpin are short-lived in vitro. J Biol Chem 277(49):46852–46857.  https://doi.org/10.1074/jbc.M207740200 CrossRefPubMedGoogle Scholar
  99. 99.
    Yepes M, Lawrence DA (2004) Neuroserpin: a selective inhibitor of tissue-type plasminogen activator in the central nervous system. Thromb Haemost 91(3):457–464.  https://doi.org/10.1160/TH03-12-0766 CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Cinelli P, Madani R, Tsuzuki N, Vallet P, Arras M, Zhao CN, Osterwalder T, Rulicke T, Sonderegger P (2001) Neuroserpin, a neuroprotective factor in focal ischemic stroke. Mol Cell Neurosci 18(5):443–457.  https://doi.org/10.1006/mcne.2001.1028 CrossRefPubMedGoogle Scholar
  101. 101.
    Tanswell P, Seifried E, Stang E, Krause J (1991) Pharmacokinetics and hepatic catabolism of tissue-type plasminogen activator. Arzneimittelforschung 41(12):1310–1319PubMedGoogle Scholar
  102. 102.
    Strickland DK, Medved L (2006) Low-density lipoprotein receptor-related protein (LRP)-mediated clearance of activated blood coagulation co-factors and proteases: clearance mechanism or regulation? J Thromb Haemost JTH 4(7):1484–1486.  https://doi.org/10.1111/j.1538-7836.2006.01987.x CrossRefPubMedGoogle Scholar
  103. 103.
    Berg DT, Burck PJ, Berg DH, Grinnell BW (1993) Kringle glycosylation in a modified human tissue plasminogen activator improves functional properties. Blood 81(5):1312–1322PubMedGoogle Scholar
  104. 104.
    Biessen EA, van Teijlingen M, Vietsch H, Barrett-Bergshoeff MM, Bijsterbosch MK, Rijken DC, van Berkel TJ, Kuiper J (1997) Antagonists of the mannose receptor and the LDL receptor-related protein dramatically delay the clearance of tissue plasminogen activator. Circulation 95(1):46–52CrossRefPubMedGoogle Scholar
  105. 105.
    Ishiguro M, Imai Y, Kohsaka S (1995) Expression and distribution of low density lipoprotein receptor-related protein mRNA in the rat central nervous system. Brain Res Mol Brain Res 33(1):37–46CrossRefPubMedGoogle Scholar
  106. 106.
    Daneman R, Prat A (2015) The blood–brain barrier. Cold Spring Harb Perspect Biol 7(1):a020412.  https://doi.org/10.1101/cshperspect.a020412 CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    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.  https://doi.org/10.1016/j.nbd.2009.07.030 CrossRefPubMedGoogle Scholar
  108. 108.
    Keaney J, Campbell M (2015) The dynamic blood–brain barrier. FEBS J 282(21):4067–4079.  https://doi.org/10.1111/febs.13412 CrossRefPubMedGoogle Scholar
  109. 109.
    Vakili A, Kataoka H, Plesnila N (2005) Role of arginine vasopressin V1 and V2 receptors for brain damage after transient focal cerebral ischemia. J Cereb Blood Flow Metab 25(8):1012–1019.  https://doi.org/10.1038/sj.jcbfm.9600097 CrossRefPubMedGoogle Scholar
  110. 110.
    Lopes Pinheiro MA, Kooij G, Mizee MR, Kamermans A, Enzmann G, Lyck R, Schwaninger M, Engelhardt B, de Vries HE (2016) Immune cell trafficking across the barriers of the central nervous system in multiple sclerosis and stroke. Biochem Biophys Acta 1862(3):461–471.  https://doi.org/10.1016/j.bbadis.2015.10.018 CrossRefPubMedGoogle Scholar
  111. 111.
    Rogers B, Yakopson V, Teng ZP, Guo Y, Regan RF (2003) Heme oxygenase-2 knockout neurons are less vulnerable to hemoglobin toxicity. Free Radical Biol Med 35(8):872–881CrossRefGoogle Scholar
  112. 112.
    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.  https://doi.org/10.1126/science.1206936 CrossRefPubMedGoogle Scholar
  113. 113.
    Benchenane K, Berezowski V, Fernandez-Monreal M, Brillault J, Valable S, Dehouck MP, Cecchelli R, Vivien D, Touzani O, Ali C (2005) Oxygen glucose deprivation switches the transport of tPA across the blood–brain barrier from an LRP-dependent to an increased LRP-independent process. Stroke 36(5):1065–1070.  https://doi.org/10.1161/01.STR.0000163050.39122.4f CrossRefPubMedGoogle Scholar
  114. 114.
    Tsuji K, Aoki T, Tejima E, Arai K, Lee SR, Atochin DN, Huang PL, Wang X, Montaner J, Lo EH (2005) Tissue plasminogen activator promotes matrix metalloproteinase-9 upregulation after focal cerebral ischemia. Stroke 36(9):1954–1959.  https://doi.org/10.1161/01.STR.0000177517.01203.eb CrossRefPubMedGoogle Scholar
  115. 115.
    Zhang C, An J, Haile WB, Echeverry R, Strickland DK, Yepes M (2009) Microglial low-density lipoprotein receptor-related protein 1 mediates the effect of tissue-type plasminogen activator on matrix metalloproteinase-9 activity in the ischemic brain. J Cereb Blood Flow Metab 29(12):1946–1954.  https://doi.org/10.1038/jcbfm.2009.174 CrossRefPubMedGoogle Scholar
  116. 116.
    Lee SR, Guo SZ, Scannevin RH, Magliaro BC, Rhodes KJ, Wang X, Lo EH (2007) Induction of matrix metalloproteinase, cytokines and chemokines in rat cortical astrocytes exposed to plasminogen activators. Neurosci Lett 417(1):1–5.  https://doi.org/10.1016/j.neulet.2007.01.017 CrossRefPubMedGoogle Scholar
  117. 117.
    Wang X, Lee SR, Arai K, Lee SR, Tsuji K, Rebeck GW, Lo EH (2003) Lipoprotein receptor-mediated induction of matrix metalloproteinase by tissue plasminogen activator. Nat Med 9(10):1313–1317.  https://doi.org/10.1038/nm926 CrossRefPubMedGoogle Scholar
  118. 118.
    Fujimura M, Gasche Y, Morita-Fujimura Y, Massengale J, Kawase M, Chan PH (1999) Early appearance of activated matrix metalloproteinase-9 and blood–brain barrier disruption in mice after focal cerebral ischemia and reperfusion. Brain Res 842(1):92–100CrossRefPubMedGoogle Scholar
  119. 119.
    Rosell A, Cuadrado E, Ortega-Aznar A, Hernandez-Guillamon M, Lo EH, Montaner J (2008) MMP-9-positive neutrophil infiltration is associated to blood–brain barrier breakdown and basal lamina type IV collagen degradation during hemorrhagic transformation after human ischemic stroke. Stroke 39(4):1121–1126.  https://doi.org/10.1161/STROKEAHA.107.500868 CrossRefPubMedGoogle Scholar
  120. 120.
    Yang Y, Rosenberg GA (2011) MMP-mediated disruption of claudin-5 in the blood–brain barrier of rat brain after cerebral ischemia. Methods Mol Biol 762:333–345.  https://doi.org/10.1007/978-1-61779-185-7_24 CrossRefPubMedPubMedCentralGoogle Scholar
  121. 121.
    Wei CC, Kong YY, Hua X, Li GQ, Zheng SL, Cheng MH, Wang P, Miao CY (2017) NAD replenishment with nicotinamide mononucleotide protects blood–brain barrier integrity and attenuates delayed tissue plasminogen activator-induced haemorrhagic transformation after cerebral ischaemia. Br J Pharmacol.  https://doi.org/10.1111/bph.13979 CrossRefPubMedPubMedCentralGoogle Scholar
  122. 122.
    Ma B, Sen T, Asnaghi L, Valapala M, Yang F, Hose S, McLeod DS, Lu Y, Eberhart C, Zigler JS Jr, Sinha D (2011) betaA3/A1-Crystallin controls anoikis-mediated cell death in astrocytes by modulating PI3K/AKT/mTOR and ERK survival pathways through the PKD/Bit1-signaling axis. Cell Death Dis 2:e217.  https://doi.org/10.1038/cddis.2011.100 CrossRefPubMedPubMedCentralGoogle Scholar
  123. 123.
    Chen ZL, Strickland S (1997) Neuronal death in the hippocampus is promoted by plasmin-catalyzed degradation of laminin. Cell 91(7):917–925CrossRefPubMedGoogle Scholar
  124. 124.
    Lee SR, Lok J, Rosell A, Kim HY, Murata Y, Atochin D, Huang PL, Wang X, Ayata C, Moskowitz MA, Lo EH (2007) Reduction of hippocampal cell death and proteolytic responses in tissue plasminogen activator knockout mice after transient global cerebral ischemia. Neuroscience 150(1):50–57.  https://doi.org/10.1016/j.neuroscience.2007.06.029 CrossRefPubMedGoogle Scholar
  125. 125.
    Ortolano S, Spuch C (2013) tPA in the central nervous system: relations between tPA and cell surface LRPs. Recent Pat Endocr Metab Immune Drug Discov 7(1):65–76CrossRefPubMedGoogle Scholar
  126. 126.
    Polavarapu R, Gongora MC, Yi H, Ranganthan S, Lawrence DA, Strickland D, Yepes M (2007) Tissue-type plasminogen activator-mediated shedding of astrocytic low-density lipoprotein receptor-related protein increases the permeability of the neurovascular unit. Blood 109(8):3270–3278.  https://doi.org/10.1182/blood-2006-08-043125 CrossRefPubMedPubMedCentralGoogle Scholar
  127. 127.
    Kim SY, Cheon SY, Kim EJ, Lee JH, Kam EH, Kim JM, Park M, Koo BN (2017) Isoflurane postconditioning inhibits tPA-induced matrix metalloproteinases activation after hypoxic injury via low-density lipoprotein receptor-related protein and extracellular signal-regulated kinase pathway. Neurochem Res 42(5):1533–1542.  https://doi.org/10.1007/s11064-017-2211-2 CrossRefPubMedGoogle Scholar
  128. 128.
    Su EJ, Fredriksson L, Geyer M, Folestad E, Cale J, Andrae J, Gao Y, Pietras K, Mann K, Yepes M, Strickland DK, Betsholtz C, Eriksson U, Lawrence DA (2008) Activation of PDGF-CC by tissue plasminogen activator impairs blood–brain barrier integrity during ischemic stroke. Nat Med 14(7):731–737.  https://doi.org/10.1038/nm1787 CrossRefPubMedPubMedCentralGoogle Scholar
  129. 129.
    Wahlgren N, Thoren M, Hojeberg B, Kall TB, Laska AC, Sjostrand C, Hoijer J, Almqvist H, Holmin S, Lilja A, Fredriksson L, Lawrence D, Eriksson U, Ahmed N (2017) Randomized assessment of imatinib in patients with acute ischaemic stroke treated with intravenous thrombolysis. J Intern Med 281(3):273–283.  https://doi.org/10.1111/joim.12576 CrossRefPubMedGoogle Scholar
  130. 130.
    Macrez R, Obiang P, Gauberti M, Roussel B, Baron A, Parcq J, Casse F, Hommet Y, Orset C, Agin V, Bezin L, Berrocoso TG, Petersen KU, Montaner J, Maubert E, Vivien D, Ali C (2011) Antibodies preventing the interaction of tissue-type plasminogen activator with N-methyl-d-aspartate receptors reduce stroke damages and extend the therapeutic window of thrombolysis. Stroke 42(8):2315–2322.  https://doi.org/10.1161/STROKEAHA.110.606293 CrossRefPubMedGoogle Scholar
  131. 131.
    Macrez R, Ortega MC, Bardou I, Mehra A, Fournier A, Van der Pol SM, Haelewyn B, Maubert E, Lesept F, Chevilley A, de Castro F, De Vries HE, Vivien D, Clemente D, Docagne F (2016) Neuroendothelial NMDA receptors as therapeutic targets in experimental autoimmune encephalomyelitis. Brain J Neurol 139(Pt 9):2406–2419.  https://doi.org/10.1093/brain/aww172 CrossRefGoogle Scholar
  132. 132.
    Knowland D, Arac A, Sekiguchi KJ, Hsu M, Lutz SE, Perrino J, Steinberg GK, Barres BA, Nimmerjahn A, Agalliu D (2014) Stepwise recruitment of transcellular and paracellular pathways underlies blood–brain barrier breakdown in stroke. Neuron 82(3):603–617.  https://doi.org/10.1016/j.neuron.2014.03.003 CrossRefPubMedPubMedCentralGoogle Scholar
  133. 133.
    Krueger M, Hartig W, Reichenbach A, Bechmann I, Michalski D (2013) Blood–brain barrier breakdown after embolic stroke in rats occurs without ultrastructural evidence for disrupting tight junctions. PLoS One 8(2):e56419.  https://doi.org/10.1371/journal.pone.0056419 CrossRefPubMedPubMedCentralGoogle Scholar
  134. 134.
    Zhao XJ, Larkin TM, Lauver MA, Ahmad S, Ducruet AF (2017) Tissue plasminogen activator mediates deleterious complement cascade activation in stroke. PLoS One 12(7):e0180822.  https://doi.org/10.1371/journal.pone.0180822 CrossRefPubMedPubMedCentralGoogle Scholar
  135. 135.
    Hiu T, Nakagawa S, Hayashi K, Kitagawa N, Tsutsumi K, Kawakubo J, Honda M, Suyama K, Nagata I, Niwa M (2008) Tissue plasminogen activator enhances the hypoxia/reoxygenation-induced impairment of the blood–brain barrier in a primary culture of rat brain endothelial cells. Cell Mol Neurobiol 28(8):1139–1146.  https://doi.org/10.1007/s10571-008-9294-x CrossRefPubMedGoogle Scholar
  136. 136.
    Benchenane K, Berezowski V, Ali C, Fernandez-Monreal M, Lopez-Atalaya JP, Brillault J, Chuquet J, Nouvelot A, MacKenzie ET, Bu G, Cecchelli R, Touzani O, Vivien D (2005) Tissue-type plasminogen activator crosses the intact blood–brain barrier by low-density lipoprotein receptor-related protein-mediated transcytosis. Circulation.  https://doi.org/10.1161/01.cir.0000163542.48611.a2 CrossRefPubMedGoogle Scholar
  137. 137.
    Choi DW (1988) Glutamate neurotoxicity and diseases of the nervous system. Neuron 1(8):623–634CrossRefPubMedGoogle Scholar
  138. 138.
    Rothman SM (1983) Synaptic activity mediates death of hypoxic neurons. Science 220(4596):536–537CrossRefPubMedGoogle Scholar
  139. 139.
    Dawson LA, Djali S, Gonzales C, Vinegra MA, Zaleska MM (2000) Characterization of transient focal ischemia-induced increases in extracellular glutamate and aspartate in spontaneously hypertensive rats. Brain Res Bull 53(6):767–776CrossRefPubMedGoogle Scholar
  140. 140.
    Lebeurrier N, Liot G, Lopez-Atalaya JP, Orset C, Fernandez-Monreal M, Sonderegger P, Ali C, Vivien D (2005) The brain-specific tissue-type plasminogen activator inhibitor, neuroserpin, protects neurons against excitotoxicity both in vitro and in vivo. Mol Cell Neurosci 30(4):552–558.  https://doi.org/10.1016/j.mcn.2005.09.005 CrossRefPubMedGoogle Scholar
  141. 141.
    Tsirka SE, Gualandris A, Amaral DG, Strickland S (1995) Excitotoxin-induced neuronal degeneration and seizure are mediated by tissue plasminogen activator. Nature 377(6547):340–344.  https://doi.org/10.1038/377340a0 CrossRefPubMedGoogle Scholar
  142. 142.
    Siddiq MM, Tsirka SE (2004) Modulation of zinc toxicity by tissue plasminogen activator. Mol Cell Neurosci 25(1):162–171.  https://doi.org/10.1016/j.mcn.2003.10.007 CrossRefPubMedGoogle Scholar
  143. 143.
    Fernandez-Monreal M, Lopez-Atalaya JP, Benchenane K, Leveille F, Cacquevel M, Plawinski L, MacKenzie ET, Bu G, Buisson A, Vivien D (2004) Is tissue-type plasminogen activator a neuromodulator? Mol Cell Neurosci 25(4):594–601.  https://doi.org/10.1016/j.mcn.2003.11.002 CrossRefPubMedGoogle Scholar
  144. 144.
    Wroge CM, Hogins J, Eisenman L, Mennerick S (2012) Synaptic NMDA receptors mediate hypoxic excitotoxic death. J Neurosci 32(19):6732–6742.  https://doi.org/10.1523/JNEUROSCI.6371-11.2012 CrossRefPubMedPubMedCentralGoogle Scholar
  145. 145.
    Choi DW (1985) Glutamate neurotoxicity in cortical cell culture is calcium dependent. Neurosci Lett 58(3):293–297CrossRefPubMedGoogle Scholar
  146. 146.
    Centonze D, Napolitano M, Saulle E, Gubellini P, Picconi B, Martorana A, Pisani A, Gulino A, Bernardi G, Calabresi P (2002) Tissue plasminogen activator is required for corticostriatal long-term potentiation. Eur J Neurosci 16(4):713–721CrossRefPubMedGoogle Scholar
  147. 147.
    Fernandez-Monreal M, Lopez-Atalaya JP, Benchenane K, Cacquevel M, Dulin F, Le Caer JP, Rossier J, Jarrige AC, Mackenzie ET, Colloc’h N, Ali C, Vivien D (2004) Arginine 260 of the amino-terminal domain of NR1 subunit is critical for tissue-type plasminogen activator-mediated enhancement of N-methyl-d-aspartate receptor signaling. J Biol Chem 279(49):50850–50856.  https://doi.org/10.1074/jbc.M407069200 CrossRefPubMedGoogle Scholar
  148. 148.
    Goulay R, Naveau M, Gaberel T, Vivien D, Parcq J (2018) Optimized tPA: a non-neurotoxic fibrinolytic agent for the drainage of intracerebral hemorrhages. J Cereb Blood Flow Metab 38(7):1180–1189.  https://doi.org/10.1177/0271678X17719180 CrossRefPubMedGoogle Scholar
  149. 149.
    Baron A, Montagne A, Casse F, Launay S, Maubert E, Ali C, Vivien D (2010) NR2D-containing NMDA receptors mediate tissue plasminogen activator-promoted neuronal excitotoxicity. Cell Death Differ 17(5):860–871.  https://doi.org/10.1038/cdd.2009.172 CrossRefPubMedGoogle Scholar
  150. 150.
    Jullienne A, Montagne A, Orset C, Lesept F, Jane DE, Monaghan DT, Maubert E, Vivien D, Ali C (2011) Selective inhibition of GluN2D-containing N-methyl-d-aspartate receptors prevents tissue plasminogen activator-promoted neurotoxicity both in vitro and in vivo. Mol Neurodegener 6:68.  https://doi.org/10.1186/1750-1326-6-68 CrossRefPubMedPubMedCentralGoogle Scholar
  151. 151.
    Fu Y, Liu Q, Anrather J, Shi FD (2015) Immune interventions in stroke. Nat Rev Neurol 11(9):524–535.  https://doi.org/10.1038/nrneurol.2015.144 CrossRefPubMedPubMedCentralGoogle Scholar
  152. 152.
    Asahi M, Asahi K, Jung JC, del Zoppo GJ, Fini ME, Lo EH (2000) Role for matrix metalloproteinase 9 after focal cerebral ischemia: effects of gene knockout and enzyme inhibition with BB-94. J Cereb Blood Flow Metab 20(12):1681–1689.  https://doi.org/10.1097/00004647-200012000-00007 CrossRefPubMedGoogle Scholar
  153. 153.
    Matsuo Y, Onodera H, Shiga Y, Shozuhara H, Ninomiya M, Kihara T, Tamatani T, Miyasaka M, Kogure K (1994) Role of cell adhesion molecules in brain injury after transient middle cerebral artery occlusion in the rat. Brain Res 656(2):344–352CrossRefPubMedGoogle Scholar
  154. 154.
    Hickey WF, Vass K, Lassmann H (1992) Bone marrow-derived elements in the central nervous system: an immunohistochemical and ultrastructural survey of rat chimeras. J Neuropathol Exp Neurol 51(3):246–256CrossRefPubMedGoogle Scholar
  155. 155.
    Kreutzberg GW (1996) Microglia: a sensor for pathological events in the CNS. Trends Neurosci 19(8):312–318CrossRefPubMedGoogle Scholar
  156. 156.
    Lenglet S, Montecucco F, Denes A, Coutts G, Pinteaux E, Mach F, Schaller K, Gasche Y, Copin JC (2014) Recombinant tissue plasminogen activator enhances microglial cell recruitment after stroke in mice. J Cereb Blood Flow Metab 34(5):802–812.  https://doi.org/10.1038/jcbfm.2014.9 CrossRefPubMedPubMedCentralGoogle Scholar
  157. 157.
    Rogove AD, Siao C, Keyt B, Strickland S, Tsirka SE (1999) Activation of microglia reveals a non-proteolytic cytokine function for tissue plasminogen activator in the central nervous system. J Cell Sci 112(Pt 22):4007–4016PubMedGoogle Scholar
  158. 158.
    Won S, Lee JK, Stein DG (2015) Recombinant tissue plasminogen activator promotes, and progesterone attenuates, microglia/macrophage M1 polarization and recruitment of microglia after MCAO stroke in rats. Brain Behav Immun 49:267–279.  https://doi.org/10.1016/j.bbi.2015.06.007 CrossRefPubMedGoogle Scholar
  159. 159.
    Cunningham C (2013) Microglia and neurodegeneration: the role of systemic inflammation. Glia 61(1):71–90.  https://doi.org/10.1002/glia.22350 CrossRefPubMedGoogle Scholar
  160. 160.
    Gregersen R, Lambertsen K, Finsen B (2000) Microglia and macrophages are the major source of tumor necrosis factor in permanent middle cerebral artery occlusion in mice. J Cereb Blood Flow Metab 20(1):53–65.  https://doi.org/10.1097/00004647-200001000-00009 CrossRefPubMedGoogle Scholar
  161. 161.
    Chao CC, Hu S, Ehrlich L, Peterson PK (1995) Interleukin-1 and tumor necrosis factor-alpha synergistically mediate neurotoxicity: involvement of nitric oxide and of N-methyl-d-aspartate receptors. Brain Behav Immun 9(4):355–365CrossRefPubMedGoogle Scholar
  162. 162.
    Clausen B, Degn M, Martin N, Couch Y, Karimi L, Ormhoj M et al (2014) Systemically administered anti-TNF therapy ameliorates functional outcomes after focal cerebral ischemia. J Neuroinflamm 11:203CrossRefGoogle Scholar
  163. 163.
    Perego C, Fumagalli S, De Simoni MG (2011) Temporal pattern of expression and colocalization of microglia/macrophage phenotype markers following brain ischemic injury in mice. J Neuroinflamm 8:174.  https://doi.org/10.1186/1742-2094-8-174 CrossRefGoogle Scholar
  164. 164.
    Hu X, Li P, Guo Y, Wang H, Leak RK, Chen S, Gao Y, Chen J (2012) Microglia/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia. Stroke 43(11):3063–3070.  https://doi.org/10.1161/STROKEAHA.112.659656 CrossRefPubMedGoogle Scholar
  165. 165.
    Gelderblom M, Neumann M, Ludewig P, Bernreuther C, Krasemann S, Arunachalam P, Gerloff C, Glatzel M, Magnus T (2013) Deficiency in serine protease inhibitor neuroserpin exacerbates ischemic brain injury by increased postischemic inflammation. PLoS One 8(5):e63118.  https://doi.org/10.1371/journal.pone.0063118 CrossRefPubMedPubMedCentralGoogle Scholar
  166. 166.
    Abe Y, Nakamura H, Yoshino O, Oya T, Kimura T (2003) Decreased neural damage after spinal cord injury in tPA-deficient mice. J Neurotrauma 20(1):43–57.  https://doi.org/10.1089/08977150360517173 CrossRefPubMedGoogle Scholar
  167. 167.
    Pekny M, Nilsson M (2005) Astrocyte activation and reactive gliosis. Glia 50(4):427–434.  https://doi.org/10.1002/glia.20207 CrossRefPubMedGoogle Scholar
  168. 168.
    Yip HK, Yuen CM, Chen KH, Chai HT, Chung SY, Tong MS, Chen SY, Kao GS, Chen CH, Chen YL, Huang TH, Sun CK, Lee MS (2016) Tissue plasminogen activator deficiency preserves neurological function and protects against murine acute ischemic stroke. Int J Cardiol 205:133–141.  https://doi.org/10.1016/j.ijcard.2015.11.168 CrossRefPubMedGoogle Scholar
  169. 169.
    Bao Y, Qin L, Kim E, Bhosle S, Guo H, Febbraio M, Haskew-Layton RE, Ratan R, Cho S (2012) CD36 is involved in astrocyte activation and astroglial scar formation. J Cereb Blood Flow Metab 32(8):1567–1577.  https://doi.org/10.1038/jcbfm.2012.52 CrossRefPubMedPubMedCentralGoogle Scholar
  170. 170.
    Cekanaviciute E, Buckwalter MS (2016) Astrocytes: integrative regulators of neuroinflammation in stroke and other neurological diseases. Neurother J Am Soc Exp Neurother 13(4):685–701.  https://doi.org/10.1007/s13311-016-0477-8 CrossRefGoogle Scholar
  171. 171.
    Kim YH, Park JH, Hong SH, Koh JY (1999) Nonproteolytic neuroprotection by human recombinant tissue plasminogen activator. Science 284(5414):647–650CrossRefPubMedGoogle Scholar
  172. 172.
    Lu B, Nagappan G, Guan X, Nathan PJ, Wren P (2013) BDNF-based synaptic repair as a disease-modifying strategy for neurodegenerative diseases. Nat Rev Neurosci 14(6):401–416.  https://doi.org/10.1038/nrn3505 CrossRefPubMedGoogle Scholar
  173. 173.
    Rudge JS, Mather PE, Pasnikowski EM, Cai N, Corcoran T, Acheson A, Anderson K, Lindsay RM, Wiegand SJ (1998) Endogenous BDNF protein is increased in adult rat hippocampus after a kainic acid induced excitotoxic insult but exogenous BDNF is not neuroprotective. Exp Neurol 149(2):398–410.  https://doi.org/10.1006/exnr.1997.6737 CrossRefPubMedGoogle Scholar
  174. 174.
    Pang PT, Teng HK, Zaitsev E, Woo NT, Sakata K, Zhen S, Teng KK, Yung WH, Hempstead BL, Lu B (2004) Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity. Science 306(5695):487–491.  https://doi.org/10.1126/science.1100135 CrossRefPubMedPubMedCentralGoogle Scholar
  175. 175.
    Rodier M, Prigent-Tessier A, Bejot Y, Jacquin A, Mossiat C, Marie C, Garnier P (2014) Exogenous t-PA administration increases hippocampal mature BDNF levels. plasmin- or NMDA-dependent mechanism? PLoS One 9(3):e92416.  https://doi.org/10.1371/journal.pone.0092416 CrossRefPubMedPubMedCentralGoogle Scholar
  176. 176.
    Papadia S, Stevenson P, Hardingham NR, Bading H, Hardingham GE (2005) Nuclear Ca2 + and the cAMP response element-binding protein family mediate a late phase of activity-dependent neuroprotection. J Neurosci 25(17):4279–4287.  https://doi.org/10.1523/JNEUROSCI.5019-04.2005 CrossRefPubMedGoogle Scholar
  177. 177.
    Zhang SJ, Buchthal B, Lau D, Hayer S, Dick O, Schwaninger M, Veltkamp R, Zou M, Weiss U, Bading H (2011) A signaling cascade of nuclear calcium-CREB-ATF3 activated by synaptic NMDA receptors defines a gene repression module that protects against extrasynaptic NMDA receptor-induced neuronal cell death and ischemic brain damage. J Neurosci 31(13):4978–4990.  https://doi.org/10.1523/JNEUROSCI.2672-10.2011 CrossRefPubMedGoogle Scholar
  178. 178.
    An J, Haile WB, Wu F, Torre E, Yepes M (2014) Tissue-type plasminogen activator mediates neuroglial coupling in the central nervous system. Neuroscience 257:41–48.  https://doi.org/10.1016/j.neuroscience.2013.10.060 CrossRefPubMedGoogle Scholar
  179. 179.
    Liot G, Roussel BD, Lebeurrier N, Benchenane K, Lopez-Atalaya JP, Vivien D, Ali C (2006) Tissue-type plasminogen activator rescues neurones from serum deprivation-induced apoptosis through a mechanism independent of its proteolytic activity. J Neurochem 98(5):1458–1464.  https://doi.org/10.1111/j.1471-4159.2006.03982.x CrossRefPubMedGoogle Scholar
  180. 180.
    Nakka VP, Gusain A, Raghubir R (2010) Endoplasmic reticulum stress plays critical role in brain damage after cerebral ischemia/reperfusion in rats. Neurotox Res 17(2):189–202.  https://doi.org/10.1007/s12640-009-9110-5 CrossRefPubMedGoogle Scholar
  181. 181.
    Goswami P, Gupta S, Biswas J, Joshi N, Swarnkar S, Nath C, Singh S (2016) Endoplasmic reticulum stress plays a key role in rotenone-induced apoptotic death of neurons. Mol Neurobiol 53(1):285–298.  https://doi.org/10.1007/s12035-014-9001-5 CrossRefPubMedGoogle Scholar
  182. 182.
    Louessard M, Bardou I, Lemarchand E, Thiebaut AM, Parcq J, Leprince J, Terrisse A, Carraro V, Fafournoux P, Bruhat A, Orset C, Vivien D, Ali C, Roussel BD (2017) Activation of cell surface GRP78 decreases endoplasmic reticulum stress and neuronal death. Cell Death Differ 24(9):1518–1529.  https://doi.org/10.1038/cdd.2017.35 CrossRefPubMedPubMedCentralGoogle Scholar
  183. 183.
    Wu F, Nicholson AD, Haile WB, Torre E, An J, Chen C, Lee AK, Duong DM, Dammer EB, Seyfried NT, Tong FC, Votaw JR, Yepes M (2013) Tissue-type plasminogen activator mediates neuronal detection and adaptation to metabolic stress. J Cereb Blood Flow Metab 33(11):1761–1769.  https://doi.org/10.1038/jcbfm.2013.124 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Neurology, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina

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