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Current Neuropharmacology


ISSN (Print): 1570-159X
ISSN (Online): 1875-6190

Review Article

Crosstalk between Inflammation and the BBB in Stroke

Author(s): Yuyou Huang, Shengpan Chen, Yumin Luo* and Ziping Han*

Volume 18, Issue 12, 2020

Page: [1227 - 1236] Pages: 10

DOI: 10.2174/1570159X18666200620230321

Price: $65


The blood-brain barrier (BBB), which is located at the interface between the central nervous system (CNS) and the circulatory system, is instrumental in establishing and maintaining the microenvironmental homeostasis of the CNS. BBB disruption following stroke promotes inflammation by enabling leukocytes, T cells and other immune cells to migrate via both the paracellular and transcellular routes across the BBB and to infiltrate the CNS parenchyma. Leukocytes promote the removal of necrotic tissues and neuronal recovery, but they also aggravate BBB injury and exacerbate stroke outcomes, especially after late reperfusion. Moreover, the swelling of astrocyte endfeet is thought to contribute to the ‘no-reflow’ phenomenon observed after cerebral ischemia, that is, blood flow cannot return to capillaries after recanalization of large blood vessels. Pericyte recruitment and subsequent coverage of endothelial cells (ECs) alleviate BBB disruption, which causes the transmigration of inflammatory cells across the BBB to be a dynamic process. Furthermore, interneurons and perivascular microglia also make contacts with ECs, astrocytes and pericytes to establish the neurovascular unit. BBB-derived factors after cerebral ischemia triggered microglial activation. During the later stage of injury, microglia remain associated with brain ECs and contribute to repair mechanisms, including postinjury angiogenesis, by acquiring a protective phenotype, which possibly occurs through the release of microglia-derived soluble factors. Taken together, we reviewed dynamic and bidirectional crosstalk between inflammation and the BBB during stroke and revealed targeted interventions based on the crosstalk between inflammation and the BBB, which will provide novel insights for developing new therapeutic strategies.

Keywords: Stroke, blood-brain barrier, inflammation, innate immunity, adaptive immunity, treatment.

Graphical Abstract
Keaney, J.; Campbell, M. The dynamic blood-brain barrier. FEBS J., 2015, 282(21), 4067-4079.
Villabona-Rueda, A.; Erice, C.; Pardo, C.A.; Stins, M.F. The evolving concept of the blood brain barrier (bbb): from a single static barrier to a heterogeneous and dynamic relay center. Front. Cell. Neurosci., 2019, 13, 405.
Wu, J.; He, J.; Tian, X.; Zhong, J.; Li, H.; Sun, X. Activation of the hedgehog pathway promotes recovery of neurological function after traumatic brain injury by protecting the neurovascular unit. Transl. Stroke Res., 2020, 11(4), 720-733.
[] [PMID: 31898187]
Kim, J.S. tPA Helpers in the treatment of acute ischemic stroke: are they ready for clinical use? J. Stroke, 2019, 21(2), 160-174.
Jiang, X.; Andjelkovic, A.V.; Zhu, L.; Yang, T.; Bennett, M.V.L.; Chen, J.; Keep, R.F.; Shi, Y. Blood-brain barrier dysfunction and recovery after ischemic stroke. Prog. Neurobiol., 2017, 163-164, 144-171.
Gaitan, M.I.; Shea, C.D.; Evangelou, I.E.; Stone, R.D.; Fenton, K.M.; Bielekova, B.; Massacesi, L.; Reich, D.S. Evolution of the blood-brain barrier in newly forming multiple sclerosis lesions. Ann. Neurol., 2011, 70(11), 22-29.
Zhao, S.C.; Ma, L.S.; Chu, Z.H.; Xu, H.; Wu, W.Q.; Liu, F. Regulation of microglial activation in stroke. Acta Pharmacol. Sin., 2017, 38(4), 445-458.
Jones, K.A.; Maltby, S.; Plank, M.W.; Kluge, M.; Nilsson, M.; Foster, P.S.; Walker, F.R. Peripheral immune cells infiltrate into sites of secondary neurodegeneration after ischemic stroke. Brain Behav. Immun., 2018, 67299-67307.
Moisan, A.; Favre, I.M.; Rome, C.; Grillon, E.; Naegele, B.; Barbieux, M.; De Fraipont, F.; Richard, M.J.; Barbier, E.L.; Remy, C.; Detante, O. Microvascular plasticity after experimental stroke: a molecular and MRI study. Cerebrovasc. Dis., 2014, 38(5), 344-353.
Lin, C.S.; Krishnan, A.V.; Lee, M.J.; Zagami, A.S.; You, H.L.; Yang, C.C.; Bostock, H.; Kiernan, M.C. Nerve function and dysfunction in acute intermittent porphyria. Brain, 2008, 131(Pt 9), 2510-2519.
Duris, K.; Splichal, Z.; Jurajda, M. The role of inflammatory response in stroke associated programmed cell death. Curr. Neuropharmacol., 2018, 16(9), 1365-1374.
Planas, A.M. Role of immune cells migrating to the ischemic brain. Stroke, 2018, 49(9), 2261-2267.
Gelderblom, M.; Leypoldt, F.; Steinbach, K.; Behrens, D.; Choe, C.U.; Siler, D.A.; Arumugam, T.V.; Orthey, E.; Gerloff, C.; Tolosa, E.; Magnus, T. Temporal and spatial dynamics of cerebral immune cell accumulation in stroke. Stroke, 2009, 40(5), 1849-1857.
Kollikowski, A.M.; Schuhmann, M.K.; Nieswandt, B.; Mullges, W.; Stoll, G.; Pham, M. Local leukocyte invasion during hyperacute human ischemic stroke. Ann. Neurol., 2020, 87(3), 466-479.
Kim, D.D.; Barr, A.M.; Fredrikson, D.H.; Honer, W.G.; Procyshyn, R.M. Association between serum lipids and antipsychotic response in schizophrenia. Curr. Neuropharmacol., 2019, 17(9), 852-860.
Yang, C.S.; Yuk, J.M.; Shin, D.M.; Kang, J.; Lee, S.J.; Jo, E.K. Secretory phospholipase A2 plays an essential role in microglial inflammatory responses to Mycobacterium tuberculosis. Glia, 2009, 57(10), 1091-1103.
Schilling, M.; Besselmann, M.; Leonhard, C.; Mueller, M.; Ringelstein, E.B.; Kiefer, R. Microglial activation precedes and predominates over macrophage infiltration in transient focal cerebral ischemia: a study in green fluorescent protein transgenic bone marrow chimeric mice. Exp. Neurol., 2003, 183(1), 25-33.
Lampron, A.; Elali, A.; Rivest, S. Innate immunity in the CNS: redefining the relationship between the CNS and its environment. Neuron, 2013, 78(2), 214-232.
Su, E.J.; Cao, C.; Fredriksson, L.; Nilsson, I.; Stefanitsch, C.; Stevenson, T.K.; Zhao, J.; Ragsdale, M.; Sun, Y.Y.; Yepes, M.; Kuan, C.Y.; Eriksson, U.; Strickland, D.K.; Lawrence, D.A.; Zhang, L. Microglial-mediated PDGF-CC activation increases cerebrovascular permeability during ischemic stroke. Acta Neuropathol., 2017, 134(4), 585-604.
Zhao, C.; Wang, H.; Xiong, C.; Liu, Y. Hypoxic glioblastoma release exosomal VEGF-A induce the permeability of blood-brain barrier. Biochem. Biophys. Res. Commun., 2018, 502(3), 324-331.
Potente, M.; Gerhardt, H.; Carmeliet, P. Basic and therapeutic aspects of angiogenesis. Cell, 2011, 146(6), 873-887.
Dudvarski Stankovic, N.; Teodorczyk, M.; Ploen, R.; Zipp, F.; Schmidt, M.H.H. Microglia-blood vessel interactions: a double-edged sword in brain pathologies. Acta Neuropathol., 2016, 131(3), 347-363.
Thomsen, M.S.; Routhe, L.J.; Moos, T. The vascular basement membrane in the healthy and pathological brain. J. Cereb. Blood Flow Metab., 2017, 37(10), 3300-3317.
Anrather, J.; Iadecola, C. Inflammation and stroke: an overview. Neurotherapeutics, 2016, 13(4), 61-670.
Halder, S.K.; Milner, R. A critical role for microglia in maintaining vascular integrity in the hypoxic spinal cord. Proc. Natl. Acad. Sci. USA, 2019, 116(51), 26029-26037.
Haruwaka, K.; Ikegami, A.; Tachibana, Y.; Ohno, N.; Konishi, H.; Hashimoto, A.; Matsumoto, M.; Kato, D.; Ono, R.; Kiyama, H.; Moorhouse, A.J.; Nabekura, J.; Wake, H. Dual microglia effects on blood brain barrier permeability induced by systemic inflammation. Nat. Commun., 2019, 10(1), 5816.
Blecharz-Lang, K.G.; Wagner, J.; Fries, A.; Nieminen-Kelha, M.; Rosner, J.; Schneider, U.C.; Vajkoczy, P. Interleukin 6-mediated endothelial barrier disturbances can be attenuated by blockade of the il6 receptor expressed in brain microvascular endothelial cells. Transl. Stroke Res., 2018, 9(6), 631-642.
Liddelow, S.A.; Barres, B.A. Reactive astrocytes: production, function, and therapeutic potential. Immunity, 2017, 46(6), 957-967.
Yang, S.; Jin, H.; Zhu, Y.; Wan, Y.; Opoku, E.N.; Zhu, L.; Hu, B. Diverse functions and mechanisms of pericytes in ischemic stroke. Curr. Neuropharmacol., 2017, 15(6), 892-905.
Ozen, I.; Deierborg, T.; Miharada, K.; Padel, T.; Englund, E.; Genove, G.; Paul, G. Brain pericytes acquire a microglial phenotype after stroke. Acta Neuropathol., 2014, 128(3), 381-396.
Thurgur, H.; Pinteaux, E. Microglia in the neurovascular unit: blood-brain barrier-microglia interactions after central nervous system disorders. Neuroscience, 2019, 40, 555-567.
Lo, E.H. A new penumbra: transitioning from injury into repair after stroke. Nat. Med., 2008, 14(5), 497-500.
Abdullahi, W.; Tripathi, D.; Ronaldson, P.T. Blood-brain barrier dysfunction in ischemic stroke: targeting tight junctions and transporters for vascular protection. Am. J. Physiol. Cell Physiol., 2018, 315(3), C343-C356.
Ahn, G.O.; Tseng, D.; Liao, C.H.; Dorie, M.J.; Czechowicz, A.; Brown, J.M. Inhibition of Mac-1 (CD11b/CD18) enhances tumor response to radiation by reducing myeloid cell recruitment. Proc. Natl. Acad. Sci. USA, 2010, 107(18), 8363-8368.
Kanazawa, M.; Ninomiya, I.; Hatakeyama, M.; Takahashi, T.; Shimohata, T. Microglia and monocytes/macrophages polarizationreveal novel therapeutic mechanism against stroke. Int. J. Mol. Sci., 2017, 18(10), 2135.
Jolivel, V.; Bicker, F.; Biname, F.; Ploen, R.; Keller, S.; Gollan, R.; Jurek, B.; Birkenstock, J.; Poisa-Beiro, L.; Bruttger, J.; Opitz, V.; Thal, S.C.; Waisman, A.; Bauerle, T.; Schafer, M.K.; Zipp, F.; Schmidt, M.H.H. Perivascular microglia promote blood vessel disintegration in the ischemic penumbra. Acta Neuropathol., 2015, 129(2), 279-295.
Yu, I.C.; Kuo, P.C.; Yen, J.H.; Paraiso, H.C.; Curfman, E.T.; Hong-Goka, B.C.; Sweazey, R.D.; Chang, F.L. A Combination of three repurposed drugs administered at reperfusion as a promising therapy for postischemic brain injury. Transl. Stroke Res., 2017, 8(6), 560-577.
Kant, R.; Halder, S.K.; Fernandez, J.A.; Griffin, J.H.; Milner, R. Activated Protein C Attenuates experimental autoimmune encephalomyelitis progression by enhancing vascular integrity and suppressing microglial activation. Front. Neurosci., 2020, 14, 333.
Yang, Y.; Salayandia, V.M.; Thompson, J.F.; Yang, L.Y.; Estrada, E.Y.; Yang, Y. Attenuation of acute stroke injury in rat brain by minocycline promotes blood-brain barrier remodeling and alternative microglia/macrophage activation during recovery. J. Neuroinflammation, 2015, 12, 26.
Lou, N.; Takano, T.; Pei, Y.; Xavier, A.L.; Goldman, S.A.; Nedergaard, M. Purinergic receptor P2RY12-dependent microglial closure of the injured blood-brain barrier. Proc. Natl. Acad. Sci. USA, 2016, 113(4), 1074-1079.
Rosenberg, G.A. Extracellular matrix inflammation in vascular cognitive impairment and dementia. Clin. Sci. (Lond.), 2017, 131(6), 425-437.
Milner, R. Microglial expression of alphavbeta3 and alphavbeta5 integrins is regulated by cytokines and the extracellular matrix: beta5 integrin null microglia show no defects in adhesion or MMP-9 expression on vitronectin. Glia, 2009, 57(7), 714-723.
Obermeier, B.; Daneman, R.; Ransohoff, R.M. Development, maintenance and disruption of the blood-brain barrier. Nat. Med., 2013, 19(12), 1584-1596.
van Horssen, J.; Vos, C.M.; Admiraal, L.; van Haastert, E.S.; Montagne, L.; van der Valk, P.; de Vries, H.E. Matrix metalloproteinase-19 is highly expressed in active multiple sclerosis lesions. Neuropathol. Appl. Neurobiol., 2006, 32(6), 585-593.
Asano, S.; Chantler, P.D.; Barr, T.L. Gene expression profiling in stroke: relevance of blood-brain interaction. Curr. Opin. Pharmacol., 2016, 2680-2686.
Gelderblom, M.; Weymar, A.; Bernreuther, C.; Velden, J.; Arunachalam, P.; Steinbach, K.; Orthey, E.; Arumugam, T.V.; Leypoldt, F.; Simova, O.; Thom, V.; Friese, M.A.; Prinz, I.; Holscher, C.; Glatzel, M.; Korn, T.; Gerloff, C.; Tolosa, E.; Magnus, T. Neutralization of the IL-17 axis diminishes neutrophil invasion and protects from ischemic stroke. Blood, 2012, 120(18), 3793-3802.
Wong, R.; Lenart, N.; Hill, L.; Toms, L.; Coutts, G.; Martinecz, B.; Csaszar, E.; Nyiri, G.; Papaemmanouil, A.; Waisman, A.; Muller, W.; Schwaninger, M.; Rothwell, N.; Francis, S.; Pinteaux, E.; Denes, A.; Allan, S.M. Interleukin-1 mediates ischaemic brain injury via distinct actions on endothelial cells and cholinergic neurons. Brain Behav. Immun., 2019, 76, 126-138.
Gorina, R.; Lyck, R.; Vestweber, D.; Engelhardt, B. 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., 2014, 192(1), 324-337.
Gautam, J.; Miner, J.H.; Yao, Y. Loss of endothelial laminin alpha5 exacerbates hemorrhagic brain injury. Transl. Stroke Res., 2019, 10(6), 705-718.
Cuartero, M.I.; Ballesteros, I.; Moraga, A.; Nombela, F.; Vivancos, J.; Hamilton, J.A.; Corbi, A.L.; Lizasoain, I.; Moro, M.A. N2 neutrophils, novel players in brain inflammation after stroke: modulation by the PPARgamma agonist rosiglitazone. Stroke, 2013, 44(12), 3498-3508.
Amantea, D.; Micieli, G.; Tassorelli, C.; Cuartero, M.I.; Ballesteros, I.; Certo, M.; Moro, M.A.; Lizasoain, I.; Bagetta, G. Rational modulation of the innate immune system for neuroprotection in ischemic stroke. Front. Neurosci., 2015, 91, 47.
Enzmann, G.; Mysiorek, C.; Gorina, R.; Cheng, Y.J.; Ghavampour, S.; Hannocks, M.J.; Prinz, V.; Dirnagl, U.; Endres, M.; Prinz, M.; Beschorner, R.; Harter, P.N.; Mittelbronn, M.; Engelhardt, B.; Sorokin, L. The neurovascular unit as a selective barrier to polymorphonuclear granulocyte (PMN) infiltration into the brain after ischemic injury. Acta Neuropathol., 2013, 125(3), 395-412.
Perez-de-Puig, I.; Miro-Mur, F.; Ferrer-Ferrer, M.; Gelpi, E.; Pedragosa, J.; Justicia, C.; Urra, X.; Chamorro, A.; Planas, A.M. Neutrophil recruitment to the brain in mouse and human ischemic stroke. Acta Neuropathol., 2015, 129(2), 239-257.
Neumann, J.; Riek-Burchardt, M.; Herz, J.; Doeppner, T.R.; Konig, R.; Hutten, H.; Etemire, E.; Mann, L.; Klingberg, A.; Fischer, T.; Gortler, M.W.; Heinze, H.J.; Reichardt, P.; Schraven, B.; Hermann, D.M.; Reymann, K.G.; Gunzer, M. Very-late-antigen-4 (VLA-4)-mediated brain invasion by neutrophils leads to interactions with microglia, increased ischemic injury and impaired behavior in experimental stroke. Acta Neuropathol., 2015, 129(2), 259-277.
Carman, C.V.; Springer, T.A. Trans-cellular migration: cell-cell contacts get intimate. Curr. Opin. Cell Biol., 2008, 20(5), 533-540.
Shen, Q.; Rigor, R.R.; Pivetti, C.D.; Wu, M.H.; Yuan, S.Y. Myosin light chain kinase in microvascular endothelial barrier function. Cardiovasc. Res., 2010, 87(2), 272-280.
Zhang, D.; Tang, Q.; Zheng, G.; Wang, C.; Zhou, Y.; Wu, Y.; Xuan, J.; Tian, N.; Wang, X.; Wu, Y.; Xu, H.; Zhang, X. Metformin ameliorates BSCB disruption by inhibiting neutrophil infiltration and MMP-9 expression but not direct TJ proteins expression regulation. J. Cell. Mol. Med., 2017, 21(12), 3322-3336.
Chen, C.; Li, T.; Zhao, Y.; Qian, Y.; Li, X.; Dai, X.; Huang, D.; Pan, T.; Zhou, L. Platelet glycoprotein receptor Ib blockade ameliorates experimental cerebral ischemia-reperfusion injury by strengthening the blood-brain barrier function and anti-thrombo-inflammatory property. Brain Behav. Immun., 2018, 69, 255-263.
Lim, K.; Sumagin, R.; Hyun, Y.M. Extravasating neutrophil-derived microparticles preserve vascular barrier function in inflamed tissue. Immune Netw., 2013, 13(3), 102-106.
Lindsberg, P.J.; Strbian, D.; Karjalainen-Lindsberg, M.L. Mast cells as early responders in the regulation of acute blood-brain barrier changes after cerebral ischemia and hemorrhage. J. Cereb. Blood Flow Metab., 2010, 30(4), 689-702.
Wilcock, A.; Bahri, R.; Bulfone-Paus, S.; Arkwright, P.D. Mast cell disorders: From infancy to maturity. Allergy, 2019, 74(1), 53-63.
Parrella, E.; Porrini, V.; Benarese, M.; Pizzi, M. The role of Mast cells in stroke. Cells, 2019, 8(5)
Tran, H.; Mittal, A.; Sagi, V.; Luk, K.; Nguyen, A.; Gupta, M.; Nguyen, J.; Lamarre, Y.; Lei, J.; Guedes, A.; Gupta, K. Mast cells induce blood brain barrier damage in scd by causing endoplasmic reticulum stress in the endothelium. Front. Cell. Neurosci., 2019, 1356.
McKittrick, C.M.; Lawrence, C.E.; Carswell, H.V. Mast cells promote blood brain barrier breakdown and neutrophil infiltration in a mouse model of focal cerebral ischemia. J. Cereb. Blood Flow Metab., 2015, 35(5), 638-647.
Kuhn, K.A.; Stappenbeck, T.S. Peripheral education of the immune system by the colonic microbiota. Semin. Immunol., 2013, 25(5), 364-369.
Vartanian, K.B.; Stevens, S.L.; Marsh, B.J.; Williams-Karnesky, R.; Lessov, N.S.; Stenzel-Poore, M.P. LPS preconditioning redirects TLR signaling following stroke: TRIF-IRF3 plays a seminal role in mediating tolerance to ischemic injury. J. Neuroinflammation, 2011, 81, 40.
Ribatti, D. The crucial role of mast cells in blood-brain barrier alterations. Exp. Cell Res., 2015, 338(1), 119-125.
Strbian, D.; Karjalainen-Lindsberg, M.L.; Tatlisumak, T.; Lindsberg, P.J. Cerebral mast cells regulate early ischemic brain swelling and neutrophil accumulation. J. Cereb. Blood Flow Metab., 2006, 26(5), 605-612.
Wimmer, I.; Tietz, S.; Nishihara, H.; Deutsch, U.; Sallusto, F.; Gosselet, F.; Lyck, R.; Muller, W.A.; Lassmann, H.; Engelhardt, B. PECAM-1 Stabilizes blood-brain barrier integrity and favors paracellular t-cell diapedesis across the blood-brain barrier during neuroinflammation. Front. Immunol., 2019, 10, 711.
de Graaf, M.T.; Smitt, P.A.; Luitwieler, R.L.; van Velzen, C.; van den Broek, P.D.; Kraan, J.; Gratama, J.W. Central memory CD4+ T cells dominate the normal cerebrospinal fluid. Cytometry B Clin. Cytom., 2011, 80(1), 43-50.
Xie, L.; Yang, S.H. Interaction of astrocytes and T cells in physiological and pathological conditions. Brain Res., 2015, 16, 2363-2373.
Kebir, H.; Kreymborg, K.; Ifergan, I.; Dodelet-Devillers, A.; Cayrol, R.; Bernard, M.; Giuliani, F.; Arbour, N.; Becher, B.; Prat, A. Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation. Nat. Med., 2007, 13(10), 1173-1175.
Shekhar, S.; Cunningham, M.W.; Pabbidi, M.R.; Wang, S.; Booz, G.W.; Fan, F. Targeting vascular inflammation in ischemic stroke: Recent developments on novel immunomodulatory approaches. Eur. J. Pharmacol., 2018, 83, 3531-3544.
Chen, Z.; Bozec, A.; Ramming, A.; Schett, G. Anti-inflammatory and immune-regulatory cytokines in rheumatoid arthritis. Nat. Rev. Rheumatol., 2019, 15(1), 9-17.
Beurel, E. Regulation of inflammation and T cells by glycogen synthase kinase-3: links to mood disorders. Neuroimmunomodulation, 2014, 21(2-3), 140-144.
Lopes Pinheiro, M.A.; Kooij, G.; Mizee, M.R.; Kamermans, A.; Enzmann, G.; Lyck, R.; Schwaninger, M.; Engelhardt, B.; de Vries, H.E. Immune cell trafficking across the barriers of the central nervous system in multiple sclerosis and stroke. Biochim. Biophys. Acta, 2016, 1862(3), 461-471.
Mao, L.; Li, P.; Zhu, W.; Cai, W.; Liu, Z.; Wang, Y.; Luo, W.; Stetler, R.A.; Leak, R.K.; Yu, W.; Gao, Y.; Chen, J.; Chen, G.; Hu, X. Regulatory T cells ameliorate tissue plasminogen activator-induced brain haemorrhage after stroke. Brain, 2017, 140(7), 1914-1931.
Xie, L.; Choudhury, G.R.; Winters, A.; Yang, S.H.; Jin, K. Cerebral regulatory T cells restrain microglia/macrophage-mediated inflammatory responses via IL-10. Eur. J. Immunol., 2015, 45(1), 180-191.
Mezey, E.; Palkovits, M. Neuroanatomy: Forgotten findings of brain lymphatics. Nature, 2015, 254(7566), 415.
Semyachkina-Glushkovskaya, O.; Abdurashitov, A.; Dubrovsky, A.; Bragin, D.; Bragina, O.; Shushunova, N.; Maslyakova, G.; Navolokin, N.; Bucharskaya, A.; Tuchin, V.; Kurths, J.; Shirokov, A. Application of optical coherence tomography for in vivo monitoring of the meningeal lymphatic vessels during opening of blood-brain barrier: mechanisms of brain clearing. J. Biomed. Opt., 2017, 22(12), 1-9.
Chen, Y.; Won, S.J.; Xu, Y.; Swanson, R.A. Targeting microglial activation in stroke therapy: pharmacological tools and gender effects. Curr. Med. Chem., 2014, 21(19), 2146-2155.
Lampl, Y.; Boaz, M.; Gilad, R.; Lorberboym, M.; Dabby, R.; Rapoport, A.; Anca-Hershkowitz, M.; Sadeh, M. Minocycline treatment in acute stroke: an open-label, evaluator-blinded study. Neurology, 2007, 69(14), 1404-1410.
Koistinaho, M.; Malm, T.M.; Kettunen, M.I.; Goldsteins, G.; Starckx, S.; Kauppinen, R.A.; Opdenakker, G.; Koistinaho, J. Minocycline protects against permanent cerebral ischemia in wild type but not in matrix metalloprotease-9-deficient mice. J. Cereb. Blood Flow Metab., 2005, 25(4), 460-467.
Yenari, M.A.; Xu, L.; Tang, X.N.; Qiao, Y.; Giffard, R.G. Microglia potentiate damage to blood-brain barrier constituents: improvement by minocycline in vivo and in vitro. Stroke, 2006, 37(4), 1087-1093.
Drieu, A.; Buendia, I.; Levard, D.; Helie, P.; Brodin, C.; Vivien, D.; Rubio, M. immune responses and anti-inflammatory strategies in a clinically relevant model of thromboembolic ischemic stroke with reperfusion. Transl. Stroke Res., 2019, 11(3), 481-495.
[] [PMID: 31522409]
Murata, Y.; Rosell, A.; Scannevin, R.H.; Rhodes, K.J.; Wang, X.; Lo, E.H. Extension of the thrombolytic time window with minocycline in experimental stroke. Stroke, 2008, 39(12), 3372-3377.
Chen, F.; Wang, W.; Ding, H.; Yang, Q.; Dong, Q.; Cui, M. The glucagon-like peptide-1 receptor agonist exendin-4 ameliorates warfarin-associated hemorrhagic transformation after cerebral ischemia. J. Neuroinflammation, 2016, 13(1), 204.
Sohrabji, F.; Williams, M. Stroke neuroprotection: oestrogen and insulin-like growth factor-1 interactions and the role of microglia. J. Neuroendocrinol., 2013, 25(11), 1173-1181.
Lalancette-Hebert, M.; Gowing, G.; Simard, A.; Weng, Y.C.; Kriz, J. Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain. J. Neurosci., 2007, 27(10), 2596-2605.
Kitamura, Y.; Takata, K.; Inden, M.; Tsuchiya, D.; Yanagisawa, D.; Nakata, J.; Taniguchi, T. Intracerebroventricular injection of microglia protects against focal brain ischemia. J. Pharmacol. Sci., 2004, 94(2), 203-206.
Lu, Y.; Li, C.; Chen, Q.; Liu, P.; Guo, Q.; Zhang, Y.; Chen, X.; Zhang, Y.; Zhou, W.; Liang, D.; Zhang, Y.; Sun, T.; Lu, W.; Jiang, C. Microthrombus-targeting micelles for neurovascular remodeling and enhanced microcirculatory perfusion in acute ischemic stroke. Adv. Mater., 2019, 31(21)e1808361
Chen, F.; Weng, Z.; Xia, Q.; Cao, C.; Leak, R.K.; Han, L.; Xiao, J.; Graham, S.H.; Cao, G. Intracerebroventricular delivery of recombinant nampt deters inflammation and protects against cerebral ischemia. Transl. Stroke Res., 2019, 10(6), 719-728.
da Fonseca, A. C.; Matias, D.; Garcia, C.; Amaral, R.; Geraldo, L. H.; Freitas, C.; Lima, F. R. The impact of microglial activation on blood-brain barrier in brain diseases.Front. Cell Neurosci , 2014, 83-62.
Ghuman, H.; Massensini, A.R.; Donnelly, J.; Kim, S.M.; Medberry, C.J.; Badylak, S.F.; Modo, M. ECM hydrogel for the treatment of stroke: Characterization of the host cell infiltrate. Biomaterials, 2016, 91, 166-181.
Pradillo, J.M.; Denes, A.; Greenhalgh, A.D.; Boutin, H.; Drake, C.; McColl, B.W.; Barton, E.; Proctor, S.D.; Russell, J.C.; Rothwell, N.J.; Allan, S.M. Delayed administration of interleukin-1 receptor antagonist reduces ischemic brain damage and inflammation in comorbid rats. J. Cereb. Blood Flow Metab., 2012, 32(9), 1810-1819.
Fu, Y.; Hao, J.; Zhang, N.; Ren, L.; Sun, N.; Li, Y.J.; Yan, Y.; Huang, D.; Yu, C.; Shi, F.D. Fingolimod for the treatment of intracerebral hemorrhage: a 2-arm proof-of-concept study. JAMA Neurol., 2014, 71(9), 1092-1101.
Fu, Y.; Zhang, N.; Ren, L.; Yan, Y.; Sun, N.; Li, Y.J.; Han, W.; Xue, R.; Liu, Q.; Hao, J.; Yu, C.; Shi, F.D. Impact of an immune modulator fingolimod on acute ischemic stroke. Proc. Natl. Acad. Sci. USA, 2014, 111(51), 18315-18320.
Wei, Y.; Yemisci, M.; Kim, H.H.; Yung, L.M.; Shin, H.K.; Hwang, S.K.; Guo, S.; Qin, T.; Alsharif, N.; Brinkmann, V.; Liao, J.K.; Lo, E.H.; Waeber, C. Fingolimod provides long-term protection in rodent models of cerebral ischemia. Ann. Neurol., 2011, 69(1), 119-129.
During, M.J.; Symes, C.W.; Lawlor, P.A.; Lin, J.; Dunning, J.; Fitzsimons, H.L.; Poulsen, D.; Leone, P.; Xu, R.; Dicker, B.L.; Lipski, J.; Young, D. An oral vaccine against NMDAR1 with efficacy in experimental stroke and epilepsy. Science, 2000, 287(5457), 1453-1460.
Zhao, R.; Jiang, J.; Li, H.; Chen, M.; Liu, R.; Sun, S. Phosphatidylserine-microbubble targeting-activated microglia/macrophage in inflammation combined with ultrasound for breaking through the blood-brain barrier. J. Neuroinflammation, 2018, 15(1), 334.
Pocock, S.J.; McMurray, J.J.V.; Collier, T.J. Statistical controversies in reporting of clinical trials: part 2 of a 4-part series on statistics for clinical trials. J. Am. Coll. Cardiol., 2015, 66(23), 2648-2662.
Kim, J.Y.; Kawabori, M.; Yenari, M.A. Innate inflammatory responses in stroke: mechanisms and potential therapeutic targets. Curr. Med. Chem., 2014, 21(18), 2076-2097.

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