Functions of Reactive Astrocytes in Ischemic Brain Injury

Yıl 2023, Cilt: 49 Sayı: 1, 133 - 143, 09.06.2023

Nursel Hasanoğlu Akbulut , Gonca Topal , Özhan Eyigör

https://doi.org/10.32708/uutfd.1261257

Öz

Stroke is the second leading cause of death worldwide. It is important to investigate the pathophysiology of astrocytes, which constitute the most common glial cell group in the mammalian central nervous system (CNS), in the acute and chronic stages of stroke. In pathological conditions following disease and brain damage, astrocytes transform into reactive form. It has been proven by studies that they alleviate oxidative stress damage by releasing GSH (Glutathione) after ischemic injury, contribute to neuron development and survival by secreting neurotrophic factors, have a role in the regulation of cerebral edema, and contribute to angiogenesis by secreting erythropoietin and inhibit neuronal apaptosis. However, besides all these, it has been shown that it causes neuronal death and increases the permeability of the BBB by inducing excitotoxicity after ischemia and causing excessive release of inflammatory factors. There are studies showing that the glial scar formed after ischemic injury provides homeostasis in healthy tissue by preventing the spread of tissue damage in the acute period, but prevents axon growth in the chronic period. Therefore, the functions of reactive astrocytes are controversial. It has been found that genetically reactive astrocytes can undergo transformation into two polarization states, neurotoxic (A1) and neuroprotective (A2). Different types of astrocytes will help discover effective treatment approaches for neurological diseases. In this review; the functions of reactive astrocytes in stroke caused by ischemic brain injury the physiological and histomorphological changes of astrocytes in this process are included.

Anahtar Kelimeler

Stroke, astrocyte, blood–brain barrier, cerebral edema, oxidative stress.

İskemik Beyin Hasarında Reaktif Astrositlerin Fonksiyonları

Öz

İnme, dünya çapında ikinci önde gelen ölüm nedenidir. Memeli merkezi sinir sistemindeki (MSS) en yaygın glial hücre grubunu oluşturan astrositlerin inmenin akut ve kronik evresindeki patofizyolojilerinin araştırılması önemlidir. Hastalık ve beyin hasarlarını takiben görülen patolojik durumlarda astrositler reaktif forma dönüşürler. İskemik hasar sonrası Glutatyon (GSH) salgılayarak oksidatif stres hasarını hafiflettikleri, nörotrofik faktörler salgılayarak nöron gelişimi ve sağ kalımına katkıda bulundukları, serebral ödemin düzenlenmesinde rolleri olduğu ve eritropoietin salgılayarak anjiyogeneze katkı sağladığı ve nöronal apoptozu inhibe ettiği yapılan çalışmalarla kanıtlanmıştır. Ancak tüm bunların yanı sıra, iskemi sonrası eksitotoksisiteyi indükleyerek ve inflamatuar faktörlerin aşırı salınımına yol açarak nöronal ölüme yol açtığı ve kan-beyin bariyeri (KBB)’nin geçirgenliğini attırdığı gösterilmiştir. İskemik hasar sonrası oluşan glial skarın akut dönemde doku hasarının yayılmasını önleyerek sağlıklı dokudaki homeostazı sağladığı ancak kronik dönemde akson büyümesine engel olduğunu gösteren çalışmalar mevcuttur. Bu yüzden reaktif astrositlerin işlevleri tartışmalıdır. Genetik olarak reaktif astrositlerin nörotoksik (A1) ve nöroprotektif (A2) iki polarizasyon durumuna dönüşüm geçirebileceği bulunmuştur. Farklı astrosit tipleri nörolojik hastalıklar için etkili tedavi yaklaşımlarının keşfedilmesine yardımcı olacaktır. Bu derlemede; iskemik beyin hasarına bağlı olarak oluşan inmede reaktif astrositlerin fonksiyonlarına ve bu süreçte astrositlerin fizyolojik ve histomorfolojik değişimlerine yer verilmiştir.

Anahtar Kelimeler

İnme, astrosit, kan-beyin bariyeri, serebral ödem, oksidatif stres.

Kaynakça

• 1. Feigin VL, Lawes CM, Bennett DA, Barker-Collo SL, Parag V. Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review. Lancet Neurol 2009;8:355-369.
• 2. Lozano R, Naghavi M, Foreman K, ve ark. Global and regional mortality from 235 causes of death f or 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease study 2010. Ihme 2012;3:369.
• 3. Pekny M, Wilhelmsson U, Pekna M. The dual role of astrocyte activation and reactive gliosis. Neurosci Letters 2014;30:565–8.
• 4. Pekny M, Nilsson M. Astrocyte activation and reactive gliosis. Glia 2005;50:427-34.
• 5. Anderson MF, Blomstrand F, Blomstrand C, Eriksson PS, Nilsson M. Astrocytes and stroke: Networking for survival? Neurochemical Research 2003;28:293-305.
• 6. Liu Z, Chopp M. Astrocytes, therapeutic targets for neuroprotection and neurorestoration in ischemic Stroke. Progress in Neurobiology 2016;144:103-120.
• 7. Eroglu C, Barres BA. Regulation of synaptic connectivity by glia. Nature 2010;468:223-31.
• 8. Ullian EM, Sapperstein SK, Christopherson KS, Barres BA. Control of synapse number by glia. Science 2001;291:657-61.
• 9. Yu G, Zhang Y, Ning B. Reactive Astrocytes in Central Nervous System Injury: Subgroup and Potential Therapy. Front Cell Neuroscience 2021;15:764-92.
• 10. Pekny M, Pekna M. Astrocyte reactivity and reactive astrogliosis: costs and benefits. Physiological Reviews 2014;94:1077-98.
• 11. Wilhelmsson U, Bushong EA, Price DL, at al. Redefining the concept of reactive astrocytes as cells that remain within their unique domains upon reaction to injury. Proc. Natl. Acad. Sci. U. S. A. 2006;103:17513-18.
• 12. Sofroniew MV. Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neuroscience 2009;32:638-47.
• 13. Zamanian JL, Xu L, Foo LC, at al. Genomic analysis of reactive astrogliosis. J Neuroscience 2012;32:6391-410.
• 14. Stapf C, Mohr JP. Ischemic stroke therapy. Annual Review 2002;53:453-75.
• 15. Phipps M, Cronin C. Management of acute ischemic stroke. BMJ 2020;83:368-69.
• 16. McLeod DD, Parsons MW, Hood R, at al. Perfusion computed tomography thresholds defining ischemic penumbra and infarct core: studies in a rat stroke model. Int. J. Stroke 2015;10:553-59.
• 17. Lipton P. Ischemic cell death in brain neurons. Physiological Reviews 1999;79:1431-568.
• 18. Hossmann KA. The two pathophysiologies of focal brain ischemia: implications for translational stroke research. J. Cereb. Blood Flow Metab. 2012;1310:1316-32.
• 19. Ermine CM, Nithianantharajah J, O’Brien K, at al. Hemispheric cortical atrophy and chronic microglial activation following mild focal ischemic stroke in adult male rats. J Neuroscience Research 2021;99:3222-237.
• 20. Patabendige A, Singh A, Jenkins S, Sen Jo, Chen R. Astrocyte Activation in Neurovascular Damage and Repair Following Ischaemic Stroke. International Journal of Molecular Sciences 2021;22:8.
• 21. Hasanoğlu Akbulut N, Koç C, Topal G, Cansev M, Eyigör E. İnme modelinde arı sütü ve içeriğinde bulunan 10-HDA maddesinin astrosit reaksiyonuna etkileri. EMK 2021, 25. Ulusal Elektron Mikroskopi Kongresi, İstanbul, Türkiye, 22 - 24 Eylül 2021, ss.102
• 22. Topal G, Hasanoğlu Akbulut N, Koç C, et al. Neuroprotective effects of royal jelly and its ingredient 10-HDA against cerebral ischemia‑reperfusion injury in rat. NICHE2022, 15th National and 1st International Congress of Histology and Embryology, Ankara, Türkiye, 26 - 28 Mayıs 2022, ss.137).
• 23. Sofroniew MV, Vinters HV. Astrocytes: biology and pathology. Acta Neuropathology 2010;119:7-35
• 24. Li H, Zhang N, Lin HY, at al. Histological, cellular and behavioral assessments of stroke outcomes after photothrombosisinduced ischemia in adult mice. BMC Neuroscience 2014;15-58.
• 25. Nedergaard M, Dirnagl U. Role of glial cells in cerebral ischemia. Glia 2005;50:281-86.
• 26. Liu Z, Li Y, Cui Y, at al. Beneficial effects of gfap/vimentin reactive astrocytes for axonal remodeling and motor behavioral recovery in mice after stroke. Glia 2014;62:2022-33.
• 27. Swanson RA, Ying W, Kauppinen TM. Astrocyte influences on ischemic neuronal death. Curr. Mol. Med. 2004;4:193-205
• 28. Dagonnier M, Donnan GA, CityplaceDavis SM, Dewey HM, Howells DW. Acute stroke biomarkers: are we there yet? Front. Neurol. 2021;12:619-721.
• 29. Senn R, Elkind MS, Montaner J, Christ-Crain M, Katan M. Potential role of blood biomarkers in the management of nontraumatic intracerebral hemorrhage. Cerebrovasc. Dis. 2014;38:395-409.
• 30. Panickar KS, Norenberg MD. Astrocytes in cerebral ischemic injury: morphological and general considerations. Glia 2005;50:287-98.
• 31. Jurga AM, Paleczna M, Kadluczka J, Kuter KZ. Beyond the GFAP-astrocyte protein markers in the brain. Biomolecule 2021;11:1361
• 32. Kajihara H, Tsutsumi E, Kinoshita A, Nakano J, Takagi K, Takeo S. Activated astrocytes with glycogen accumulation in ischemic penumbra during the early stage of brain infarction: immunohistochemical and electron microscopic studies. Brain Research 2001;909:99-101.
• 33. Nawashiro H, Brenner M, Fukui S, Shima K, Hallenbeck JM. High susceptibility to cerebral ischemia in GFAP-null mice. J. Cereb. Blood Flow Metab.2000;20:1040-44.
• 34. Balasingam V, Tejada-Berges T, Wrigh, E, Bouckova R, Yong VW. Reactive astrogliosis in the neonatal mouse brain and its modulation by cytokines. J. Neuroscience 1994;14:846-56.
• 35. Winter CG, Saotome Y, Levison SW, Hirsh D. A role for ciliary neurotrophic factor as an inducer of reactive gliosis, the glial response to central nervous system injury. Proc. Natl. Acad. Sci. U S A. 1995;92:5865-69.
• 36. Klein MA, Möller JC, Jones LL., Bluethmann H, Kreutzberg GW, Raivich G. Impaired neuroglial activation in interleukin-6 deficient mice. Glia 1997;19:227-233.
• 37. Rabchevsky AG, Weinitz JM, Coulpier M, Fages C, Tinel M, Junier MP. A role for transforming growth factor alpha as an inducer of astrogliosis. J. Neuroscience 1998;18:10541-52.
• 38. Mason RB, Pluta RM, Walbridge S, Wink DA, Oldfield EH, Boock RJ. Production of reactive oxygen species after reperfusion in vitro and in vivo: protective effect of nitric oxide. J. Neurosurg. 2000;93:99-107.
• 39. del Zoppo GJ. Inflammation and the neurovascular unit in the setting of focal cerebral ischemia. Neuroscience 2009;158:972-82.
• 40. Dringen R. Metabolism and functions of glutathione in brain. Prog. Neurobiology 2000;62:649-71.
• 41. Dringen R, Brandmann M, Hohnholt MC, Blumrich EM. Glutathione-Dependent Detoxification Processes in Astrocytes. Neurochem. Res. 2015;40:2570-82.
• 42. Mizui T, Kinouchi H, Chan PH. Depletion of brain glutathione by buthionine sulfoximine enhances cerebral ischemic injury in rats. Am. J. Physiology 1992;262:313-17.
• 43. Griffin S, Clark JB, Canevari L. Astrocyte-neurone communication following oxygen-glucose deprivation. J. Neurochem. 2005;95:1015-22.
• 44. Chen Y, Vartiainen NE, Ying W, Chan PH, Koistinaho J, Swanson RA. Astrocytes protect neurons from nitric oxide toxicity by a glutathione-dependent mechanism. J. Neurochem. 2001;77:1601-10.
• 45. Ridet JL, Malhotra SK, Privat A, Gage FH. Reactive astrocytes: cellular and molecular cues to biological function. Trends Neuroscience 1997;70:570-77.
• 46. Tokita Y, Keino H, Matsui F, at al. Regulation of neuregulin expression in the injured rat brain and cultured astrocytes. J. Neuroscience 2001;21:1257-64.
• 47. Lee TH, Kato H, Kogure K, Itoyama Y. Temporal profile of nerve growth factor-like immunoreactivity after transient focal cerebral ischemia in rats. Brain Research 1996;713:199-210.
• 48. Igarashi Y, Utsumi H, CityplaceChiba H, at al. Glial cell line-derived neurotrophic factor induces barrier function of endothelial cells forming the blood-brain barrier. Biochem. Biophys. Res. Commun. 1999;261:108-112.
• 49. Kang SS, Keasey MP, Arnold SA, Reid R, Geralds J, Hagg T. Endogenous CNTF mediates stroke-induced adult CNS neurogenesis in mice. Neurobiol. Dis. 2013;49:68-78.
• 50. Jia C, Keasey MP, Lovins C, Hagg T. Inhibition of astrocyte FAKJNK signaling promotes subventricular zone neurogenesis through CNTF. Glia 2018;66:2456-69.
• 51. Shen Y, Sun A, Wang Y, at al. Upregulation of mesencephalic astrocyte-derived neurotrophic factor in glial cells is associated with ischemia-induced glial activation. J. Neuroinflamm. 2012;9:254.
• 52. Cheng L, Zhao H, Zhang W, at al. Overexpression of conserved dopamine neurotrophic factor (CDNF) in astrocytes alleviates endoplasmic reticulum stress-induced cell damage and inflammatory cytokine secretion. Biochem. Biophys. Res. Commun.2013;435:34-39.
• 53. Zhao H, Liu Y, Chen, L, at al. Mesencephalic astrocyte-derived neurotrophic factor inhibits oxygenglucose deprivation-induced cell damage and inflammation by suppressing endoplasmic reticulum stress in rat primary astrocytes. J. Mol. Neurosci. 2013;51:671-678.
• 54. Simard JM, Kent TA, Chen M, Tarasov KV, Gerzanich V. Brain oedema in focal ischaemia: molecular pathophysiology and theoretical implications. Lancet Neurol. 2007;6: 258-268.
• 55. Ho JD, Yeh R, Sandstrom A, at al. CityplaceCrystal structure of human aquaporin 4 at 1.8 A and its mechanism of conductance. Proc. Natl. Acad. Sci. U S A. 2009;106:7437-42.
• 56. Stokum JA, Kurland DB, Gerzanich V, Simard JM. Mechanisms of astrocyte-mediated cerebral edema. Neurochem. Res. 2015;40:317-28.
• 57. Amiry-Moghaddam M, Ottersen OP. The molecular basis of water transport in the brain. Nat Rev Neurosci 2003;4:991-1001.
• 58. Liang D, Bhatta S, Gerzanich V, Simard JM. Cytotoxic edema: Mechanisms of pathological cell swelling. Neurosurg. Focus 2007;22:E2.
• 59. Michinaga S, Koyama Y. Pathogenesis of brain edema and investigation into anti-edema drugs. Int. J. Mol. Sci. 2015;16:9949-75.
• 60. Da T, Verkman AS. Aquaporin-4 gene disruption in mice protects against impaired retinal function and cell death after ischemia. Invest. Ophthalmol. Vis. Sci. 2004;45:4477-83.
• 61. Zhang Y, Xu K, Liu Y, at al. Increased cerebral vascularization and decreased water exchange across the blood-brain barrier in aquaporin-4 knockout mice. PLoS One 2019;14:218-415.
• 62. Cheng ZJ, Dai TM, Shen YY, He JL, Li J, Tu JL. Atorvastatin pretreatment attenuates ischemic brain edema by suppressing aquaporin 4. J. Stroke Cerebrovasc. Dis. 2019;27:3247-55.
• 63. Hao JQ, He XY, Yang X, at al. Acetazolamide Alleviate Cerebral Edema Induced by Ischemic Stroke Through Inhibiting the Expression of AQP4 mRNA. Neurocrit. Care 2001;36:97-105.
• 64. Shi ZF, Fang Q, Chen Y, at al. Methylene blue ameliorates brain edema in rats with experimental ischemic stroke via inhibiting aquaporin 4 expression. Acta Pharmacol. Sin. 2001;42:382-92.
• 65. Manley GT, Fujimura M, Ma T, at al. Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic Stroke. Nat. Med. 2000;6:159-63.
• 66. Hirt L, Fukuda AM, Ambadipudi K, at al. Improved long-term outcome after transient cerebral ischemia in aquaporin-4 knockout mice. J. Cereb. Blood Flow Metab. 2017;37:277-90.
• 67. Zeng XN, Xie LL, Liang R, Sun XL, Fan Y, Hu G. AQP4 knockout aggravates ischemia/reperfusion injury in mice. CNS Neurosci. Ther. 2012;18:388-94.
• 68. Verkman AS, Binder DK, Bloch O, Auguste K, Papadopoulos MC. Three distinct roles of aquaporin-4 in brain function revealed by knockout mice. Biochim. Biophys. Acta 2006;1758: 1085-93.
• 69. Kitchen P, Day RE, Taylor LH, at al. CIdentification and Molecular Mechanisms of the Rapid Tonicity-induced Relocalization of the Aquaporin 4 Channel. J. Biol. Chem. 2015;290: 16873-881
• 70. Neely JD, Amiry-Moghaddam M, Ottersen OP, Froehner SC, Agre P, Adams ME. Syntrophin-dependent expression and localization of Aquaporin-4 water channel protein. Proc. Natl. Acad. Sci. USA 2001;98:14108-113.
• 71. Sasaki R. Pleiotropic functions of erythropoietin. Int. Med.2003;42:142-49.
• 72. Marti HH, Wenger RH, Rivas LA, at al. Erythropoietin gene expression in human, monkey and murine brain. Eur J Neurosci. 1996;8:666-76.
• 73. Buemi M, Cavallaro E, Floccari F, at al. The pleiotropic effects of erythropoietin in the central nervous system. J. Neuropathol. Exp. Neurol. 2003;62:228-36.
• 74. Nguyen AQ, Cherry BH, Scott GF, Ryou MG, Mallet RT. Erythropoietin: powerful protection of ischemic and post-ischemic brain. Exp. Biol. Med. 2014;239;1461-75.
• 75. Brines, M. What evidence supports use of erythropoietin as a novel neurotherapeutic? Oncology 2002;16:79–89.
• 76. Larpthaveesarp A, Georgevits M, Ferriero DM, Gonzalez FF. Delayed erythropoietin therapy improves histological and behavioral outcomes after transient neonatal stroke. Neurobiol. Dis. 2016;93:57–63.
• 77. Sirén AL, Fratelli M, Brines M, at al. Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress. Proc. Natl. Acad. Sci. U S A. 2001;98:4044-49.
• 78. Ruscher K, Freyer D, Karsch M, at al. Erythropoietin is a paracrine mediator of ischemic tolerance in the brain: evidence from an in vitro model. J. Neurosci. 2002;22:10291-301.
• 79. Wang L, Zhang Z, Wang Y, at al. Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and improves neurological function in rats. Stroke 2004;35: 1732-37.
• 80. Chu H, Ding H, Tang Y, Dong Q. Erythropoietin protects against hemorrhagic blood-brain barrier disruption through the effects of aquaporin-4. Lab Invest 2014;94:1042-53.
• 81. Choi DW. Glutamate neurotoxicity and diseases of the nervous system. Neuron 1988;1: 623-34.
• 82. Huang YH, Bergles DE. Glutamate transporters bring competition to the synapse. Curr. Opin. Neurobiol. 2004;14:346-52.
• 83. Ullensvang K, Lehre KP, Storm-Mathisen J, Danbolt NC. Differential developmental expression of the two rat brain glutamate transporter proteins GLAST and GLT. Eur. J. Neurosci. 1997;9:1646-55.
• 84. Anderson CM, Swanson RA. Astrocyte glutamate transport: review of properties, regulation, and physiological functions. Glia 2000;32:1-14.
• 85. Rosenberg PA, Aizenman E. Hundred-fold increase in neuronal vulnerability to glutamate toxicity in astrocyte-poor cultures of rat cerebral cortex. Neurosci. Lett. 1989;103:162-68.
• 86. Longuemare MC, Swanson RA. Excitatory amino acid release from astrocytes during energy failure by reversal of sodium-dependent uptake. J. Neurosci. Res. 1995;40:379-86.
• 87. Leonova J, Thorli T, Aberg ND, Eriksson PS, Rönnbäck L, Hansson E. Endothelin-1 decreases glutamate uptake in primary cultured rat astrocytes. Am. J. Physiol. Cell Physiol. 2001;281:1495-1503.
• 88. Pajarillo E, Rizor A, Lee J, Aschner M, Lee E. The role of astrocytic glutamate transporters GLT-1 and GLAST in neurological disorders: potential targets for neurotherapeutics. Neuropharmacology 2019;161:107559.
• 89. Kostandy BB. The role of glutamate in neuronal ischemic injury: the role of spark in fire. Neurol. Sci. 2012;33:223-37.
• 90. Buffo A, Rolando C, Ceruti S. Astrocytes in the damaged brain: molecular and cellular insights into their reactive response and healing potential. Biochem. Pharmacol. 2010;79:77-89.
• 91. Pál G, Vincze C, Renner É, et al. Time course, distribution and cell types of induction of transforming growth factor betas following middle cerebral artery occlusion in the rat brain. PLoS One 2012;7:e46731.
• 92. Kuboyama K, Harada H, Tozaki-Saitoh H, Tsuda M, Ushijima K, Inoue K. Astrocytic P2Y(1) receptor is involved in the regulation of cytokine/chemokine transcription and cerebral damage in a rat model of cerebral ischemia. J. Cereb. Blood Flow Metab. 2011;31:1930-41.
• 93. Ruscher K, Kuric E, Wieloch T. Levodopa treatment improves functional recovery after experimental stroke. Stroke 2012;43:507-13.
• 94. Liu Z, Chopp M. Astrocytes, therapeutic targets for neuroprotection and neurorestoration in ischemic stroke. Prog. Neurobiol. 2016;144:103-120.
• 95. Colombo E, Farina C. Astrocytes: key regulators of neuroinflammation. Trends Immunol. 2016;37:608-20.
• 96. Liddelow SA, Guttenplan KA, Clarke LE, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 2017;541:481-87.
• 97. Wevers NR, de Vries HE. Morphogens and blood-brain barrier function in health and disease. Tissue Barriers 2016;4:e1090524.
• 98. Obermeier B, Daneman R, Ransohoff RM. Development, maintenance and disruption of the blood-brain barrier. Nat. Med. 2013;19:1584-96.
• 99. Arba F, Leigh R, Inzitari D, Warach SJ, Luby M, Lees KR. Blood-brain barrier leakage increases with small vessel disease in acute ischemic stroke. Neurology 2017;89:2143-50.
• 100. Abbott NJ. Astrocyte-endothelial interactions and blood-brain barrier permeability. J. Anat. 2001;200:629-38.
• 101. Abbott NJ, Rönnbäck L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat. Rev. Neurosci. 2016;7:41-53.
• 102. Jiang S, Xia R, Jiang Y, Wang L, Gao F. Vascular endothelial growth factors enhance the permeability of the mouse blood-brain barrier. PLoS One 2014;9:e86407.
• 103. Argaw AT, Asp L, Zhang J, et al. Astrocyte-derived VEGF-A drives blood-brain barrier disruption in CNS inflammatory disease. J Clin Invest 2012;122:2454-68.
• 104. Argaw AT, Gurfein BT, Zhang Y, Zameer A, John GR. VEGF-mediated disruption of endothelial CLN-5 promotes blood-brain barrier breakdown. Proc Natl Acad Sci U S A 2009;106:1977-82.
• 105. Zhang ZG, Zhang L, Jiang Q, et al. VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain. J Clin Invest 2000;106:829-38.
• 106. Asahi M, Wang X, Mori T, et al. Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood-brain barrier and white matter components after cerebral ischemia. J Neurosci 2001;21:7724-32.
• 107. Yang Y, Estrada E Y, Thompson JF, Liu W, Rosenberg GA. Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. J Cereb Blood Flow Metab 2007;27:697-709.
• 108. Yang Y, Rosenberg GA. MMP-mediated disruption of claudin-5 in the blood-brain barrier of rat brain after cerebral ischemia. Methods Mol Biol 2011;762:333-45.
• 109. Zhang S, An Q, Wang T, Gao S, Zhou G. Autophagyand MMP-2/9-mediated reduction and redistribution of ZO-1 Contribute to hyperglycemia-increased blood-brain barrier permeability during early reperfusion in stroke. Neuroscience 2018;377:126-37.
• 110. Gu Y, Zheng G, Xu M, et al. Caveolin-1 regulates nitric oxide-mediated matrix metalloproteinases activity and bloodbrain barrier permeability in focal cerebral ischemia and reperfusion injury. J Neurochem 2012;120:147-56.
• 111. Fu S, Gu Y, Jiang JQ, et al. Calycosin-7- O-β-D-glucoside regulates nitric oxide /caveolin-1/matrix metalloproteinases pathway and protects blood-brain barrier integrity in experimental cerebral ischemia-reperfusion injury. J Ethnopharmacol 2014;155:692-701.
• 112. Jiang Z, Li C, Arrick D M, Yang S, Baluna AE, Sun H. Role of nitric oxide synthases in early blood-brain barrier disruption following transient focal cerebral ischemia. PLoS One 2014;9:e93134.
• 113. Sharp CD, Hines I, Houghton J, et al. Glutamate causes a loss in human cerebral endothelial barrier integrity through activation of NMDA receptor. Am J Physiol Heart Circ Physiol 2003;285:H2592-98.
• 114. András IE, Del MA, Veszelk S, Hayashi K, Hennig B, Toborek M. The NMDA and AMPA/KA receptors are involved in glutamateinduced alterations of occludin expression and phosphorylation in brain endothelial cells. J Cereb Blood Flow Metab 2007;27:1431-43.
• 115. Liu X, Hunter C, Weiss HR, Chi OZ. Effects of blockade of ionotropic glutamate receptors on blood-brain barrier disruption in focal cerebral ischemia. Neurol. Sci. 2010;31:699-703.
• 116. Lu L, Hogan-Cann AD, Globa AK, et al. Astrocytes drive cortical vasodilatory signaling by activating endothelial NMDA receptors. J Cereb Blood Flow Metab 2019;39:481-96.
• 117. Lo AC, Chen AY, Hung VK, et al. Endothelin-1 overexpression leads to further water accumulation and brain edema after middle cerebral artery occlusion via aquaporin 4 expression in astrocytic end-feet. J Cereb Blood Flow Metab. 2005;25:998-1011.
• 118. Hung VK, Yeung P. K, Lai AK, et al. Selective astrocytic endothelin-1 overexpression contributes to dementia associated with ischemic stroke by exaggerating astrocyte-derived amyloid secretion. J Cereb Blood Flow Metab 2015;35:1687-96.
• 119. Lee S, Kim W J, Choi, YK, et al. SSeCKS regulates angiogenesis and tight junction formation in blood-brain barrier. Nat Med 2003;9:900-06.
• 120. Yu H, Wang P, An P, Xue Y. Recombinant humanangiopoietin1 ameliorates the expressions of ZO-1, occludin, VE-cadherin, and PKCα signaling after focal cerebralischemia/reperfusion in rats. J Mol Neurosci 2012;46:236-47.
• 121. Hill S A, Fu M, Garcia ADR. Sonic hedgehog signaling in astrocytes. Cell Mol Life Sci 2021:78:1393-1403.
• 122. Liu L, Zhao B, Xiong X, Xia Z. The neuroprotective roles ofsonic hedgehog signaling pathway in ischemic stroke. Neurochem. Res. 2018;43:2199-2211.
• 123. Xia YP, He QW, Li YN, et al. Recombinant human sonichedgehog protein regulates the expression of ZO-1 and occludin by activating angiopoietin-1 in stroke damage. PLoSOne 2013;8:e68891.
• 124. Pitt J, Wilcox KC, Tortelli V, Diniz LP, et al. Neuroprotective astrocyte-derived insulin/insulin-like growth factor 1 stimulates endocytic processing and extracellular release of neuronbound Aβ oligomers. Mol Biol Cell 2017;28:2623-36.
• 125. Wrigley S, Arafa D, Tropea D. Insulin-Like growth factor 1: at the crossroads of brain development and aging. Front Cell Neurosci 2017;11:14.
• 126. Bake S, Okoreeh A, Khosravian H, and Sohrabji F. Insulin-like Growth Factor (IGF)-1 treatment stabilizes the microvascular cytoskeleton under ischemic conditions. Exp Neurol 2019;311:162-72.
• 127. Marais AD. Apolipoprotein E in lipoprotein metabolism, health and cardiovascular disease. Pathology 2019;51:165-76.
• 128. Morikawa M, Fryer J D, Sullivan PM, et al. Production andcharacterization of astrocytederived human apolipoprotein E isoforms from immortalized astrocytes and their interactions with amyloid-beta. Neurobiol Dis 2005;19:66-76.
• 129. Koyama Y. Signaling molecules regulating phenotypic conversions of astrocytes and glial scar formation in damaged nerve tissues. Neurochem Int 2014;78:35-42.
• 130. Mizee MR, Wooldrik D, Lakeman K. et al. Retinoic acid induces blood-brain barrier development. J Neurosci 2013;33:1660-71.
• 131. Xiao W, Wang W, Chen W, et al. GDNF is involved in thebarrier-inducing effect of enteric glial cells on intestinal epithelial cells under acute ischemia reperfusion stimulation. Mol Neurobiol 2014;50:274-89.
• 132. Al-Ahmady Z S. Selective drug delivery approaches to lesioned brain through blood brain barrier disruption. Expert Opin. Drug Deliv. 2018;15:335-49.
• 133. Cohen E, Dillin A. The insulin paradox: aging, proteotoxicity and neurodegeneration. Nat Rev Neurosci 2008;9:759-67.
• 134. Song Y, Pimentel C, Walters K, et al. Neuroprotective levels ofIGF-1 exacerbate epileptogenesis after brain injury. Sci Rep2016;6:32095.
• 135. Iliff JJ, Wang M, Liao Y, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci. Transl Med 2012; 4:147ra111.
• 136. Nedergaard M. Neuroscience. garbage truck of the brain. Science 2013; 340:1529-30.
• 137. Levison SW, Jiang FJ, Stoltzfus OK, Ducceschi MH. IL-6-type cytokines enhance epidermal growth factor-stimulated astrocyte proliferation. Glia 2000;32:328-37
• 138. Gadea A, Schinelli S, Gallo V. Endothelin-1 regulates astrocyte proliferation and reactive gliosis via a JNK/c-Jun signaling pathway. J Neurosci 2008; 28:2394-2408.
• 139. Neary JT, Zimmermann H. Trophic functions of nucleotides in the central nervous system. Trends Neurosci 2009;32:189-98.
• 140. Faulkner JR, Herrmann JE, Woo M J, Tansey KE, Doan NB,Sofroniew MV. Reactive astrocytes protect tissue and preserve function after spinal cord injury. J Neurosci 2004;24:2143-55.
• 141. Rolls A, Shechter R, Schwartz M. The bright side of the glial scar in CNS repair. Nat Rev Neurosci 2009;10:235-41.
• 142. Bush TG, Puvanachandra N. Horner CH. et al. Leukocyteinfiltration, neuronal degeneration, and neurite outgrowth afterablation of scar-forming, reactive astrocytes in adult transgenic mice. Neuron 2014;23:297-308.
• 143. Burda JE. Sofroniew MV. Reactive gliosis and the multicellularresponse to CNS damage and disease. Neuron 2014;81:229-48.
• 144. Sofroniew MV. Multiple roles for astrocytes as effectors ofcytokines and inflammatory mediators. Neuroscientist 2014;20:160-72.
• 145. Myer DJ, Gurkoff GG, Lee SM, Hovda D A, Sofroniew MV.Essential protective roles of reactive astrocytes in traumatic brain injury. Brain 2006;129:2761-72.
• 146. Chung IY, Benveniste EN. Tumor necrosis factor-alpha production by astrocytes. induction by lipopolysaccharide, IFN-gamma, and IL-1 beta. J Immunol 1990;144:2999-3007.
• 147. Yiu G, He, Z. Glial inhibition of CNS axon regeneration. Nat Rev Neurosci. 2006;7:617-27.
• 148. Silver J, Schwab ME, Popovich PG. Central nervous systemregenerative failure: role of oligodendrocytes, astrocytes, and microglia. Cold Spring Harb. Perspect. Biol 2014;7:a020602
• 149. Asher RA, Morgenstern RA, Moon LD. Fawcett JW.Chondroitin sulphate proteoglycans: inhibitory components of the glial scar Prog. Brain Res.2001;132:611-19.
• 150. Liddelow S, Barres B. Reactive astrocytes: production, function, and therapeutic potential. Immunity 2017;46:957-67.
• 151. King A, Szekely B, Calapkulu E, et al. The increased densities, but different distributions, of both C3 and S100A10immunopositive astrocyte-like cells in alzheimer’s disease brains suggest possible roles for both A1 and A2 astrocytes inthe disease pathogenesis. Brain Sci 2020;10:503.
• 152. Zou LH, Shi YJ, He H, et al. Effects of FGF2/FGFR1 pathwayon expression of A1 astrocytes after infrasound exposure. Front Neurosci 2019;13:429.