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脳梗塞後に生じる血管原性浮腫の形成及び進行におけるミクログリアの役割

田中 美樹 広島大学

2022.03.23

概要

脳梗塞は脳⾎管の閉塞により脳の⾎液循環が障害される疾患であり,重度の神経機能障害をもたらすことで⽣涯にわたり患者の⽣活の質(quality of life; QOL)を悪化させる.その罹患率は極めて⾼いうえ⾼齢化進⾏による患者数の急増が危惧されており,患者のQOL向上は全世界において喫緊の課題である.QOL向上のためには急性期の治療が重要である.しかし,2022年現在,最も有効な治療法である静注⾎栓溶解療法や⾎栓回収療法は適⽤条件が厳しいため,9割以上の患者は適応外(禁忌)となり⾎流回復による治療が不可能である.

 脳梗塞発症後,虚⾎の持続により種々の⼆次障害が⽣じ,病態が重症化する.なかでも脳浮腫は脳実質に過剰量の⽔分が蓄積するものであり,脳体積増⼤による脳機能低下や脳ヘルニアを発⽣させることで患者の転機を著しく悪化させる.脳浮腫の軽減は⾮常に重要な臨床課題であるが,詳細な病態形成メカニズムは不明であるために根治療法は存在しない.脳浮腫は⽔分の蓄積場所により2つに⼤別される.⾎管原性浮腫は⾎液脳関⾨(blood brain barrier; BBB)の機能障害により細胞外腔に⽔分が蓄積する浮腫であり,脳体積増加の直接的な原因となる.主な研究対象はアクアポリン4(aquaporin 4; AQP4)などの⽔チャネルやイオントランスポーターであり,⽔の流⼊抑制を狙いとしている.しかし,これらの因⼦は⽔の排出経路としても機能するため顕著な効果は期待しがたい.

 ⽔の流⼊制御に代わる治療法として,炎症制御がある.⾎管原性浮腫の病態形成にはBBBの機能障害が重要であることから,⾎管透過性亢進に関与する因⼦の発現制御が有効だと考えられる.虚⾎後には中枢神経系の免疫細胞ミクログリアや,好中球,T細胞,B細胞などの末梢からの浸潤細胞により種々の⾎管透過性亢進因⼦が産⽣される.しかし,永久虚⾎下ではこれらの浸潤細胞の増加は認められず,治療効果が乏しいことが動物モデルを⽤いた研究により報告されている.さらに,脳梗塞患者の脳組織標本を⽤いた病理解析においても顕著な活性化を⽰すのはミクログリアであることが報告されている.上述の背景を踏まえ,永久虚⾎下において⽣じる⾎管原性浮腫の形成および進⾏過程を精査し,特にミクログリアに着⽬して有望な治療標的を⾒出すべく,2015年より研究を開始した.

 第2章では,永久虚⾎下において⽣じる脳浮腫の形成過程を時空間的に解析した.脳浮腫を評価する際には,⼀般的に,乾湿重量測定法が⽤いられる.しかしこの⼿法は脳⽔分量を算出できるのみであり,脳浮腫の動態については明らかにできない.そこで,⽣体内に存在する⽔素原⼦核(プロトン)の空間分布を解析することにより⽔分量の多い領域を描出できる核磁気共鳴画像法(magnetic resonance imaging; MRI)を⽤いた.T2強調画像(T2-weited image; T2WI)によりマウス脳を撮像すると,線条体を含む虚⾎中⼼部において⽔分量が上昇しはじめ,時間経過により浮腫範囲が増⼤することが明らかになった.トリフェニルテトラゾリウムクロライド(2,3,5-triphenyl tetrazolium chloride; TTC)染⾊により脳虚⾎後の死細胞塊(梗塞巣)を同定すると,浮腫が⽣じた領域ではその後に梗塞巣が形成されることが判明した.さらにT2WIとTTC染⾊画像の重ね合わせにより⾎管原性浮腫を描出した結果,⾎管原性浮腫は虚⾎6時間後から虚⾎中⼼部において⽣じ,時間の経過とともに虚⾎辺縁部へと進⾏することが判明した.

 第3章では,第2章で明らかにした⾎管原性浮腫の形成過程におけるミクログリアの役割を調べた.浮腫形成前後の各タイムポイントにおいてIba1とCD68の⼆重免疫蛍光染⾊や炎症性因⼦の発現解析を⾏い,ミクログリア活性状態を評価した.その結果,ミクログリアは虚⾎中⼼部において顕著な活性化をはじめ,時間経過とともに虚⾎辺縁部へと活性化が進⾏する様⼦が認められた.炎症性因⼦による内⽪細胞への影響を調べるため,マウス脳微⼩⾎管内⽪細胞bEnd.3を培養した.TNF-αとIL-6を処置すると,タイトジャンクションタンパク質(tight junction proteins; TJPs)発現が顕著に低下しており,これらの炎症性因⼦が⾎管透過性を亢進させることで⾎管原性浮腫が形成されることが⽰唆された.さらに,ミクログリア活性化抑制による⾎管原性浮腫への影響を検討するためミノサイクリン(minocycline; MINO)を投与すると,MINO投与群では⾎管原性浮腫の進⾏が顕著に抑制され,虚⾎24時間後の神経機能障害が有意に改善された.

 第4章では,虚⾎後の炎症制御因⼦として芳⾹族炭化⽔素受容体(aryl hydrocarbon receptor; AhR)に着⽬した解析を⾏なった.炎症下においてAhRは,外部環境に応じて相反する炎症反応を惹起する.しかし,虚⾎性脳浮腫に対する作⽤は不明であるため,神経炎症および⾎管原性浮腫におけるAhRの役割を検討した.虚⾎後マウス脳では,AhR下流標的遺伝⼦である薬物代謝酵素CYP1A1や炎症関連因⼦IL-1β,TNF-αおよびCOX-2が発現上昇した.AhR阻害剤CH223191を投与すると,これらの遺伝⼦の発現増加や⾎管原性浮腫の形成,および神経障害度が抑制され,AhR阻害により虚⾎後の脳障害が改善することが⽰された.THP-1マクロファージにAhRリガンドを処置すると,特に炎症条件下においてNADPH oxidase(NOX)サブユニットp47phoxが有意に発現上昇した.アポシニン処置によるNOX活性の抑制,またはSuper oxide dismutase(SOD)処置によるスーパーオキシドの除去を⾏うと,AhRリガンドにより誘導されるTNF-α発現が減少した.また,AhRリガンドはマウス初代ミクログリアにおいてp47phoxの発現を惹起した.したがって,p47phoxは酸化ストレスとそれに続く炎症に重要である可能性がある.永久虚⾎マウスでは,虚⾎によりミクログリアでのP47phoxの発現が上昇した.pMCAOによって誘導された脂質過酸化は,CH223191によって抑制された.これらの結果より,虚⾎後の神経炎症および⾎管原性浮腫の発⽣には,p47phoxの発現上昇とそれに続く酸化ストレス亢進が関与することが⽰唆された.

 本研究では永久虚⾎下において⽣じる脳浮腫の時空間的な形成過程を精査し,虚⾎中⼼部から虚⾎辺縁部へと⾎管原性浮腫が進⾏する様⼦を明らかにした.また,⾎管原性浮腫の形成に先⾏してミクログリアが活性化の様相を呈し,⾎管透過性亢進因⼦による内⽪細胞タイトジャンクションタンパク質(tight junction proteins; TJPs)の発現低下により⾎管原性浮腫が形成される可能性を⽰した.さらに,ミクログリアの炎症制御因⼦としてAhRに着⽬し,AhR-NOX2経路を介した神経炎症の抑制により⾎管原性浮腫を軽減できることを明らかにした.研究により得られた成果は,脳虚⾎におけるAhRの病態⽣理学的役割の⼀端を⽰すものであり,脳浮腫の治療薬開発に資する基礎的知⾒を提供するものである.

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参考文献

• Abdullah, Z. et al. (2015) “Inhibition of TNF-α protects in vitro brain barrier from ischaemic damage,” Molecular and cellular neurosciences. Elsevier BV, 69, pp. 65–79.

• Abramoff, M. D. (2007) “ImageJ as an image processing tool and library,” Microscopy and microanalysis: the official journal of Microscopy Society of America, Microbeam Analysis Society, Microscopical Society of Canada. Cambridge University Press (CUP), 13(S02). doi: 10.1017/s1431927607079652.

• Armstead, W. M. et al. (1992) “Polyethylene glycol superoxide dismutase and catalase attenuate increased blood-brain barrier permeability after ischemia in piglets,” Stroke; a journal of cerebral circulation. Ovid Technologies (Wolters Kluwer Health), 23(5), pp. 755– 762.

• Armstead, W. M. (2001) “Vasopressin-induced protein kinase C-dependent superoxide generation contributes to atp-sensitive potassium channel but not calcium-sensitive potassium channel function impairment after brain injury,” Stroke; a journal of cerebral circulation. Ovid Technologies (Wolters Kluwer Health), 32(6), pp. 1408–1414.

• Aronson, A. L. (1980) “Pharmacotherapeutics of the newer tetracyclines,” Journal of the American Veterinary Medical Association, 176(10 Spec), pp. 1061–1068.

• Asahi, M. et al. (2001) “Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood-brain barrier and white matter components after cerebral ischemia,” The Journal of neuroscience: the official journal of the Society for Neuroscience, 21(19), pp. 7724–7732.

• Azzi, A., Montecucco, C. and Richter, C. (1975) “The use of acetylated ferricytochrome c for the detection of superoxide radicals produced in biological membranes,” Biochemical and biophysical research communications. Elsevier BV, 65(2), pp. 597–603.

• Badaut, J. et al. (2014) “Aquaporin and brain diseases,” Biochimica et biophysica acta, 1840(5), pp. 1554–1565.

• Badawy, A. A.-B. (2017) “Kynurenine pathway of tryptophan metabolism: Regulatory and functional aspects,” International journal of tryptophan research: IJTR. SAGE Publications, 10, p. 1178646917691938.

• Barza, M. et al. (1975) “Relation between lipophilicity and pharmacological behavior of minocycline, doxycycline, tetracycline, and oxytetracycline in dogs,” Antimicrobial agents and chemotherapy, 8(6), pp. 713–720.

• Bedard, K. and Krause, K.-H. (2007) “The NOX family of ROS-generating NADPH oxidases: Physiology and pathophysiology,” Physiological reviews. American Physiological Society, 87(1), pp. 245–313.

• Berrouschot, J. et al. (1998) “Mortality of space-occupying ('malignant’) middle cerebral artery infarction under conservative intensive care,” Intensive care medicine, 24(6), pp. 620– 623.

• Bhaskar, S. et al. (2018) “Reperfusion therapy in acute ischemic stroke: dawn of a new era?,” BMC neurology, 18(1), p. 8.

• Braithwaite, I. et al. (2019) “Air pollution (particulate matter) exposure and associations with depression, anxiety, bipolar, psychosis and suicide risk: A systematic review and meta- analysis,” Environmental health perspectives. Environmental Health Perspectives, 127(12), p. 126002.

• Brott, T. et al. (1989) “Measurements of acute cerebral infarction: a clinical examination scale,” Stroke; a journal of cerebral circulation, 20(7), pp. 864–870.

• Brown, G. C. and Neher, J. J. (2012) “Eaten alive! Cell death by primary phagocytosis: ‘phagoptosis,’” Trends in biochemical sciences, 37(8), pp. 325–332.

• Cacciottolo, M. et al. (2017) “Particulate air pollutants, APOE alleles and their contributions to cognitive impairment in older women and to amyloidogenesis in experimental models,” Translational psychiatry, 7(1), p. e1022.

• Campbell, S. J. et al. (2005) “The murine Cyp1a1 gene is expressed in a restricted spatial and temporal pattern during embryonic development,” The journal of biological chemistry. Elsevier BV, 280(7), pp. 5828–5835.

• Chamorro, Á. et al. (2012) “The immunology of acute stroke,” Nature reviews. Neurology. Springer Science and Business Media LLC, 8(7), pp. 401–410.

• Chen, G. et al. (2019) “Long-Term Exposure to Air Pollution and Survival After Ischemic Stroke,” Stroke; a journal of cerebral circulation, 50(3), pp. 563–570.

• Chen, J. et al. (2001) “Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats,” Stroke; a journal of cerebral circulation, 32(4), pp. 1005–1011.

• Chen, W.-C. et al. (2019) “Aryl hydrocarbon receptor modulates stroke-induced astrogliosis and neurogenesis in the adult mouse brain,” Journal of neuroinflammation, 16(1), p. 187.

• Chopra, I. and Roberts, M. (2001) “Tetracycline antibiotics: mode of action, applications, molecular biology, and epidemiology of bacterial resistance,” Microbiology and molecular biology reviews: MMBR. American Society for Microbiology, 65(2), pp. 232–60 ; second page, table of contents.

• Choudhary, D. et al. (2003) “Comparative expression profiling of 40 mouse cytochrome P450 genes in embryonic and adult tissues,” Archives of biochemistry and biophysics. Elsevier BV, 414(1), pp. 91–100.

• Cohen, S. S. et al. (2013) “Effects of interleukin-6 on the expression of tight junction proteins in isolated cerebral microvessels from yearling and adult sheep,” Neuroimmunomodulation, 20(5), pp. 264–273.

• Colovic, M. and Caccia, S. (2003) “Liquid chromatographic determination of minocycline in brain-to-plasma distribution studies in the rat,” Journal of chromatography. B, Analytical technologies in the biomedical and life sciences, 791(1–2), pp. 337–343.

• Colpo, G. D. et al. (2019) “Systematic review on the involvement of the kynurenine pathway in stroke: Pre-clinical and clinical evidence,” Frontiers in neurology. Frontiers Media SA, 10, p. 778.

• Crockard, A. et al. (1980) “Cerebral blood flow and edema following carotid occlusion in the gerbil,” Stroke; a journal of cerebral circulation, 11(5), pp. 494–498.

• Cserr, H. F. et al. (1981) “Efflux of radiolabeled polyethylene glycols and albumin from rat brain,” The American journal of physiology, 240(4), pp. F319-28.

• Cuartero, M. I. et al. (2014) “L-kynurenine/aryl hydrocarbon receptor pathway mediates brain damage after experimental stroke,” Circulation, 130(23), pp. 2040–2051.

• Cuartero, M. I. et al. (2016) “The Kynurenine Pathway in the acute and chronic phases of cerebral ischemia,” Current pharmaceutical design, 22(8), pp. 1060–1073.

• Curran, C. P. et al. (2012) “Ahrd Cyp1a2(-/-) mice show increased susceptibility to PCB- induced developmental neurotoxicity,” Neurotoxicology, 33(6), pp. 1436–1442.

• Darlington, L. G. et al. (2007) “Altered kynurenine metabolism correlates with infarct volume in stroke,” The European journal of neuroscience, 26(8), pp. 2211–2221.

• Desai, T. R. et al. (2002) “Interleukin-6 causes endothelial barrier dysfunction via the protein kinase C pathway,” The Journal of surgical research. Elsevier BV, 104(2), pp. 118–123.

• Fadini, G. P. et al. (2013) “Monocyte-macrophage polarization balance in pre-diabetic individuals,” Acta diabetologica, 50(6), pp. 977–982.

• Farr, G. W. et al. (2019) “Functionalized Phenylbenzamides Inhibit Aquaporin-4 Reducing Cerebral Edema and Improving Outcome in Two Models of CNS Injury,” Neuroscience, 404, pp. 484–498.

• Feigin, V. L. et al. (2014) “Global and regional burden of stroke during 1990-2010: findings from the Global Burden of Disease Study 2010,” Lancet. Elsevier BV, 383(9913), pp. 245– 254.

• Feigin, V. L. et al. (2022) “World stroke organization (WSO): Global Stroke Fact Sheet 2022,” International journal of stroke: official journal of the International Stroke Society. SAGE Publications, 17(1), pp. 18–29.

• Fenske, A. et al. (1973) “Extracellular space and electrolyte distribution in cortex and white matter of dog brain in cold induced oedema,” Acta neurochirurgica. Springer Nature, 28(1– 2), pp. 81–94.

• Fernandez-Salguero, P. et al. (1995) “Immune system impairment and hepatic fibrosis in mice lacking the dioxin-binding Ah receptor,” Science (New York, N.Y.). American Association for the Advancement of Science (AAAS), 268(5211), pp. 722–726.

• Filbrandt, C. R. et al. (2004) “Presence and functional activity of the aryl hydrocarbon receptor in isolated murine cerebral vascular endothelial cells and astrocytes,” Neurotoxicology. Elsevier BV, 25(4), pp. 605–616.

• Foerch, C. et al. (2008) “The projected burden of stroke in the German federal state of Hesse up to the year 2050,” Deutsches Arzteblatt international, 105(26), pp. 467–473.

• Garcia, J. H., Liu, K. F. and Bree, M. P. (1996) “Effects of CD11b/18 monoclonal antibody on rats with permanent middle cerebral artery occlusion,” The American journal of pathology, 148(1), pp. 241–248.

• GBD 2016 Lifetime Risk of Stroke Collaborators et al. (2018) “Global, Regional, and Country-Specific Lifetime Risks of Stroke, 1990 and 2016,” The New England journal of medicine, 379(25), pp. 2429–2437.

• Gelderblom, M. et al. (2009) “Temporal and spatial dynamics of cerebral immune cell accumulation in stroke,” Stroke; a journal of cerebral circulation, 40(5), pp. 1849–1857.

• Ginhoux, F. et al. (2013) “Origin and differentiation of microglia,” Frontiers in cellular neuroscience, 7, p. 45.

• Grande, G. et al. (2020) “Association Between Cardiovascular Disease and Long-term Exposure to Air Pollution With the Risk of Dementia,” JAMA neurology, 77(7), pp. 801–809.

• Gröger, M. et al. (2005) “Release of bradykinin and expression of kinin B2 receptors in the brain: role for cell death and brain edema formation after focal cerebral ischemia in mice,” Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism. SAGE Publications, 25(8), pp. 978–989.

• Grønberg, N. V. et al. (2013) “Leukocyte infiltration in experimental stroke,” Journal of neuroinflammation. Springer Science and Business Media LLC, 10(1), p. 115.

• Gutiérrez-Vázquez, C. and Quintana, F. J. (2018) “Regulation of the Immune Response by the Aryl Hydrocarbon Receptor,” Immunity, 48(1), pp. 19–33.

• Hacke, W. et al. (1996) “‘Malignant’ middle cerebral artery territory infarction: clinical course and prognostic signs,” Archives of neurology, 53(4), pp. 309–315.

• Halstead, M. R. and Geocadin, R. G. (2019) “The Medical Management of Cerebral Edema: Past, Present, and Future Therapies,” Neurotherapeutics: the journal of the American Society for Experimental NeuroTherapeutics, 16(4), pp. 1133–1148.

• Hanisch, U.-K. (2002) “Microglia as a source and target of cytokines,” Glia, 40(2), pp. 140– 155.

• Haruwaka, K. et al. (2019) “Dual microglia effects on blood brain barrier permeability induced by systemic inflammation,” Nature communications, 10(1), p. 5816.

• Heinemeyer, T. et al. (1998) “Databases on transcriptional regulation: TRANSFAC, TRRD and COMPEL,” Nucleic acids research. Oxford University Press (OUP), 26(1), pp. 362–367.

• Holness, C. L. and Simmons, D. L. (1993) “Molecular cloning of CD68, a human macrophage marker related to lysosomal glycoproteins,” Blood, 81(6), pp. 1607–1613.

• Hossmann, V., Hossmann, K. A. and Takagi, S. (1980) “Effect of intravascular platelet aggregation on blood recirculation following prolonged ischemia of the cat brain,” Journal of neurology, 222(3), pp. 159–170.

• Iliff, J. J. et al. (2012) “A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β,” Science translational medicine. American Association for the Advancement of Science (AAAS), 4(147), p. 147ra111.

• Iliff, J. J. et al. (2013) “Brain-wide pathway for waste clearance captured by contrast- enhanced MRI,” The journal of clinical investigation, 123(3), pp. 1299–1309.

• Ishihara, Y. et al. (2019) “Interleukin 33 expression induced by aryl hydrocarbon receptor in macrophages,” Toxicological sciences: an official journal of the Society of Toxicology. Oxford University Press (OUP), 170(2), pp. 404–414.

• Jana, N. R. et al. (1998) “Strain differences in cytochrome P4501A1 gene expression caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin in the rat liver: role of the aryl hydrocarbon receptor and its nuclear translocator,” Biochemical and biophysical research communications, 248(3), pp. 554–558.

• Jin, R., Yang, G. and Li, G. (2010) “Inflammatory mechanisms in ischemic stroke: role of inflammatory cells,” Journal of leukocyte biology, 87(5), pp. 779–789.

• Johnston, K. C. et al. (1998) “Medical and neurological complications of ischemic stroke: experience from the RANTTAS trial. RANTTAS Investigators,” Stroke; a journal of cerebral circulation, 29(2), pp. 447–453.

• Jolivel, V. et al. (2015) “Perivascular microglia promote blood vessel disintegration in the ischemic penumbra,” Acta neuropathologica, 129(2), pp. 279–295.

• Kanai, M., Nakamura, T. and Funakoshi, H. (2009) “Identification and characterization of novel variants of the tryptophan 2,3-dioxygenase gene: differential regulation in the mouse nervous system during development,” Neuroscience research. Elsevier BV, 64(1), pp. 111– 117.

• Keep, R. F., Hua, Y. and Xi, G. (2012) “Brain water content. A misunderstood measurement?,” Translational stroke research. Springer Science and Business Media LLC, 3(2), pp. 263–265.

• Kettenmann, H. et al. (2011) “Physiology of microglia,” Physiological reviews, 91(2), pp. 461–553.

• Kim, G. W. et al. (2001) “The cytosolic antioxidant, copper/zinc superoxide dismutase, attenuates blood-brain barrier disruption and oxidative cellular injury after photothrombotic cortical ischemia in mice,” Neuroscience. Elsevier BV, 105(4), pp. 1007–1018.

• Kimura, E. and Tohyama, C. (2017) “Embryonic and postnatal expression of aryl hydrocarbon receptor mRNA in mouse brain,” Frontiers in neuroanatomy. Frontiers Media SA, 11, p. 4.

• King, M. D., Alleyne, C. H., Jr and Dhandapani, K. M. (2013) “TNF-alpha receptor antagonist, R-7050, improves neurological outcomes following intracerebral hemorrhage in mice,” Neuroscience letters. Elsevier BV, 542, pp. 92–96.

• Klatzo, I. (1987a) “Blood-brain barrier and ischaemic brain oedema,” Zeitschrift für Kardiologie, 76 Suppl 4, pp. 67–69.

• Klatzo, I. (1987b) “Pathophysiological aspects of brain edema,” Acta neuropathologica. Springer Nature, 72(3), pp. 236–239.

• Klein, N. C. and Cunha, B. A. (1995) “Tetracyclines,” The Medical clinics of North America. Elsevier BV, 79(4), pp. 789–801.

• Kobayashi, K. et al. (2013) “Minocycline selectively inhibits M1 polarization of microglia,” Cell death & disease. Springer Science and Business Media LLC, 4(3), pp. e525–e525.

• Kransler, K. M., McGarrigle, B. P. and Olson, J. R. (2007) “Comparative developmental toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the hamster, rat and guinea pig,” Toxicology. Elsevier BV, 229(3), pp. 214–225.

• Kurushima, H. et al. (2000) “Surface expression and rapid internalization of macrosialin (mouse CD68) on elicited mouse peritoneal macrophages,” Journal of leukocyte biology, 67(1), pp. 104–108.

• Lahvis, G. P. et al. (2005) “The aryl hydrocarbon receptor is required for developmental closure of the ductus venosus in the neonatal mouse,” Molecular pharmacology. American Society for Pharmacology & Experimental Therapeutics (ASPET), 67(3), pp. 714–720.

• Lee, Y.-H. et al. (2015) “Aryl hydrocarbon receptor mediates both proinflammatory and anti- inflammatory effects in lipopolysaccharide-activated microglia,” Glia, 63(7), pp. 1138–1154.

• Liebeskind, D. S. et al. (2019) “Cerebral Edema Associated With Large Hemispheric Infarction,” Stroke; a journal of cerebral circulation, 50(9), pp. 2619–2625.

• Liesz, A. et al. (2011) “Inhibition of lymphocyte trafficking shields the brain against deleterious neuroinflammation after stroke,” Brain: a journal of neurology. Oxford University Press (OUP), 134(Pt 3), pp. 704–720.

• Liu, H. et al. (2017) “Ambient Particulate Matter Concentrations and Hospitalization for Stroke in 26 Chinese Cities: A Case-Crossover Study,” Stroke; a journal of cerebral circulation, 48(8), pp. 2052–2059.

• Liu, W. et al. (2009) “Normobaric hyperoxia attenuates early blood-brain barrier disruption by inhibiting MMP-9-mediated occludin degradation in focal cerebral ischemia,” Journal of neurochemistry, 108(3), pp. 811–820.

• Luo, Z.-W. et al. (2020) “Drug development in targeting ion channels for brain edema,” Acta pharmacologica Sinica, 41(10), pp. 1272–1288.

• Manley, G. T. et al. (2000) “Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke,” Nature medicine, 6(2), pp. 159–163.

• McColl, B. W., Rothwell, N. J. and Allan, S. M. (2008) “Systemic inflammation alters the kinetics of cerebrovascular tight junction disruption after experimental stroke in mice,” The Journal of neuroscience: the official journal of the Society for Neuroscience, 28(38), pp. 9451–9462.

• Mescher, M. and Haarmann-Stemmann, T. (2018) “Modulation of CYP1A1 metabolism: From adverse health effects to chemoprevention and therapeutic options,” Pharmacology & therapeutics. Elsevier BV, 187, pp. 71–87.

• Mestre, H. et al. (2020) “Cerebrospinal fluid influx drives acute ischemic tissue swelling,” Science, 367(6483). doi: 10.1126/science.aax7171.

• Michinaga, S. and Koyama, Y. (2015) “Pathogenesis of brain edema and investigation into anti-edema drugs,” International journal of molecular sciences, 16(5), pp. 9949–9975.

• Miller, K. A. et al. (2007) “Long-term exposure to air pollution and incidence of cardiovascular events in women,” The New England journal of medicine, 356(5), pp. 447– 458.

• Möller, T. et al. (2016) “Critical data-based re-evaluation of minocycline as a putative specific microglia inhibitor,” Glia, 64(10), pp. 1788–1794.

• Nagelhus, E. A. and Ottersen, O. P. (2013) “Physiological roles of aquaporin-4 in brain,” Physiological reviews, 93(4), pp. 1543–1562.

• National Institute of Neurological Disorders and Stroke (NINDS) (1990) “Special report from the National Institute of Neurological Disorders and Stroke. Classification of cerebrovascular diseases III,” Stroke; a journal of cerebral circulation, 21(4), pp. 637–676.

• Nesic, O. et al. (2006) “Acute and chronic changes in aquaporin 4 expression after spinal cord injury,” Neuroscience, 143(3), pp. 779–792.

• Nguyen, L. P. and Bradfield, C. A. (2008) “The search for endogenous activators of the aryl hydrocarbon receptor,” Chemical research in toxicology. American Chemical Society (ACS), 21(1), pp. 102–116.

• Okey, A. B. et al. (2005) “Toxicological implications of polymorphisms in receptors for xenobiotic chemicals: the case of the aryl hydrocarbon receptor,” Toxicology and applied pharmacology, 207(2 Suppl), pp. 43–51.

• Okuda, T. et al. (2015) “Development of a high-volume PM2.5 particle sampler using impactor and cyclone techniques,” Aerosol and Air Quality Resarch. Taiwan Association for Aerosol Research, 15(3), pp. 759–767.

• Opitz, C. A. et al. (2011) “An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor,” Nature. Springer Science and Business Media LLC, 478(7368), pp. 197–203.

• Oshio, K. et al. (2004) “Expression of aquaporin water channels in mouse spinal cord,” Neuroscience, 127(3), pp. 685–693.

• Owolabi, M. O. et al. (2022) “Primary stroke prevention worldwide: translating evidence into action,” The lancet. Public health. Elsevier BV, 7(1), pp. e74–e85.

• Pang, T. et al. (2012) “Minocycline ameliorates LPS-induced inflammation in human monocytes by novel mechanisms including LOX-1, Nur77 and LITAF inhibition,” Biochimica et biophysica acta. General subjects. Elsevier BV, 1820(4), pp. 503‒510.

• Papadopoulos, M. C. et al. (2004) “Aquaporin-4 facilitates reabsorption of excess fluid in vasogenic brain edema,” FASEB journal: official publication of the Federation of American Societies for Experimental Biology, 18(11), pp. 1291–1293.

• Parrott, J. M. and O’Connor, J. C. (2015) “Kynurenine 3-Monooxygenase: An Influential Mediator of Neuropathology,” Frontiers in psychiatry. Frontiers Media SA, 6. doi: 10.3389/fpsyt.2015.00116.

• Patten, K. T. et al. (2021) “The Effects of Chronic Exposure to Ambient Traffic-Related Air Pollution on Alzheimer’s Disease Phenotypes in Wildtype and Genetically Predisposed Male and Female Rats,” Environmental health perspectives, 129(5), p. 57005.

• Pinel-Marie, M.-L. et al. (2009) “Aryl hydrocarbon receptor-dependent induction of the NADPH oxidase subunit NCF1/p47phox expression leading to priming of human macrophage oxidative burst,” Free radical biology & medicine. Elsevier BV, 47(6), pp. 825– 834.

• Platten, M. et al. (2019) “Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond,” Nature reviews. Drug discovery. Springer Science and Business Media LLC, 18(5), pp. 379–401.

• Pm et al. (1997) “Mass effect and death from severe acutestroke,” Neurology, 49, p. 1090 109.

• Poland, A., Glover, E. and Kende, A. S. (1976) “Stereospecific, high affinity binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin by hepatic cytosol. Evidence that the binding species is receptor for induction of aryl hydrocarbon hydroxylase,” The journal of biological chemistry. Elsevier BV, 251(16), pp. 4936–4946.

• Poland, A. and Knutson, J. C. (1982) “2,3,7,8-tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons: examination of the mechanism of toxicity,” Annual review of pharmacology and toxicology. Annual Reviews, 22(1), pp. 517–554.

• Poland, A., Palen, D. and Glover, E. (1994) “Analysis of the four alleles of the murine aryl hydrocarbon receptor,” Molecular pharmacology, 46(5), pp. 915–921.

• Pravettoni, A. et al. (2005) “Ontogenetic development, sexual differentiation, and effects of Aroclor 1254 exposure on expression of the arylhydrocarbon receptor and of the arylhydrocarbon receptor nuclear translocator in the rat hypothalamus,” Reproductive toxicology (Elmsford, N.Y.). Elsevier BV, 20(4), pp. 521–530.

• Prestigiacomo, C. J. et al. (1999) “CD18-mediated neutrophil recruitment contributes to the pathogenesis of reperfused but not nonreperfused stroke,” Stroke; a journal of cerebral circulation, 30(5), pp. 1110–1117.

• Qureshi, A. I. et al. (2003) “Timing of neurologic deterioration in massive middle cerebral artery infarction: a multicenter review,” Critical care medicine, 31(1), pp. 272–277.

• Rasmussen, M. K., Mestre, H. and Nedergaard, M. (2018) “The glymphatic pathway in neurological disorders,” Lancet neurology, 17(11), pp. 1016–1024.

• Redin, G. S. (1966) “Antibacterial activity in mice of minocycline, a new tetracycline,” Antimicrobial agents and chemotherapy, 6, pp. 371–376.

• Rochfort, K. D. et al. (2014) “Downregulation of blood-brain barrier phenotype by proinflammatory cytokines involves NADPH oxidase-dependent ROS generation: consequences for interendothelial adherens and tight junctions,” PloS one. Public Library of Science (PLoS), 9(7), p. e101815.

• Rosenberg, G. A. and Yang, Y. (2007) “Vasogenic edema due to tight junction disruption by matrix metalloproteinases in cerebral ischemia,” Neurosurgical focus, 22(5), p. E4.

• Rothhammer, V. and Quintana, F. J. (2019) “The aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease,” Nature reviews. Immunology. nature.com, 19(3), pp. 184–197.

• Saito, K., Nowak, T. S., et al. (1993) “Kynurenine pathway enzymes in brain-responses to ischemic brain injury versus systemic immune activation,” J Neurochem, 61, pp. 2061–2070.

• Saito, K., Nowak, T. S., Jr, et al. (1993) “Mechanism of delayed increases in kynurenine pathway metabolism in damaged brain regions following transient cerebral ischemia,” Journal of neurochemistry. Wiley, 60(1), pp. 180–192.

• Schindelin, J. et al. (2012) “Fiji: an open-source platform for biological-image analysis,” Nature methods. Springer Science and Business Media LLC, 9(7), pp. 676–682.

• Schmidt, J. V. et al. (1996) “Characterization of a murine Ahr null allele: involvement of the Ah receptor in hepatic growth and development,” Proceedings of the National Academy of Sciences of the United States of America. Proceedings of the National Academy of Sciences, 93(13), pp. 6731–6736.

• Schneider, C. A., Rasband, W. S. and Eliceiri, K. W. (2012) “NIH Image to ImageJ: 25 years of image analysis,” Nature methods. Springer Science and Business Media LLC, 9(7), pp. 671–675.

• Sensenbrenner, M., Lucas, M. and Deloulme, J. C. (1997) “Expression of two neuronal markers, growth-associated protein 43 and neuron-specific enolase, in rat glial cells,” Journal of molecular medicine. Springer Science and Business Media LLC, 75(9), pp. 653–663.

• Sharma, R. et al. (2016) “Minocycline as a re-purposed anti-Wolbachia macrofilaricide: superiority compared with doxycycline regimens in a murine infection model of human lymphatic filariasis,” Scientific reports, 6, p. 23458.

• Shou, Y. et al. (2019) “A review of the possible associations between ambient PM2.5 exposures and the development of Alzheimer’s disease,” Ecotoxicology and environmental safety, 174, pp. 344–352.

• Simard, J. M. et al. (2007) “Brain oedema in focal ischaemia: molecular pathophysiology and theoretical implications,” Lancet neurology. Elsevier BV, 6(3), pp. 258–268.

• Simard, J. M. et al. (2009) “Protective effect of delayed treatment with low-dose glibenclamide in three models of ischemic stroke,” Stroke; a journal of cerebral circulation, 40(2), pp. 604–609.

• Smith, M. T., Thor, H. and Orrenius, S. (1984) “Detection and measurement of drug-induced oxygen radical formation,” Methods in enzymology, 105, pp. 505–510.

• Solenov, E. et al. (2004) “Sevenfold-reduced osmotic water permeability in primary astrocyte cultures from AQP-4-deficient mice, measured by a fluorescence quenching method,” American journal of physiology. Cell physiology, 286(2), pp. C426-32.

• Starling, E. H. (1896) “On the absorption of fluids from the connective tissue spaces,” The journal of physiology. Wiley, 19(4), pp. 312–326.

• Steiner, T., Ringleb, P. and Hacke, W. (2001) “Treatment options for large hemispheric stroke,” Neurology, 57(5 Suppl 2), pp. S61-8.

• Stiver, S. I. (2009) “Complications of decompressive craniectomy for traumatic brain injury,” Neurosurgical focus, 26(6), p. E7.

• Stokum, J. A., Mehta, R. I., et al. (2015) “Heterogeneity of aquaporin-4 localization and expression after focal cerebral ischemia underlies differences in white versus grey matter swelling,” Acta neuropathologica communications. Springer Science and Business Media LLC, 3(1), p. 61.

• Stokum, J. A., Kurland, D. B., et al. (2015) “Mechanisms of astrocyte-mediated cerebral edema,” Neurochemical research. Springer Science and Business Media LLC, 40(2), pp. 317–328.

• Stokum, J. A., Gerzanich, V. and Simard, J. M. (2016) “Molecular pathophysiology of cerebral edema,” Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism, 36(3), pp. 513–538.

• Stone, T. W. et al. (2012) “Involvement of kynurenines in Huntington’s disease and stroke- induced brain damage,” Journal of neural transmission , 119(2), pp. 261–274.

• Stroke Scale 委員会委員⻑ 後藤⽂男 (1997) “⽇本脳卒中学会・脳卒中重症度スケール(急性期) の発表にあたって,” Jpn. J. Stroke, 19(1), pp. 1‒5.

• Strong, A. J. et al. (1983) “The cortical ischaemic penumbra associated with occlusion of the middle cerebral artery in the cat: 2. Studies of histopathology, water content, and in vitro neurotransmitter uptake,” Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism, 3(1), pp. 97–108.

• van Swieten, J. C. et al. (1988) “Interobserver agreement for the assessment of handicap in stroke patients,” Stroke; a journal of cerebral circulation, 19(5), pp. 604–607.

• Symon, L., Branston, N. M. and Chikovani, O. (1979) “Ischemic brain edema following middle cerebral artery occlusion in baboons: relationship between regional cerebral water content and blood flow at 1 to 2 hours,” Stroke; a journal of cerebral circulation, 10(2), pp. 184–191.

• Tait, M. J. et al. (2008) “Water movements in the brain: role of aquaporins,” Trends in neurosciences. Elsevier BV, 31(1), pp. 37–43.

• Tarpey, M. M. and Fridovich, I. (2001) “Methods of detection of vascular reactive species: nitric oxide, superoxide, hydrogen peroxide, and peroxynitrite,” Circulation research. Ovid Technologies (Wolters Kluwer Health), 89(3), pp. 224–236.

• Thrane, A. S., Rangroo Thrane, V. and Nedergaard, M. (2014) “Drowning stars: reassessing the role of astrocytes in brain edema,” Trends in neurosciences, 37(11), pp. 620–628.

• Uno, I. et al. (2014) “Record heavy PM2.5 air pollution over China in January 2013: Vertical and horizontal dimensions,” SOLA. Meteorological Society of Japan, 10(0), pp. 136–140.

• Vakili, A., Kataoka, H. and Plesnila, N. (2005) “Role of arginine vasopressin V1 and V2 receptors for brain damage after transient focal cerebral ischemia,” Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism. SAGE Publications, 25(8), pp. 1012–1019.

• Venero, J. L. et al. (2001) “Aquaporins in the central nervous system,” Progress in neurobiology. Elsevier BV, 63(3), pp. 321–336.

• Vogel, C. F. et al. (2014) “Cross-talk between Aryl Hydrocarbon Receptor and the Inflammatory Response: A role for nuclear factor-kappaB,” J. Biol. Chem, 289, pp. 1866– 1875.

• Wartenberg, K. E. (2012) “Malignant middle cerebral artery infarction,” Current opinion in critical care, 18(2), pp. 152–163.

• Weed, L. H. and McKibben, P. S. (1919) “EXPERIMENTAL ALTERATION OF BRAIN BULK,” American Journal of Physiology-Legacy Content. American Physiological Society, 48(4), pp. 531–558.

• Wolf, S. A., Boddeke, H. W. G. M. and Kettenmann, H. (2017) “Microglia in Physiology and Disease,” Annual review of physiology, 79, pp. 619–643.

• Xiong, B. et al. (2017) “Precise cerebral vascular atlas in stereotaxic coordinates of whole mouse brain,” Frontiers in neuroanatomy, 11, p. 128.

• Yang, C. et al. (2019) “Neuroinflammatory mechanisms of blood-brain barrier damage in ischemic stroke,” American journal of physiology. Cell physiology, 316(2), pp. C135–C153.

• Yang, M. et al. (2009) “Temporal changes in expression of aquaporin-3, -4, -5 and -8 in rat brains after permanent focal cerebral ischemia,” Brain research, 1290, pp. 121–132.

• Yang, W.-S. et al. (2014) “An evidence-based appraisal of global association between air pollution and risk of stroke,” International journal of cardiology. Elsevier BV, 175(2), pp. 307–313.

• Yang, Y. et al. (2007) “Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor infocal ischemia in rat,” Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism, 27(4), pp. 697‒709.

• Young, W. et al. (1987) “Regional brain sodium, potassium, and water changes in the rat middle cerebral artery occlusion model of ischemia,” Stroke; a journal of cerebral circulation, 18(4), pp. 751–759.

• Zhang, N. (2011) “The role of endogenous aryl hydrocarbon receptor signaling in cardiovascular physiology,” Journal of cardiovascular disease research. SynthesisHub Advance Scientific Research, 2(2), pp. 91–95.

• Zhang, R. L. et al. (1995) “Anti-intercellular adhesion molecule-1 antibody reduces ischemic cell damage after transient but not permanent middle cerebral artery occlusion in the Wistar rat,” Stroke; a journal of cerebral circulation, 26(8), pp. 1438–42; discussion 1443.

• Zhang, W. et al. (2004) “A Cyp1a2-luciferase transgenic CD-1 mouse model: responses to aryl hydrocarbons similar to the humanized AhR mice,” Toxicological sciences: an official journal of the Society of Toxicology. Oxford University Press (OUP), 82(1), pp. 297–307.

• Zhao, H.-Y. et al. (2021) “Chebulic acid derivatives from Balakata baccata and their antineuroinflammatory and antioxidant activities,” Bioorganic chemistry, 116, p. 105332.

• Zhou, J. et al. (2017) “Pharmacokinetics and Pharmacodynamics of Minocycline against Acinetobacter baumannii in a Neutropenic Murine Pneumonia Model,” Antimicrobial agents and chemotherapy, 61(5). doi: 10.1128/AAC.02371-16.

• Zrzavy, T. et al. (2018) “Dominant role of microglial and macrophage innate immune responses in human ischemic infarcts,” Brain pathology (Zurich, Switzerland). Wiley, 28(6), pp. 791–805.

• Zwilling, D. et al. (2011) “Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration,” Cell. Elsevier BV, 145(6), pp. 863–874.

• 今井浩孝,⼩椋康光 (2020) 衛⽣薬学(改訂第 3 版):基礎・予防・臨床. 南江堂.

• 国循脳卒中データバンク 2021 編集委員会 (ed.) (2021) 脳卒中データバンク 2021. 中⼭書店.

• 政策統括官付参事官付世帯統計室 (2020) 2019 年 国⺠⽣活基礎調査の概況. 厚⽣労働省. Available at: https://www.mhlw.go.jp/toukei/saikin/hw/k-tyosa/k-tyosa19/dl/14.pdf.

• 政策統括官付参事官付⼈⼝動態・保健社会統計室 (2021) 2020 年 ⼈⼝動態統計の概況. 厚⽣労働省. Available at: https://www.mhlw.go.jp/toukei/saikin/hw/jinkou/kakutei20/dl/15_all.pdf.

• 政策統括官付参事官付保健統計室 (2019a) 平成 29 年 (2017) 患者調査の概況. 厚⽣労働省. Available at: https://www.mhlw.go.jp/toukei/saikin/hw/kanja/17/dl/kanja.pdf.

• 政策統括官付参事官付保健統計室 (2019b) 平成 29 年 国⺠医療費の概況. 厚⽣労働省. Available at: https://www.mhlw.go.jp/toukei/saikin/hw/k-iryohi/17/dl/data.pdf.

• 脳卒中ガイドライン委員会⽇本脳卒中学会 (ed.) (2021) 脳卒中治療ガイドライン2021. 協和企画.

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