The Relationship of Astrocytes and Microglia with Different Stages of
Ischemic Stroke

Zhen      Liang; Yingyue      Lou; Yulei      Hao; Hui      Li; Jiachun      Feng; Songyan      Liu
doi:10.2174/1570159X21666230718104634
Abstract

Ischemic stroke is the predominant cause of severe morbidity and mortality worldwide. Post-stroke neuroinflammation has recently received increasing attention with the aim of providing a new effective treatment strategy for ischemic stroke. Microglia and astrocytes are major components of the innate immune system of the central nervous system. They can be involved in all phases of ischemic stroke, from the early stage, contributing to the first wave of neuronal cell death, to the late stage involving phagocytosis and repair. In the early stage of ischemic stroke, a vicious cycle exists between the activation of microglia and astrocytes (through astrocytic connexin 43 hemichannels), aggravating neuroinflammatory injury post-stroke. However, in the late stage of ischemic stroke, repeatedly activated microglia can induce the formation of glial scars by triggering reactive astrogliosis in the peri-infarct regions, which may limit the movement of activated microglia in reverse and restrict the diffusion of inflammation to healthy brain tissues, alleviating the neuroinflammatory injury poststroke. In this review, we elucidated the various roles of astrocytes and microglia and summarized their relationship with neuroinflammation. We also examined how astrocytes and microglia influence each other at different stages of ischemic stroke. Several potential therapeutic approaches targeting astrocytes and microglia in ischemic stroke have been reviewed. Understanding the details of astrocytemicroglia interaction processes will contribute to a better understanding of the mechanisms underlying ischemic stroke, contributing to the identification of new therapeutic interventions.
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Graphical Abstract

[1]
Lo, E.H.; Dalkara, T.; Moskowitz, M.A. Mechanisms, challenges and opportunities in stroke. Nat. Rev. Neurosci.,  2003, 4(5), 399-414.
 [http://dx.doi.org/10.1038/nrn1106] [PMID: 12728267]

[2]
Timmis, A.; Townsend, N.; Gale, C.P.; Torbica, A.; Lettino, M.; Petersen, S.E.; Mossialos, E.A.; Maggioni, A.P.; Kazakiewicz, D.; May, H.T.; De Smedt, D.; Flather, M.; Zuhlke, L.; Beltrame, J.F.; Huculeci, R.; Tavazzi, L.; Hindricks, G.; Bax, J.; Casadei, B.; Achenbach, S.; Wright, L.; Vardas, P.; Mimoza, L.; Artan, G.; Aurel, D.; Chettibi, M.; Hammoudi, N.; Sisakian, H.; Pepoyan, S.; Metzler, B.; Siostrzonek, P.; Weidinger, F.; Jahangirov, T.; Aliyev, F.; Rustamova, Y.; Manak, N.; Mrochak, A.; Lancellotti, P.; Pasquet, A.; Claeys, M. Kušljugić Z.; Dizdarević Hudić, L.; Smajić, E.; Tokmakova, M.P.; Gatzov, P.M.; Milicic, D.; Bergovec, M.; Christou, C.; Moustra, H.H.; Christodoulides, T.; Linhart, A.; Taborsky, M.; Hansen, H.S.; Holmvang, L.; Kristensen, S.D.; Abdelhamid, M.; Shokry, K.; Kampus, P.; Viigimaa, M.; Ryödi, E.; Niemelä, M.; Rissanen, T.T.; Le Heuzey, J-Y.; Gilard, M.; Aladashvili, A.; Gamkrelidze, A.; Kereselidze, M.; Zeiher, A.; Katus, H.; Bestehorn, K.; Tsioufis, C.; Goudevenos, J.; Csanádi, Z.; Becker, D.; Tóth, K.; Jóna, H.Þ.; Crowley, J.; Kearney, P.; Dalton, B.; Zahger, D.; Wolak, A.; Gabrielli, D.; Indolfi, C.; Urbinati, S.; Imantayeva, G.; Berkinbayev, S.; Bajraktari, G.; Ahmeti, A.; Berisha, G.; Erkin, M.; Saamay, A.; Erglis, A.; Bajare, I.; Jegere, S.; Mohammed, M.; Sarkis, A.; Saadeh, G.; Zvirblyte, R.; Sakalyte, G.; Slapikas, R.; Ellafi, K.; El Ghamari, F.; Banu, C.; Beissel, J.; Felice, T.; Buttigieg, S.C.; Xuereb, R.G.; Popovici, M.; Boskovic, A.; Rabrenovic, M.; Ztot, S.; Abir-Khalil, S.; van Rossum, A.C.; Mulder, B.J.M.; Elsendoorn, M.W.; Srbinovska-Kostovska, E.; Kostov, J.; Marjan, B.; Steigen, T.; Mjølstad, O.C.; Ponikowski, P.; Witkowski, A.; Jankowski, P.; Gil, V.M.; Mimoso, J.; Baptista, S.; Vinereanu, D.; Chioncel, O.; Popescu, B.A.; Shlyakhto, E.; Oganov, R.; Foscoli, M.; Zavatta, M.; Dikic, A.D.; Beleslin, B.; Radovanovic, M.R.; Hlivák, P.; Hatala, R.; Kaliská, G.; Kenda, M.; Fras, Z.; Anguita, M.; Cequier, Á.; Muñiz, J.; James, S.; Johansson, B.; Platonov, P.; Zellweger, M.J.; Pedrazzini, G.B.; Carballo, D.; Shebli, H.E.; Kabbani, S.; Abid, L.; Addad, F.; Bozkurt, E.; Kayıkçıoğlu, M.; Erol, M.K.; Kovalenko, V.; Nesukay, E.; Wragg, A.; Ludman, P.; Ray, S.; Kurbanov, R.; Boateng, D.; Daval, G.; de Benito, R.V.; Sebastiao, D.; de Courtelary, P.T.; Bardinet, I. European society of cardiology: Cardiovascular disease statistics 2019. Eur. Heart J.,  2020, 41(1), 12-85.
 [http://dx.doi.org/10.1093/eurheartj/ehz859] [PMID: 31820000]

[3]
Guzik, A.; Bushnell, C. Stroke epidemiology and risk factor management. Continuum,  2017, 23, 15-39.
 [http://dx.doi.org/10.1212/CON.0000000000000416]

[4]
Zini, A. Reperfusion therapies in acute ischemic stroke. G. Ital. Cardiol.,  2019, 20(5), 279-288.
 [PMID: 31066370]

[5]
Iadecola, C.; Anrather, J. The immunology of stroke: From mechanisms to translation. Nat. Med.,  2011, 17(7), 796-808.
 [http://dx.doi.org/10.1038/nm.2399] [PMID: 21738161]

[6]
Bernardo-Castro, S.; Sousa, J.A.; Brás, A.; Cecília, C.; Rodrigues, B.; Almendra, L.; Machado, C.; Santo, G.; Silva, F.; Ferreira, L.; Santana, I.; Sargento-Freitas, J. Pathophysiology of blood–brain barrier permeability throughout the different stages of ischemic stroke and its implication on hemorrhagic transformation and recovery. Front. Neurol.,  2020, 11, 594672.
 [http://dx.doi.org/10.3389/fneur.2020.594672] [PMID: 33362697]

[7]
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.,  2018, 163-164, 144-171.
 [http://dx.doi.org/10.1016/j.pneurobio.2017.10.001] [PMID: 28987927]

[8]
Pelvig, D.P.; Pakkenberg, H.; Stark, A.K.; Pakkenberg, B. Neocortical glial cell numbers in human brains. Neurobiol. Aging,  2008, 29(11), 1754-1762.
 [http://dx.doi.org/10.1016/j.neurobiolaging.2007.04.013] [PMID: 17544173]

[9]
Goshi, N.; Morgan, R.K.; Lein, P.J.; Seker, E. A primary neural cell culture model to study neuron, astrocyte, and microglia interactions in neuroinflammation. J. Neuroinflammation,  2020, 17(1), 155.
 [http://dx.doi.org/10.1186/s12974-020-01819-z] [PMID: 32393376]

[10]
Vandenbark, A.A.; Offner, H.; Matejuk, S.; Matejuk, A. Microglia and astrocyte involvement in neurodegeneration and brain cancer. J. Neuroinflammation,  2021, 18(1), 298.
 [http://dx.doi.org/10.1186/s12974-021-02355-0] [PMID: 34949203]

[11]
Pekny, M.; Wilhelmsson, U.; Tatlisumak, T.; Pekna, M. Astrocyte activation and reactive gliosis—A new target in stroke? Neurosci. Lett.,  2019, 689, 45-55.
 [http://dx.doi.org/10.1016/j.neulet.2018.07.021] [PMID: 30025833]

[12]
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, 9, 147.
 [http://dx.doi.org/10.3389/fnins.2015.00147] [PMID: 25972779]

[13]
Dirnagl, U.; Iadecola, C.; Moskowitz, M.A. Pathobiology of ischaemic stroke: An integrated view. Trends Neurosci.,  1999, 22(9), 391-397.
 [http://dx.doi.org/10.1016/S0166-2236(99)01401-0] [PMID: 10441299]

[14]
Xing, C.; Arai, K.; Lo, E.H.; Hommel, M. Pathophysiologic cascades in ischemic stroke. Int. J. Stroke,  2012, 7(5), 378-385.
 [http://dx.doi.org/10.1111/j.1747-4949.2012.00839.x] [PMID: 22712739]

[15]
Liang, Z.; Wang, X.; Hao, Y.; Qiu, L.; Lou, Y.; Zhang, Y.; Ma, D.; Feng, J. The multifaceted role of astrocyte connexin 43 in ischemic stroke through forming hemichannels and gap junctions. Front. Neurol.,  2020, 11, 703.
 [http://dx.doi.org/10.3389/fneur.2020.00703] [PMID: 32849190]

[16]
Grewer, C.; Gameiro, A.; Zhang, Z.; Tao, Z.; Braams, S.; Rauen, T. Glutamate forward and reverse transport: From molecular mechanism to transporter-mediated release after ischemia. IUBMB Life,  2008, 60(9), 609-619.
 [http://dx.doi.org/10.1002/iub.98] [PMID: 18543277]

[17]
Dong, Q.; He, J.; Chai, Z. Astrocytic Ca2+ waves mediate activation of extrasynaptic NMDA receptors in hippocampal neurons to aggravate brain damage during ischemia. Neurobiol. Dis.,  2013, 58, 68-75.
 [http://dx.doi.org/10.1016/j.nbd.2013.05.005] [PMID: 23702310]

[18]
Kitchen, P.; Salman, M.M.; Halsey, A.M.; Clarke-Bland, C.; MacDonald, J.A.; Ishida, H.; Vogel, H.J.; Almutiri, S.; Logan, A.; Kreida, S.; Al-Jubair, T.; Winkel Missel, J.; Gourdon, P.; Törnroth-Horsefield, S.; Conner, M.T.; Ahmed, Z.; Conner, A.C.; Bill, R.M. Targeting aquaporin-4 subcellular localization to treat central nervous system edema. Cell,  2020, 181(4), 784-799.e19.
 [http://dx.doi.org/10.1016/j.cell.2020.03.037] [PMID: 32413299]

[19]
Pereda, A.E. Electrical synapses and their functional interactions with chemical synapses. Nat. Rev. Neurosci.,  2014, 15(4), 250-263.
 [http://dx.doi.org/10.1038/nrn3708] [PMID: 24619342]

[20]
Li, H.; Zhang, N.; Lin, H.Y.; Yu, Y.; Cai, Q.Y.; Ma, L.; Ding, S. Histological, cellular and behavioral assessments of stroke outcomes after photothrombosis-induced ischemia in adult mice. BMC Neurosci.,  2014, 15(1), 58.
 [http://dx.doi.org/10.1186/1471-2202-15-58] [PMID: 24886391]

[21]
Pekny, M.; Nilsson, M. Astrocyte activation and reactive gliosis. Glia,  2005, 50(4), 427-434.
 [http://dx.doi.org/10.1002/glia.20207] [PMID: 15846805]

[22]
Zong, X.; Li, Y.; Liu, C.; Qi, W.; Han, D.; Tucker, L.; Dong, Y.; Hu, S.; Yan, X.; Zhang, Q. Theta-burst transcranial magnetic stimulation promotes stroke recovery by vascular protection and neovascularization. Theranostics,  2020, 10(26), 12090-12110.
 [http://dx.doi.org/10.7150/thno.51573] [PMID: 33204331]

[23]
Zhou, M.; Zhang, T.; Zhang, X.; Zhang, M.; Gao, S.; Zhang, T.; Li, S.; Cai, X.; Li, J.; Lin, Y. Effect of tetrahedral framework nucleic acids on neurological recovery via ameliorating apoptosis and regulating the activation and polarization of astrocytes in ischemic stroke. ACS Appl. Mater. Interfaces,  2022, 14(33), 37478-37492.
 [http://dx.doi.org/10.1021/acsami.2c10364] [PMID: 35951372]

[24]
Liddelow, S.A.; Guttenplan, K.A.; Clarke, L.E.; Bennett, F.C.; Bohlen, C.J.; Schirmer, L.; Bennett, M.L.; Münch, A.E.; Chung, W.S.; Peterson, T.C.; Wilton, D.K.; Frouin, A.; Napier, B.A.; Panicker, N.; Kumar, M.; Buckwalter, M.S.; Rowitch, D.H.; Dawson, V.L.; Dawson, T.M.; Stevens, B.; Barres, B.A. Neurotoxic reactive astrocytes are induced by activated microglia. Nature,  2017, 541(7638), 481-487.
 [http://dx.doi.org/10.1038/nature21029] [PMID: 28099414]

[25]
Zamanian, J.L.; Xu, L.; Foo, L.C.; Nouri, N.; Zhou, L.; Giffard, R.G.; Barres, B.A. Genomic analysis of reactive astrogliosis. J. Neurosci.,  2012, 32(18), 6391-6410.
 [http://dx.doi.org/10.1523/JNEUROSCI.6221-11.2012] [PMID: 22553043]

[26]
Bush, T.G.; Puvanachandra, N.; Horner, C.H.; Polito, A.; Ostenfeld, T.; Svendsen, C.N.; Mucke, L.; Johnson, M.H.; Sofroniew, M.V. Leukocyte infiltration, neuronal degeneration, and neurite outgrowth after ablation of scar-forming, reactive astrocytes in adult transgenic mice. Neuron,  1999, 23(2), 297-308.
 [http://dx.doi.org/10.1016/S0896-6273(00)80781-3] [PMID: 10399936]

[27]
Faulkner, J.R.; Herrmann, J.E.; Woo, M.J.; Tansey, K.E.; Doan, N.B.; Sofroniew, M.V. Reactive astrocytes protect tissue and preserve function after spinal cord injury. J. Neurosci.,  2004, 24(9), 2143-2155.
 [http://dx.doi.org/10.1523/JNEUROSCI.3547-03.2004] [PMID: 14999065]

[28]
Okada, S.; Nakamura, M.; Katoh, H.; Miyao, T.; Shimazaki, T.; Ishii, K.; Yamane, J.; Yoshimura, A.; Iwamoto, Y.; Toyama, Y.; Okano, H. Conditional ablation of Stat3 or Socs3 discloses a dual role for reactive astrocytes after spinal cord injury. Nat. Med.,  2006, 12(7), 829-834.
 [http://dx.doi.org/10.1038/nm1425] [PMID: 16783372]

[29]
Liddelow, S.A.; Barres, B.A. Reactive astrocytes: Production, function, and therapeutic potential. Immunity,  2017, 46(6), 957-967.
 [http://dx.doi.org/10.1016/j.immuni.2017.06.006] [PMID: 28636962]

[30]
Ito, D.; Tanaka, K.; Suzuki, S.; Dembo, T.; Fukuuchi, Y. Enhanced expression of Iba1, ionized calcium-binding adapter molecule 1, after transient focal cerebral ischemia in rat brain. Stroke,  2001, 32(5), 1208-1215.
 [http://dx.doi.org/10.1161/01.STR.32.5.1208] [PMID: 11340235]

[31]
Cherry, J.D.; Olschowka, J.A.; O’Banion, M.K. Neuroinflammation and M2 microglia: The good, the bad, and the inflamed. J. Neuroinflammation,  2014, 11(1), 98.
 [http://dx.doi.org/10.1186/1742-2094-11-98] [PMID: 24889886]

[32]
Masuda, T.; Sankowski, R.; Staszewski, O.; Prinz, M. Microglia heterogeneity in the single-cell era. Cell Rep.,  2020, 30(5), 1271-1281.
 [http://dx.doi.org/10.1016/j.celrep.2020.01.010] [PMID: 32023447]

[33]
Keren-Shaul, H.; Spinrad, A.; Weiner, A.; Matcovitch-Natan, O.; Dvir-Szternfeld, R.; Ulland, T.K.; David, E.; Baruch, K.; Lara-Astaiso, D.; Toth, B.; Itzkovitz, S.; Colonna, M.; Schwartz, M.; Amit, I. A unique microglia type associated with restricting development of alzheimer’s disease. Cell,  2017, 169(7), 1276-1290.e17.
 [http://dx.doi.org/10.1016/j.cell.2017.05.018] [PMID: 28602351]

[34]
Deczkowska, A.; Keren-Shaul, H.; Weiner, A.; Colonna, M.; Schwartz, M.; Amit, I. Disease-associated microglia: A universal immune sensor of neurodegeneration. Cell,  2018, 173(5), 1073-1081.
 [http://dx.doi.org/10.1016/j.cell.2018.05.003] [PMID: 29775591]

[35]
Andersen, R.S.; Anand, A.; Harwood, D.S.L.; Kristensen, B.W. Tumor-associated microglia and macrophages in the glioblastoma microenvironment and their implications for therapy. Cancers,  2021, 13(17), 4255.
 [http://dx.doi.org/10.3390/cancers13174255] [PMID: 34503065]

[36]
Bachiller, S.; Jiménez-Ferrer, I.; Paulus, A.; Yang, Y.; Swanberg, M.; Deierborg, T.; Boza-Serrano, A. Microglia in neurological diseases: A road map to brain-disease dependent-inflammatory response. Front. Cell. Neurosci.,  2018, 12, 488.
 [http://dx.doi.org/10.3389/fncel.2018.00488] [PMID: 30618635]

[37]
De Biase, L.M.; Schuebel, K.E.; Fusfeld, Z.H.; Jair, K.; Hawes, I.A.; Cimbro, R.; Zhang, H.Y.; Liu, Q.R.; Shen, H.; Xi, Z.X.; Goldman, D.; Bonci, A. Local cues establish and maintain region-specific phenotypes of basal ganglia microglia. Neuron,  2017, 95(2), 341-356.e6.
 [http://dx.doi.org/10.1016/j.neuron.2017.06.020] [PMID: 28689984]

[38]
Chen, D.; Li, J.; Huang, Y.; Wei, P.; Miao, W.; Yang, Y.; Gao, Y. Interleukin 13 promotes long-term recovery after ischemic stroke by inhibiting the activation of STAT3. J. Neuroinflammation,  2022, 19(1), 112.
 [http://dx.doi.org/10.1186/s12974-022-02471-5] [PMID: 35578342]

[39]
Xu, S.; Lu, J.; Shao, A.; Zhang, J.H.; Zhang, J. Glial cells: Role of the immune response in ischemic stroke. Front. Immunol.,  2020, 11, 294-294.
 [http://dx.doi.org/10.3389/fimmu.2020.00294] [PMID: 32174916]

[40]
Xia, Y.; Pu, H.; Leak, R.K.; Shi, Y.; Mu, H.; Hu, X.; Lu, Z.; Foley, L.M.; Hitchens, T.K.; Dixon, C.E.; Bennett, M.V.L.; Chen, J. Tissue plasminogen activator promotes white matter integrity and functional recovery in a murine model of traumatic brain injury. Proc. Natl. Acad. Sci.,  2018, 115(39), E9230-E9238.
 [http://dx.doi.org/10.1073/pnas.1810693115] [PMID: 30201709]

[41]
Correa, F.; Gauberti, M.; Parcq, J.; Macrez, R.; Hommet, Y.; Obiang, P.; Hernangómez, M.; Montagne, A.; Liot, G.; Guaza, C.; Maubert, E.; Ali, C.; Vivien, D.; Docagne, F. Tissue plasminogen activator prevents white matter damage following stroke. J. Exp. Med.,  2011, 208(6), 1229-1242.
 [http://dx.doi.org/10.1084/jem.20101880] [PMID: 21576385]

[42]
Wan, T.; Zhu, W.; Zhao, Y.; Zhang, X.; Ye, R.; Zuo, M.; Xu, P.; Huang, Z.; Zhang, C.; Xie, Y.; Liu, X. Astrocytic phagocytosis contributes to demyelination after focal cortical ischemia in mice. Nat. Commun.,  2022, 13(1), 1134.
 [http://dx.doi.org/10.1038/s41467-022-28777-9] [PMID: 35241660]

[43]
Hu, X.; Leak, R.K.; Shi, Y.; Suenaga, J.; Gao, Y.; Zheng, P.; Chen, J. Microglial and macrophage polarization—new prospects for brain repair. Nat. Rev. Neurol.,  2015, 11(1), 56-64.
 [http://dx.doi.org/10.1038/nrneurol.2014.207] [PMID: 25385337]

[44]
Ma, Y.; Wang, J.; Wang, Y.; Yang, G.Y. The biphasic function of microglia in ischemic stroke. Prog. Neurobiol.,  2017, 157, 247-272.
 [http://dx.doi.org/10.1016/j.pneurobio.2016.01.005] [PMID: 26851161]

[45]
Hu, X.; Li, P.; Guo, Y.; Wang, H.; Leak, R.K.; Chen, S.; Gao, Y.; Chen, J. Microglia/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia. Stroke,  2012, 43(11), 3063-3070.
 [http://dx.doi.org/10.1161/STROKEAHA.112.659656] [PMID: 22933588]

[46]
Song, S.; Wang, S.; Pigott, V.M.; Jiang, T.; Foley, L.M.; Mishra, A.; Nayak, R.; Zhu, W.; Begum, G.; Shi, Y.; Carney, K.E.; Hitchens, T.K.; Shull, G.E.; Sun, D. Selective role of Na+/H+ exchanger in Cx3cr1+ microglial activation, white matter demyelination, and post‐stroke function recovery. Glia,  2018, 66(11), 2279-2298.
 [http://dx.doi.org/10.1002/glia.23456] [PMID: 30043461]

[47]
Xing, L.; Yang, T.; Cui, S.; Chen, G. Connexin hemichannels in astrocytes: Role in CNS disorders. Front. Mol. Neurosci.,  2019, 12, 23-23.
 [http://dx.doi.org/10.3389/fnmol.2019.00023] [PMID: 30787868]

[48]
Rash, J.E.; Yasumura, T.; Dudek, F.E.; Nagy, J.I. Cell-specific expression of connexins and evidence of restricted gap junctional coupling between glial cells and between neurons. J. Neurosci.,  2001, 21(6), 1983-2000.
 [http://dx.doi.org/10.1523/JNEUROSCI.21-06-01983.2001] [PMID: 11245683]

[49]
Ma, D.; Feng, L.; Cheng, Y.; Xin, M.; You, J.; Yin, X.; Hao, Y.; Cui, L.; Feng, J. Astrocytic gap junction inhibition by carbenoxolone enhances the protective effects of ischemic preconditioning following cerebral ischemia. J. Neuroinflammation,  2018, 15(1), 198.
 [http://dx.doi.org/10.1186/s12974-018-1230-5] [PMID: 29976213]

[50]
Zhou, M.; Kiyoshi, C.M. Astrocyte syncytium: A functional reticular system in the brain. Neural Regen. Res.,  2019, 14(4), 595-596.
 [http://dx.doi.org/10.4103/1673-5374.247462] [PMID: 30632498]

[51]
Walz, W.; Hertz, L. Functional interactions between neurons and astrocytes. II. Potassium homeostasis at the cellular level. Prog. Neurobiol.,  1983, 20(1-2), 133-183.
 [http://dx.doi.org/10.1016/0301-0082(83)90013-8] [PMID: 6141593]

[52]
Goldberg, G.S.; Lampe, P.D.; Nicholson, B.J. Selective transfer of endogenous metabolites through gap junctions composed of different connexins. Nat. Cell Biol.,  1999, 1(7), 457-459.
 [http://dx.doi.org/10.1038/15693] [PMID: 10559992]

[53]
Verkhratsky, A.; Parpura, V.; Vardjan, N.; Zorec, R. Physiology of astroglia. Adv. Exp. Med. Biol.,  2019, 1175, 45-91.
 [http://dx.doi.org/10.1007/978-981-13-9913-8_3] [PMID: 31583584]

[54]
Huang, Y.H.; Bergles, D.E. Glutamate transporters bring competition to the synapse. Curr. Opin. Neurobiol.,  2004, 14(3), 346-352.
 [http://dx.doi.org/10.1016/j.conb.2004.05.007] [PMID: 15194115]

[55]
Cronin, M.; Anderson, P.N.; Cook, J.E.; Green, C.R.; Becker, D.L. Blocking connexin43 expression reduces inflammation and improves functional recovery after spinal cord injury. Mol. Cell. Neurosci.,  2008, 39(2), 152-160.
 [http://dx.doi.org/10.1016/j.mcn.2008.06.005] [PMID: 18617007]

[56]
Cooper, C.D.; Lampe, P.D. Casein kinase 1 regulates connexin-43 gap junction assembly. J. Biol. Chem.,  2002, 277(47), 44962-44968.
 [http://dx.doi.org/10.1074/jbc.M209427200] [PMID: 12270943]

[57]
Contreras, J.E.; Sánchez, H.A.; Eugenín, E.A.; Speidel, D.; Theis, M.; Willecke, K.; Bukauskas, F.F.; Bennett, M.V.L.; Sáez, J.C. Metabolic inhibition induces opening of unapposed connexin 43 gap junction hemichannels and reduces gap junctional communication in cortical astrocytes in culture. Proc. Natl. Acad. Sci.,  2002, 99(1), 495-500.
 [http://dx.doi.org/10.1073/pnas.012589799] [PMID: 11756680]

[58]
Kostandy, B.B. The role of glutamate in neuronal ischemic injury: The role of spark in fire. Neurol. Sci.,  2012, 33(2), 223-237.
 [http://dx.doi.org/10.1007/s10072-011-0828-5] [PMID: 22044990]

[59]
Montero, T.D.; Orellana, J.A. Hemichannels: New pathways for gliotransmitter release. Neuroscience,  2015, 286, 45-59.
 [http://dx.doi.org/10.1016/j.neuroscience.2014.11.048] [PMID: 25475761]

[60]
Ding, S.; Wang, T.; Cui, W.; Haydon, P.G. Photothrombosis ischemia stimulates a sustained astrocytic Ca 2+ signaling in vivo. Glia,  2009, 57(7), 767-776.
 [http://dx.doi.org/10.1002/glia.20804] [PMID: 18985731]

[61]
Papadopoulos, M.C.; Verkman, A.S. Aquaporin water channels in the nervous system. Nat. Rev. Neurosci.,  2013, 14(4), 265-277.
 [http://dx.doi.org/10.1038/nrn3468] [PMID: 23481483]

[62]
Sylvain, N.J.; Salman, M.M.; Pushie, M.J.; Hou, H.; Meher, V.; Herlo, R.; Peeling, L.; Kelly, M.E. The effects of trifluoperazine on brain edema, aquaporin-4 expression and metabolic markers during the acute phase of stroke using photothrombotic mouse model. Biochim. Biophys. Acta Biomembr.,  2021, 1863(5), 183573.
 [http://dx.doi.org/10.1016/j.bbamem.2021.183573] [PMID: 33561476]

[63]
Wagner, D.C.; Scheibe, J.; Glocke, I.; Weise, G.; Deten, A.; Boltze, J.; Kranz, A. Object-based analysis of astroglial reaction and astrocyte subtype morphology after ischemic brain injury. Acta Neurobiol. Exp.,  2013, 73(1), 79-87.
 [PMID: 23595285]

[64]
Wang, H.; Song, G.; Chuang, H.; Chiu, C.; Abdelmaksoud, A.; Ye, Y.; Zhao, L. Portrait of glial scar in neurological diseases. Int. J. Immunopathol. Pharmacol.,  2018, 31, 2058738418801406.
 [http://dx.doi.org/10.1177/2058738418801406] [PMID: 30309271]

[65]
Göritz, C.; Dias, D.O.; Tomilin, N.; Barbacid, M.; Shupliakov, O.; Frisén, J. A pericyte origin of spinal cord scar tissue. Science,  2011, 333(6039), 238-242.
 [http://dx.doi.org/10.1126/science.1203165] [PMID: 21737741]

[66]
Liu, Z.; Chopp, M. Astrocytes, therapeutic targets for neuroprotection and neurorestoration in ischemic stroke. Prog. Neurobiol.,  2016, 144, 103-120.
 [http://dx.doi.org/10.1016/j.pneurobio.2015.09.008] [PMID: 26455456]

[67]
Teh, D.B.L.; Prasad, A.; Jiang, W.; Ariffin, M.Z.; Khanna, S.; Belorkar, A.; Wong, L.; Liu, X.; All, A.H. Transcriptome analysis reveals neuroprotective aspects of human reactive astrocytes induced by interleukin 1β. Sci. Rep.,  2017, 7(1), 13988.
 [http://dx.doi.org/10.1038/s41598-017-13174-w] [PMID: 29070875]

[68]
Sofroniew, M.V. Reactive astrocytes in neural repair and protection. Neuroscientist,  2005, 11(5), 400-407.
 [http://dx.doi.org/10.1177/1073858405278321] [PMID: 16151042]

[69]
de Pablo, Y.; Nilsson, M.; Pekna, M.; Pekny, M. Intermediate filaments are important for astrocyte response to oxidative stress induced by oxygen–glucose deprivation and reperfusion. Histochem. Cell Biol.,  2013, 140(1), 81-91.
 [http://dx.doi.org/10.1007/s00418-013-1110-0] [PMID: 23756782]

[70]
Liu, Z.; Li, Y.; Cui, Y.; Roberts, C.; Lu, M.; Wilhelmsson, U.; Pekny, M.; Chopp, M. Beneficial effects of gfap/vimentin reactive astrocytes for axonal remodeling and motor behavioral recovery in mice after stroke. Glia,  2014, 62(12), 2022-2033.
 [http://dx.doi.org/10.1002/glia.22723] [PMID: 25043249]

[71]
Li, L.; Lundkvist, A.; Andersson, D.; Wilhelmsson, U.; Nagai, N.; Pardo, A.C.; Nodin, C.; Ståhlberg, A.; Aprico, K.; Larsson, K.; Yabe, T.; Moons, L.; Fotheringham, A.; Davies, I.; Carmeliet, P.; Schwartz, J.P.; Pekna, M.; Kubista, M.; Blomstrand, F.; Maragakis, N.; Nilsson, M.; Pekny, M. Protective role of reactive astrocytes in brain ischemia. J. Cereb. Blood Flow Metab.,  2008, 28(3), 468-481.
 [http://dx.doi.org/10.1038/sj.jcbfm.9600546] [PMID: 17726492]

[72]
Yamashita, K.; Vogel, P.; Fritze, K.; Back, T.; Hossmann, K.A.; Wiessner, C. Monitoring the temporal and spatial activation pattern of astrocytes in focal cerebral ischemia using in situ hybridization to GFAP mRNA: Comparison withsgp-2 andhsp70 mRNA and the effect of glutamate receptor antagonists. Brain Res.,  1996, 735(2), 285-297.
 [http://dx.doi.org/10.1016/0006-8993(96)00578-1] [PMID: 8911667]

[73]
Barone, F.C.; Irving, E.A.; Ray, A.M.; Lee, J.C.; Kassis, S.; Kumar, S.; Badger, A.M.; White, R.F.; McVey, M.J.; Legos, J.J.; Erhardt, J.A.; Nelson, A.H.; Ohlstein, E.H.; Hunter, A.J.; Ward, K.; Smith, B.R.; Adams, J.L.; Parsons, A.A. SB 239063, a second-generation p38 mitogen-activated protein kinase inhibitor, reduces brain injury and neurological deficits in cerebral focal ischemia. J. Pharmacol. Exp. Ther.,  2001, 296(2), 312-321.
 [PMID: 11160612]

[74]
Sriram, K.; Benkovic, S.A.; Hebert, M.A.; Miller, D.B.; O’Callaghan, J.P. Induction of gp130-related cytokines and activation of JAK2/STAT3 pathway in astrocytes precedes up-regulation of glial fibrillary acidic protein in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of neurodegeneration: Key signaling pathway for astrogliosis in vivo? J. Biol. Chem.,  2004, 279(19), 19936-19947.
 [http://dx.doi.org/10.1074/jbc.M309304200] [PMID: 14996842]

[75]
O’Callaghan, J.P.; Kelly, K.A.; VanGilder, R.L.; Sofroniew, M.V.; Miller, D.B. Early activation of STAT3 regulates reactive astrogliosis induced by diverse forms of neurotoxicity. PLoS One,  2014, 9(7), e102003.
 [http://dx.doi.org/10.1371/journal.pone.0102003] [PMID: 25025494]

[76]
Lei, C.; Deng, J.; Wang, B.; Cheng, D.; Yang, Q.; Dong, H.; Xiong, L. Reactive oxygen species scavenger inhibits STAT3 activation after transient focal cerebral ischemia-reperfusion injury in rats. Anesth. Analg.,  2011, 113(1), 153-159.
 [http://dx.doi.org/10.1213/ANE.0b013e31821a9fbe] [PMID: 21525184]

[77]
Moon, L.D.F.; Fawcett, J.W. Reduction in CNS scar formation without concomitant increase in axon regeneration following treatment of adult rat brain with a combination of antibodies to TGFβ;1 and β;2. Eur. J. Neurosci.,  2001, 14(10), 1667-1677.
 [http://dx.doi.org/10.1046/j.0953-816x.2001.01795.x] [PMID: 11860461]

[78]
Schachtrup, C.; Ryu, J.K.; Helmrick, M.J.; Vagena, E.; Galanakis, D.K.; Degen, J.L.; Margolis, R.U.; Akassoglou, K. Fibrinogen triggers astrocyte scar formation by promoting the availability of active TGF-beta after vascular damage. J. Neurosci.,  2010, 30(17), 5843-5854.
 [http://dx.doi.org/10.1523/JNEUROSCI.0137-10.2010] [PMID: 20427645]

[79]
Cekanaviciute, E.; Fathali, N.; Doyle, K.P.; Williams, A.M.; Han, J.; Buckwalter, M.S. Astrocytic transforming growth factor-beta signaling reduces subacute neuroinflammation after stroke in mice. Glia,  2014, 62(8), 1227-1240.
 [http://dx.doi.org/10.1002/glia.22675] [PMID: 24733756]

[80]
Bao, Y.; Qin, L.; Kim, E.; Bhosle, S.; Guo, H.; Febbraio, M.; Haskew-Layton, R.E.; Ratan, R.; Cho, S. CD36 is involved in astrocyte activation and astroglial scar formation. J. Cereb. Blood Flow Metab.,  2012, 32(8), 1567-1577.
 [http://dx.doi.org/10.1038/jcbfm.2012.52] [PMID: 22510603]

[81]
Jayaraj, R.L.; Azimullah, S.; Beiram, R.; Jalal, F.Y.; Rosenberg, G.A. Neuroinflammation: Friend and foe for ischemic stroke. J. Neuroinflammation,  2019, 16(1), 142.
 [http://dx.doi.org/10.1186/s12974-019-1516-2] [PMID: 31291966]

[82]
Alliot, F.; Godin, I.; Pessac, B. Microglia derive from progenitors, originating from the yolk sac, and which proliferate in the brain. Brain Res. Dev. Brain Res.,  1999, 117(2), 145-152.
 [http://dx.doi.org/10.1016/S0165-3806(99)00113-3] [PMID: 10567732]

[83]
Kanazawa, M.; Ninomiya, I.; Hatakeyama, M.; Takahashi, T.; Shimohata, T. Microglia and monocytes/macrophages polarization reveal novel therapeutic mechanism against stroke. Int. J. Mol. Sci.,  2017, 18(10), 2135.
 [http://dx.doi.org/10.3390/ijms18102135] [PMID: 29027964]

[84]
Pocock, J.M.; Kettenmann, H. Neurotransmitter receptors on microglia. Trends Neurosci.,  2007, 30(10), 527-535.
 [http://dx.doi.org/10.1016/j.tins.2007.07.007] [PMID: 17904651]

[85]
Hoek, R.M.; Ruuls, S.R.; Murphy, C.A.; Wright, G.J.; Goddard, R.; Zurawski, S.M.; Blom, B.; Homola, M.E.; Streit, W.J.; Brown, M.H.; Barclay, A.N.; Sedgwick, J.D. Down-regulation of the macrophage lineage through interaction with OX2 (CD200). Science,  2000, 290(5497), 1768-1771.
 [http://dx.doi.org/10.1126/science.290.5497.1768] [PMID: 11099416]

[86]
Sunnemark, D.; Eltayeb, S.; Nilsson, M.; Wallström, E.; Lassmann, H.; Olsson, T.; Berg, A.L.; Ericsson-Dahlstrand, A. CX3CL1 (fractalkine) and CX3CR1 expression in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis: Kinetics and cellular origin. J. Neuroinflammation,  2005, 2(1), 17.
 [http://dx.doi.org/10.1186/1742-2094-2-17] [PMID: 16053521]

[87]
Kierdorf, K.; Prinz, M. Factors regulating microglia activation. Front. Cell. Neurosci.,  2013, 7, 44.
 [http://dx.doi.org/10.3389/fncel.2013.00044] [PMID: 23630462]

[88]
Nimmerjahn, A.; Kirchhoff, F.; Helmchen, F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science,  2005, 308(5726), 1314-1318.
 [http://dx.doi.org/10.1126/science.1110647] [PMID: 15831717]

[89]
Kalkman, H.O.; Feuerbach, D. Antidepressant therapies inhibit inflammation and microglial M1-polarization. Pharmacol. Ther.,  2016, 163, 82-93.
 [http://dx.doi.org/10.1016/j.pharmthera.2016.04.001] [PMID: 27101921]

[90]
Park, H.J.; Oh, S.H.; Kim, H.N.; Jung, Y.J.; Lee, P.H. Mesenchymal stem cells enhance α-synuclein clearance via M2 microglia polarization in experimental and human parkinsonian disorder. Acta Neuropathol.,  2016, 132(5), 685-701.
 [http://dx.doi.org/10.1007/s00401-016-1605-6] [PMID: 27497943]

[91]
Zhou, T.; Huang, Z.; Sun, X.; Zhu, X.; Zhou, L.; Li, M.; Cheng, B.; Liu, X.; He, C. Microglia polarization with M1/M2 phenotype changes in rd1 mouse model of retinal degeneration. Front. Neuroanat.,  2017, 11, 77.
 [http://dx.doi.org/10.3389/fnana.2017.00077] [PMID: 28928639]

[92]
Orihuela, R.; McPherson, C.A.; Harry, G.J. Microglial M1/M2 polarization and metabolic states. Br. J. Pharmacol.,  2016, 173(4), 649-665.
 [http://dx.doi.org/10.1111/bph.13139] [PMID: 25800044]

[93]
Jadhav, P.; Karande, M.; Sarkar, A.; Sahu, S.; Sarmah, D.; Datta, A.; Chaudhary, A.; Kalia, K.; Sharma, A.; Wang, X.; Bhattacharya, P. Glial Cells Response in Stroke. Cell. Mol. Neurobiol.,  2022, 43, 99-113.
 [PMID: 35066715]

[94]
Matsumoto, H.; Kumon, Y.; Watanabe, H.; Ohnishi, T.; Takahashi, H.; Imai, Y.; Tanaka, J. Expression of CD200 by macrophage-like cells in ischemic core of rat brain after transient middle cerebral artery occlusion. Neurosci. Lett.,  2007, 418(1), 44-48.
 [http://dx.doi.org/10.1016/j.neulet.2007.03.027] [PMID: 17403569]

[95]
Yang, Y.; Zhang, X.; Zhang, C.; Chen, R.; Li, L.; He, J.; Xie, Y.; Chen, Y. Loss of neuronal CD200 contributed to microglial activation after acute cerebral ischemia in mice. Neurosci. Lett.,  2018, 678, 48-54.
 [http://dx.doi.org/10.1016/j.neulet.2018.05.004] [PMID: 29729356]

[96]
Sun, H.; He, X.; Tao, X.; Hou, T.; Chen, M.; He, M.; Liao, H. The CD200/CD200R signaling pathway contributes to spontaneous functional recovery by enhancing synaptic plasticity after stroke. J. Neuroinflammation,  2020, 17(1), 171-171.
 [http://dx.doi.org/10.1186/s12974-020-01845-x] [PMID: 32473633]

[97]
Singhal, G.; Baune, B.T. Microglia: An interface between the loss of neuroplasticity and depression. Front. Cell. Neurosci.,  2017, 11, 270.
 [http://dx.doi.org/10.3389/fncel.2017.00270] [PMID: 28943841]

[98]
Tang, Y.; Le, W. Differential roles of M1 and M2 microglia in neurodegenerative diseases. Mol. Neurobiol.,  2016, 53(2), 1181-1194.
 [http://dx.doi.org/10.1007/s12035-014-9070-5] [PMID: 25598354]

[99]
Liu, X.; Liu, J.; Zhao, S.; Zhang, H.; Cai, W.; Cai, M.; Ji, X.; Leak, R.K.; Gao, Y.; Chen, J.; Hu, X. Interleukin-4 is essential for Microglia/Macrophage M2 polarization and long-term recovery after cerebral ischemia. Stroke,  2016, 47(2), 498-504.
 [http://dx.doi.org/10.1161/STROKEAHA.115.012079] [PMID: 26732561]

[100]
Zhu, J.; Cao, D.; Guo, C.; Liu, M.; Tao, Y.; Zhou, J.; Wang, F.; Zhao, Y.; Wei, J.; Zhang, Y.; Fang, W.; Li, Y. Berberine facilitates angiogenesis against ischemic stroke through modulating microglial polarization via AMPK signaling. Cell. Mol. Neurobiol.,  2019, 39(6), 751-768.
 [http://dx.doi.org/10.1007/s10571-019-00675-7] [PMID: 31020571]

[101]
Choi, J.Y.; Kim, J.Y.; Kim, J.Y.; Park, J.; Lee, W.T.; Lee, J.E. M2 phenotype microglia-derived cytokine stimulates proliferation and neuronal differentiation of endogenous stem cells in ischemic brain. Exp. Neurobiol.,  2017, 26(1), 33-41.
 [http://dx.doi.org/10.5607/en.2017.26.1.33] [PMID: 28243165]

[102]
Eugenín, E.A.; Eckardt, D.; Theis, M.; Willecke, K.; Bennett, M.V.L.; Sáez, J.C. Microglia at brain stab wounds express connexin 43 and in vitro form functional gap junctions after treatment with interferon-γ and tumor necrosis factor-α. Proc. Natl. Acad. Sci.,  2001, 98(7), 4190-4195.
 [http://dx.doi.org/10.1073/pnas.051634298] [PMID: 11259646]

[103]
Kielian, T. Glial connexins and gap junctions in CNS inflammation and disease. J. Neurochem.,  2008, 106(3), 1000-1016.
 [http://dx.doi.org/10.1111/j.1471-4159.2008.05405.x] [PMID: 18410504]

[104]
Contreras, J.E.; Sáez, J.C.; Bukauskas, F.F.; Bennett, M.V.L. Gating and regulation of connexin 43 (Cx43) hemichannels. Proc. Natl. Acad. Sci.,  2003, 100(20), 11388-11393.
 [http://dx.doi.org/10.1073/pnas.1434298100] [PMID: 13130072]

[105]
Jin, R.; Yang, G.; Li, G. Inflammatory mechanisms in ischemic stroke: Role of inflammatory cells. J. Leukoc. Biol.,  2010, 87(5), 779-789.
 [http://dx.doi.org/10.1189/jlb.1109766] [PMID: 20130219]

[106]
Nakajima, K.; Kohsaka, S. Microglia: Neuroprotective and neurotrophic cells in the central nervous system. Curr. Drug Targets Cardiovasc. Haematol. Disord.,  2004, 4(1), 65-84.
 [http://dx.doi.org/10.2174/1568006043481284] [PMID: 15032653]

[107]
Gilchrist, S.E.; Goudarzi, S.; Hafizi, S. Gas6 inhibits toll-like receptor-mediated inflammatory pathways in mouse microglia via Axl and Mer. Front. Cell. Neurosci.,  2020, 14, 576650.
 [http://dx.doi.org/10.3389/fncel.2020.576650] [PMID: 33192322]

[108]
Lu, Y.; Li, X.; Liu, S.; Zhang, Y.; Zhang, D. Toll-like receptors and inflammatory bowel disease. Front. Immunol.,  2018, 9, 72.
 [http://dx.doi.org/10.3389/fimmu.2018.00072] [PMID: 29441063]

[109]
Dabrowska, S.; Andrzejewska, A.; Lukomska, B.; Janowski, M. Neuroinflammation as a target for treatment of stroke using mesenchymal stem cells and extracellular vesicles. J. Neuroinflammation,  2019, 16(1), 178.
 [http://dx.doi.org/10.1186/s12974-019-1571-8] [PMID: 31514749]

[110]
Rupalla, K.; Allegrini, P.R.; Sauer, D.; Wiessner, C. Time course of microglia activation and apoptosis in various brain regions after permanent focal cerebral ischemia in mice. Acta Neuropathol.,  1998, 96(2), 172-178.
 [http://dx.doi.org/10.1007/s004010050878] [PMID: 9705133]

[111]
Morioka, T.; Kalehua, A.N.; Streit, W.J. Characterization of microglial reaction after middle cerebral artery occlusion in rat brain. J. Comp. Neurol.,  1993, 327(1), 123-132.
 [http://dx.doi.org/10.1002/cne.903270110] [PMID: 8432904]

[112]
Gebicke-Haerter, P.J. Microglia in neurodegeneration: Molecular aspects. Microsc. Res. Tech.,  2001, 54(1), 47-58.
 [http://dx.doi.org/10.1002/jemt.1120] [PMID: 11526957]

[113]
Yin, X.; Feng, L.; Ma, D.; Yin, P.; Wang, X.; Hou, S.; Hao, Y.; Zhang, J.; Xin, M.; Feng, J. Roles of astrocytic connexin-43, hemichannels, and gap junctions in oxygen-glucose deprivation/reperfusion injury induced neuroinflammation and the possible regulatory mechanisms of salvianolic acid B and carbenoxolone. J. Neuroinflammation,  2018, 15(1), 97-97.
 [http://dx.doi.org/10.1186/s12974-018-1127-3] [PMID: 29587860]

[114]
Kim, Y.; Davidson, J.O.; Green, C.R.; Nicholson, L.F.B.; O’Carroll, S.J.; Zhang, J. Connexins and pannexins in cerebral ischemia. Biochim. Biophys. Acta Biomembr.,  2018, 1860(1), 224-236.
 [http://dx.doi.org/10.1016/j.bbamem.2017.03.018] [PMID: 28347700]

[115]
Wixey, J.A.; Reinebrant, H.E.; Carty, M.L.; Buller, K.M. Delayed P2X4R expression after hypoxia-ischemia is associated with microglia in the immature rat brain. J. Neuroimmunol.,  2009, 212(1-2), 35-43.
 [http://dx.doi.org/10.1016/j.jneuroim.2009.04.016] [PMID: 19447505]

[116]
Weinstein, J.R.; Koerner, I.P.; Möller, T. Microglia in ischemic brain injury. Future Neurol.,  2010, 5(2), 227-246.
 [http://dx.doi.org/10.2217/fnl.10.1] [PMID: 20401171]

[117]
Iosif, R.E.; Ahlenius, H.; Ekdahl, C.T.; Darsalia, V.; Thored, P.; Jovinge, S.; Kokaia, Z.; Lindvall, O. Suppression of stroke-induced progenitor proliferation in adult subventricular zone by tumor necrosis factor receptor 1. J. Cereb. Blood Flow Metab.,  2008, 28(9), 1574-1587.
 [http://dx.doi.org/10.1038/jcbfm.2008.47] [PMID: 18493257]

[118]
Même, W.; Calvo, C.F.; Froger, N.; Ezan, P.; Amigou, E.; Koulakoff, A.; Giaume, C. Proinflammatory cytokines released from microglia inhibit gap junctions in astrocytes: Potentiation by β‐amyloid. FASEB J.,  2006, 20(3), 494-496.
 [http://dx.doi.org/10.1096/fj.05-4297fje] [PMID: 16423877]

[119]
Faustmann, P.M.; Haase, C.G.; Romberg, S.; Hinkerohe, D.; Szlachta, D.; Smikalla, D.; Krause, D.; Dermietzel, R. Microglia activation influences dye coupling and Cx43 expression of the astrocytic network. Glia,  2003, 42(2), 101-108.
 [http://dx.doi.org/10.1002/glia.10141] [PMID: 12655594]

[120]
Koulakoff, A.; Ezan, P.; Giaume, C. Neurons control the expression of connexin 30 and connexin 43 in mouse cortical astrocytes. Glia,  2008, 56(12), 1299-1311.
 [http://dx.doi.org/10.1002/glia.20698] [PMID: 18512249]

[121]
Retamal, M.A.; Froger, N.; Palacios-Prado, N.; Ezan, P.; Sáez, P.J.; Sáez, J.C.; Giaume, C. Cx43 hemichannels and gap junction channels in astrocytes are regulated oppositely by proinflammatory cytokines released from activated microglia. J. Neurosci.,  2007, 27(50), 13781-13792.
 [http://dx.doi.org/10.1523/JNEUROSCI.2042-07.2007] [PMID: 18077690]

[122]
Lambertsen, K.L.; Biber, K.; Finsen, B. Inflammatory cytokines in experimental and human stroke. J. Cereb. Blood Flow Metab.,  2012, 32(9), 1677-1698.
 [http://dx.doi.org/10.1038/jcbfm.2012.88] [PMID: 22739623]

[123]
Mestriner, R.G.; Pagnussat, A.S.; Boisserand, L.S.B.; Valentim, L.; Netto, C.A. Skilled reaching training promotes astroglial changes and facilitated sensorimotor recovery after collagenase-induced intracerebral hemorrhage. Exp. Neurol.,  2011, 227(1), 53-61.
 [http://dx.doi.org/10.1016/j.expneurol.2010.09.009] [PMID: 20850433]

[124]
Krupinski, J.; Kaluza, J.; Kumar, P.; Kumar, S. Immunocytochemical studies of cellular reaction in human ischemic brain stroke. MAB anti-CD68 stains macrophages, astrocytes and microglial cells in infarcted area. Folia Neuropathol.,  1996, 34(1), 17-24.
 [PMID: 8855083]

[125]
Price, C.J.S.; Wang, D.; Menon, D.K.; Guadagno, J.V.; Cleij, M.; Fryer, T.; Aigbirhio, F.; Baron, J.C.; Warburton, E.A. Intrinsic activated microglia map to the peri-infarct zone in the subacute phase of ischemic stroke. Stroke,  2006, 37(7), 1749-1753.
 [http://dx.doi.org/10.1161/01.STR.0000226980.95389.0b] [PMID: 16763188]

[126]
Faiz, M.; Sachewsky, N.; Gascón, S.; Bang, K.W.A.; Morshead, C.M.; Nagy, A. Adult neural stem cells from the subventricularzone give rise to reactive astrocytes in the cortex after stroke. Celll Stem Cell,  2015, 17(5), 624-634.
 [http://dx.doi.org/10.1016/j.stem.2015.08.002] [PMID: 26456685]

[127]
Wang, W.; Redecker, C.; Yu, Z.Y.; Xie, M.J.; Tian, D.S.; Zhang, L.; Bu, B.T.; Witte, O.W. Rat focal cerebral ischemia induced astrocyte proliferation and delayed neuronal death are attenuated by cyclin-dependent kinase inhibition. J. Clin. Neurosci.,  2008, 15(3), 278-285.
 [http://dx.doi.org/10.1016/j.jocn.2007.02.004] [PMID: 18207409]

[128]
Zhou, Y.; Fang, S.; Ye, Y.; Chu, L.; Zhang, W.; Wang, M.; Wei, E. Caffeic acid ameliorates early and delayed brain injuries after focal cerebral ischemia in rats. Acta Pharmacol. Sin.,  2006, 27(9), 1103-1110.
 [http://dx.doi.org/10.1111/j.1745-7254.2006.00406.x] [PMID: 16923329]

[129]
Fang, S.H.; Wei, E.Q.; Zhou, Y.; Wang, M.L.; Zhang, W.P.; Yu, G.L.; Chu, L.S.; Chen, Z. Increased expression of cysteinyl leukotriene receptor-1 in the brain mediates neuronal damage and astrogliosis after focal cerebral ischemia in rats. Neuroscience,  2006, 140(3), 969-979.
 [http://dx.doi.org/10.1016/j.neuroscience.2006.02.051] [PMID: 16650938]

[130]
Chu, K.; Lee, S.T.; Sinn, D.I.; Ko, S.Y.; Kim, E.H.; Kim, J.M.; Kim, S.J.; Park, D.K.; Jung, K.H.; Song, E.C.; Lee, S.K.; Kim, M.; Roh, J.K. Pharmacological induction of ischemic tolerance by glutamate transporter-1 (EAAT2) upregulation. Stroke,  2007, 38(1), 177-182.
 [http://dx.doi.org/10.1161/01.STR.0000252091.36912.65] [PMID: 17122424]

[131]
Ouyang, Y.B.; Voloboueva, L.A.; Xu, L.J.; Giffard, R.G. Selective dysfunction of hippocampal CA1 astrocytes contributes to delayed neuronal damage after transient forebrain ischemia. J. Neurosci.,  2007, 27(16), 4253-4260.
 [http://dx.doi.org/10.1523/JNEUROSCI.0211-07.2007] [PMID: 17442809]

[132]
Lee, E.S.Y.; Sidoryk, M.; Jiang, H.; Yin, Z.; Aschner, M. Estrogen and tamoxifen reverse manganese-induced glutamate transporter impairment in astrocytes. J. Neurochem.,  2009, 110(2), 530-544.
 [http://dx.doi.org/10.1111/j.1471-4159.2009.06105.x] [PMID: 19453300]

[133]
Kimelberg, H.K.; Feustel, P.J.; Jin, Y.; Paquette, J.; Boulos, A.; Keller, R.W., Jr; Tranmer, B.I. Acute treatment with tamoxifen reduces ischemic damage following middle cerebral artery occlusion. Neuroreport,  2000, 11(12), 2675-2679.
 [http://dx.doi.org/10.1097/00001756-200008210-00014] [PMID: 10976942]

[134]
Mehta, S.H.; Dhandapani, K.M.; De Sevilla, L.M.; Webb, R.C.; Mahesh, V.B.; Brann, D.W. Tamoxifen, a selective estrogen receptor modulator, reduces ischemic damage caused by middle cerebral artery occlusion in the ovariectomized female rat. Neuroendocrinology,  2003, 77(1), 44-50.
 [http://dx.doi.org/10.1159/000068332] [PMID: 12624540]

[135]
Shen, Y.; He, P.; Fan, Y.; Zhang, J.; Yan, H.; Hu, W.; Ohtsu, H.; Chen, Z. Carnosine protects against permanent cerebral ischemia in histidine decarboxylase knockout mice by reducing glutamate excitotoxicity. Free Radic. Biol. Med.,  2010, 48(5), 727-735.
 [http://dx.doi.org/10.1016/j.freeradbiomed.2009.12.021] [PMID: 20043985]

[136]
Szydlowska, K.; Zawadzka, M.; Kaminska, B. Neuroprotectant FK506 inhibits glutamate-induced apoptosis of astrocytes in vitro and in vivo. J. Neurochem.,  2006, 99(3), 965-975.
 [http://dx.doi.org/10.1111/j.1471-4159.2006.04136.x] [PMID: 17076660]

[137]
Justicia, C.; Pérez-Asensio, F.J.; Burguete, M.C.; Salom, J.B.; Planas, A.M. Administration of transforming growth factor-alpha reduces infarct volume after transient focal cerebral ischemia in the rat. J. Cereb. Blood Flow Metab.,  2001, 21(9), 1097-1104.
 [http://dx.doi.org/10.1097/00004647-200109000-00007] [PMID: 11524614]

[138]
Sharif, A.; Legendre, P.; Prévot, V.; Allet, C.; Romao, L.; Studler, J-M.; Chneiweiss, H.; Junier, M-P. Transforming growth factor α promotes sequential conversion of mature astrocytes into neural progenitors and stem cells. Oncogene,  2007, 26(19), 2695-2706.
 [http://dx.doi.org/10.1038/sj.onc.1210071] [PMID: 17057735]

[139]
Wang, H.; Wang, G.; Yu, Y.; Wang, Y. The role of phosphoinositide-3-kinase/Akt pathway in propofol-induced postconditioning against focal cerebral ischemia-reperfusion injury in rats. Brain Res.,  2009, 1297, 177-184.
 [http://dx.doi.org/10.1016/j.brainres.2009.08.054] [PMID: 19703434]

[140]
Daskalopoulos, R.; Korcok, J.; Tao, L.; Wilson, J.X. Accumulation of intracellular ascorbate from dehydroascorbic acid by astrocytes is decreased after oxidative stress and restored by propofol. Glia,  2002, 39(2), 124-132.
 [http://dx.doi.org/10.1002/glia.10099] [PMID: 12112364]

[141]
Li, P.C.; Jiao, Y.; Ding, J.; Chen, Y.C.; Cui, Y.; Qian, C.; Yang, X.Y.; Ju, S.H.; Yao, H.H.; Teng, G.J. Cystamine improves functional recovery via axon remodeling and neuroprotection after stroke in mice. CNS Neurosci. Ther.,  2015, 21(3), 231-240.
 [http://dx.doi.org/10.1111/cns.12343] [PMID: 25430473]

[142]
Minami, M.; Satoh, M. Chemokines and their receptors in the brain: Pathophysiological roles in ischemic brain injury. Life Sci.,  2003, 74(2-3), 321-327.
 [http://dx.doi.org/10.1016/j.lfs.2003.09.019] [PMID: 14607260]

[143]
Evans, W.H.; Leybaert, L. Mimetic peptides as blockers of connexin channel-facilitated intercellular communication. Cell Commun. Adhes.,  2007, 14(6), 265-273.
 [http://dx.doi.org/10.1080/15419060801891034] [PMID: 18392994]

[144]
Li, X.; Zhao, H.; Tan, X.; Kostrzewa, R.M.; Du, G.; Chen, Y.; Zhu, J.; Miao, Z.; Yu, H.; Kong, J.; Xu, X. Inhibition of connexin43 improves functional recovery after ischemic brain injury in neonatal rats. Glia,  2015, 63(9), 1553-1567.
 [http://dx.doi.org/10.1002/glia.22826] [PMID: 25988944]

[145]
Zhang, L.; Li, Y.M.; Jing, Y.H.; Wang, S.Y.; Song, Y.F.; Yin, J. Protective effects of carbenoxolone are associated with attenuation of oxidative stress in ischemic brain injury. Neurosci. Bull.,  2013, 29(3), 311-320.
 [http://dx.doi.org/10.1007/s12264-013-1342-y] [PMID: 23650049]

[146]
Zhang, Y.; Proenca, R.; Maffei, M.; Barone, M.; Leopold, L.; Friedman, J.M. Positional cloning of the mouse obese gene and its human homologue. Nature,  1994, 372(6505), 425-432.
 [http://dx.doi.org/10.1038/372425a0] [PMID: 7984236]

[147]
Kriz, J.; Lalancette-Hébert, M. Inflammation, plasticity and real-time imaging after cerebral ischemia. Acta Neuropathol.,  2009, 117(5), 497-509.
 [http://dx.doi.org/10.1007/s00401-009-0496-1] [PMID: 19225790]

[148]
Kreutzberg, G.W. Microglia: A sensor for pathological events in the CNS. Trends Neurosci.,  1996, 19(8), 312-318.
 [http://dx.doi.org/10.1016/0166-2236(96)10049-7] [PMID: 8843599]

[149]
Schwartz, M. Macrophages and microglia in central nervous system injury: Are they helpful or harmful? J. Cereb. Blood Flow Metab.,  2003, 23(4), 385-394.
 [http://dx.doi.org/10.1097/01.WCB.0000061881.75234.5E] [PMID: 12679714]

[150]
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.
 [http://dx.doi.org/10.1007/s12975-017-0543-5] [PMID: 28624878]

[151]
Prinz, M.; Priller, J.; Sisodia, S.S.; Ransohoff, R.M. Heterogeneity of CNS myeloid cells and their roles in neurodegeneration. Nat. Neurosci.,  2011, 14(10), 1227-1235.
 [http://dx.doi.org/10.1038/nn.2923] [PMID: 21952260]

[152]
Xi, Z.; Xu, C.; Chen, X.; Wang, B.; Zhong, Z.; Sun, Q.; Sun, Y.; Bian, L. Protocatechuic acid suppresses microglia activation and facilitates M1 to M2 phenotype switching in intracerebral hemorrhage mice. J. Stroke Cerebrovasc. Dis.,  2021, 30(6), 105765.
 [http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2021.105765] [PMID: 33813082]

[153]
Hovens, I.; Nyakas, C.; Schoemaker, R. A novel method for evaluating microglial activation using ionized calcium-binding adaptor protein-1 staining: Cell body to cell size ratio. Neuroimmunol. Neuroinflamm.,  2014, 1(2), 82.
 [http://dx.doi.org/10.4103/2347-8659.139719]

[154]
Zhou, X.; Lu, W.; Wang, Y.; Li, J.; Luo, Y. A20-binding inhibitor of NF-κB 1 ameliorates neuroinflammation and mediates antineuroinflammatory effect of electroacupuncture in cerebral ischemia/reperfusion rats. Evid. Based Complement. Alternat. Med.,  2020, 2020, 1-14.
 [http://dx.doi.org/10.1155/2020/6980398] [PMID: 33110436]

[155]
Jiang, J.; Luo, Y.; Qin, W.; Ma, H.; Li, Q.; Zhan, J.; Zhang, Y. Electroacupuncture suppresses the NF-κB signaling pathway by upregulating cylindromatosis to alleviate inflammatory injury in cerebral ischemia/reperfusion rats. Front. Mol. Neurosci.,  2017, 10, 363.
 [http://dx.doi.org/10.3389/fnmol.2017.00363] [PMID: 29163038]

[156]
Wei, T.H.; Hsieh, C.L. Effect of acupuncture on the p38 signaling pathway in several nervous system diseases: A systematic review. Int. J. Mol. Sci.,  2020, 21(13), 4693.
 [http://dx.doi.org/10.3390/ijms21134693] [PMID: 32630156]

[157]
Jin, Q.; Cheng, J.; Liu, Y.; Wu, J.; Wang, X.; Wei, S.; Zhou, X.; Qin, Z.; Jia, J.; Zhen, X. Improvement of functional recovery by chronic metformin treatment is associated with enhanced alternative activation of microglia/macrophages and increased angiogenesis and neurogenesis following experimental stroke. Brain Behav. Immun.,  2014, 40, 131-142.
 [http://dx.doi.org/10.1016/j.bbi.2014.03.003] [PMID: 24632338]

[158]
Liu, S.; Jin, R.; Xiao, A.Y.; Zhong, W.; Li, G. Inhibition of CD147 improves oligodendrogenesis and promotes white matter integrity and functional recovery in mice after ischemic stroke. Brain Behav. Immun.,  2019, 82, 13-24.
 [http://dx.doi.org/10.1016/j.bbi.2019.07.027] [PMID: 31356925]

[159]
Liu, Z.J.; Ran, Y.Y.; Qie, S.Y.; Gong, W.J.; Gao, F.H.; Ding, Z.T.; Xi, J.N. Melatonin protects against ischemic stroke by modulating microglia/macrophage polarization toward anti‐inflammatory phenotype through STAT3 pathway. CNS Neurosci. Ther.,  2019, 25(12), 1353-1362.
 [http://dx.doi.org/10.1111/cns.13261] [PMID: 31793209]

[160]
Wang, X.; Figueroa, B.E.; Stavrovskaya, I.G.; Zhang, Y.; Sirianni, A.C.; Zhu, S.; Day, A.L.; Kristal, B.S.; Friedlander, R.M. Methazolamide and melatonin inhibit mitochondrial cytochrome C release and are neuroprotective in experimental models of ischemic injury. Stroke,  2009, 40(5), 1877-1885.
 [http://dx.doi.org/10.1161/STROKEAHA.108.540765] [PMID: 19299628]

[161]
Li, F.; Ma, Q.; Zhao, H.; Wang, R.; Tao, Z.; Fan, Z.; Zhang, S.; Li, G.; Luo, Y. L-3-n-Butylphthalide reduces ischemic stroke injury and increases M2 microglial polarization. Metab. Brain Dis.,  2018, 33(6), 1995-2003.
 [http://dx.doi.org/10.1007/s11011-018-0307-2] [PMID: 30117100]

[162]
Bourgault, S.; Vaudry, D.; Dejda, A.; Doan, N.; Vaudry, H.; Fournier, A. Pituitary adenylate cyclase-activating polypeptide: Focus on structure-activity relationships of a neuroprotective Peptide. Curr. Med. Chem.,  2009, 16(33), 4462-4480.
 [http://dx.doi.org/10.2174/092986709789712899] [PMID: 19835562]

[163]
Brifault, C.; Gras, M.; Liot, D.; May, V.; Vaudry, D.; Wurtz, O. Delayed pituitary adenylate cyclase-activating polypeptide delivery after brain stroke improves functional recovery by inducing m2 microglia/macrophage polarization. Stroke,  2015, 46(2), 520-528.
 [http://dx.doi.org/10.1161/STROKEAHA.114.006864] [PMID: 25550371]

[164]
Lu, Y.; Zhou, M.; Li, Y.; Li, Y.; Hua, Y.; Fan, Y. Minocycline promotes functional recovery in ischemic stroke by modulating microglia polarization through STAT1/STAT6 pathways. Biochem. Pharmacol.,  2021, 186, 114464.
 [http://dx.doi.org/10.1016/j.bcp.2021.114464] [PMID: 33577892]

[165]
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.
 [http://dx.doi.org/10.1212/01.wnl.0000277487.04281.db] [PMID: 17909152]

[166]
Kikuchi, K.; Tanaka, E.; Murai, Y.; Tancharoen, S. Clinical trials in acute ischemic stroke. CNS Drugs,  2014, 28(10), 929-938.
 [http://dx.doi.org/10.1007/s40263-014-0199-6] [PMID: 25160686]

[167]
Liu, M.; Xu, Z.; Wang, L.; Zhang, L.; Liu, Y.; Cao, J.; Fu, Q.; Liu, Y.; Li, H.; Lou, J.; Hou, W.; Mi, W.; Ma, Y. Cottonseed oil alleviates ischemic stroke injury by inhibiting the inflammatory activation of microglia and astrocyte. J. Neuroinflammation,  2020, 17(1), 270.
 [http://dx.doi.org/10.1186/s12974-020-01946-7] [PMID: 32917229]

[168]
Zhang, B.; Zhang, H.X.; Shi, S.T.; Bai, Y.L.; Zhe, X.; Zhang, S.J.; Li, Y.J. Interleukin-11 treatment protected against cerebral ischemia/reperfusion injury. Biomed. Pharmacother.,  2019, 115, 108816.
 [http://dx.doi.org/10.1016/j.biopha.2019.108816] [PMID: 31096144]

[169]
Li, X.M.; Wang, X.; Feng, X.W.; Shao, M.M.; Liu, W.F.; Ma, Q.Q.; Wang, E.P.; Chen, J.; Shao, B. Serum interleukin‐33 as a novel marker for long‐term prognosis and recurrence in acute ischemic stroke patients. Brain Behav.,  2019, 9(9), e01369.
 [http://dx.doi.org/10.1002/brb3.1369] [PMID: 31397082]

[170]
Pomeshchik, Y.; Kidin, I.; Korhonen, P.; Savchenko, E.; Jaronen, M.; Lehtonen, S.; Wojciechowski, S.; Kanninen, K.; Koistinaho, J.; Malm, T. Interleukin-33 treatment reduces secondary injury and improves functional recovery after contusion spinal cord injury. Brain Behav. Immun.,  2015, 44, 68-81.
 [http://dx.doi.org/10.1016/j.bbi.2014.08.002] [PMID: 25153903]

[171]
Li, L.Z.; Huang, Y.Y.; Yang, Z.H.; Zhang, S.J.; Han, Z.P.; Luo, Y.M. Potential microglia‐based interventions for stroke. CNS Neurosci. Ther.,  2020, 26(3), 288-296.
 [http://dx.doi.org/10.1111/cns.13291] [PMID: 32064759]

[172]
Yang, Y.; Liu, H.; Zhang, H.; Ye, Q.; Wang, J.; Yang, B.; Mao, L.; Zhu, W.; Leak, R.K.; Xiao, B.; Lu, B.; Chen, J.; Hu, X. ST2/IL-33-dependent microglial response limits acute ischemic brain injury. J. Neurosci.,  2017, 37(18), 4692-4704.
 [http://dx.doi.org/10.1523/JNEUROSCI.3233-16.2017] [PMID: 28389473]
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DOI https://dx.doi.org/10.2174/1570159X21666230718104634	Print ISSN 1570-159X
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Current Neuropharmacology

The Relationship of Astrocytes and Microglia with Different Stages of Ischemic Stroke

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