Effects of fasudil on blood-brain barrier integrity

• 資料種別: 博士論文
• タイトル: Effects of fasudil on blood-brain barrier integrity
• 著者・編者: 佐藤, 慧
• 著者標目: 佐藤, 慧
• 出版事項: BioMed Central Ltd
• 出版年月日等: 2022-12-07
• 出版年（W3CDTF）: 2022-12-07
• 並列タイトル等: ファスジルの血液脳関門保護効果
• 授与機関名: Nagasaki University (長崎大学)
• 授与年月日: 2022-12-07
• 授与年月日（W3CDTF）: 2022-12-07
• 報告番号: 甲医歯薬第1473号
• 学位: 博士(医学)
• 本文の言語コード: eng
• 件名標目: Acute ischemic stroke; Astrocytes; Blood–brain barrier; Fasudil; Oxygen–glucose deprivationreoxygenation; Pericytes; Rho-kinase inhibitor; Tight junction; Thromboxane A2
• 対象利用者: 一般
• 一般注記: Background: Cerebral infarction accounts for 85% of all stroke cases. Even in an era of rapid and effective recanalization using an intravascular approach, the majority of patients have poor functional outcomes. Thus, there is an urgent need for the development of therapeutic agents to treat acute ischemic stroke. We evaluated the effect of fasudil, a Rho kinase inhibitor, on blood brain barrier (BBB) functions under normoxia or oxygen–glucose deprivation (OGD) conditions using a primary cell-based in vitro BBB model.Methods: BBB models from rat primary cultures (brain capillary endothelial cells, astrocytes, and pericytes) were subjected to either normoxia or 6 h OGD/24 h reoxygenation. To assess the effects of fasudil on BBB functions, we evaluated real time impedance, transendothelial electrical resistance (TEER), sodium fluorescein permeability, and tight junction protein expression using western blotting. Lastly, to understand the observed protective mechanism on BBB functions by fasudil we examined the role of cyclooxygenase-2 and thromboxane A2 receptor agonist U-46619 in BBB-forming cells.Results: We found that treatment with 0.3–30 µM of fasudil increased cellular impedance. Fasudil enhanced barrier properties in a concentration-dependent manner, as measured by an increased (TEER) and decreased permeability. Fasudil also increased the expression of tight junction protein claudin-5. Reductions in TEER and increased permeability were observed after OGD/reoxygenation exposure in mono- and co-culture models. The improvement in BBB integrity by fasudil was confirmed in both of the models, but was significantly higher in the co-culture than in the monoculture model. Treatment with U-46619 did not show significant changes in TEER in the monoculture model, whereas it showed a significant reduction in TEER in the co-culture model. Fasudil significantly improved the U-46619-induced TEER reduction in the co-culture models. Pericytes and astrocytes have opposite effects on endothelial cells and may contribute to endothelial injury in hyperacute ischemic stroke. Overall, fasudil protects the integrity of BBB both by a direct protective effect on endothelial cells and by a pathway mediated via pericytes and astrocytes.Conclusions: Our findings suggest that fasudil is a BBB-protective agent against acute ischemic stroke.; 長崎大学学位論文 学位記番号:博(医歯薬)甲第1473号 学位授与年月日:令和4年12月7日; Author: Kei Sato, Shinsuke Nakagawa, Yoichi Morofuji, Yuki Matsunaga, Takashi Fujimoto, Daisuke Watanabe, Tsuyoshi Izumo, Masami Niwa, Fruzsina R. Walter, Judit P. Vigh, Ana Raquel Santa-Maria, Maria A. Deli & Takayuki Matsuo; Citation: Fluids and Barriers of the CNS, 19, art.no. 43; 2022; identifier:Nagasaki University (長崎大学), 博士(医学) (2022-12-07); http://hdl.handle.net/10069/00041980
• 国立国会図書館永続的識別子: info:ndljp/pid/12693486; https://dl.ndl.go.jp/pid/12693486
• コレクション（共通）: 障害者向け資料
• コレクション（障害者向け資料：レベル1）: テキストデータ
• コレクション（個別）: 国立国会図書館デジタルコレクション > デジタル化資料 > 博士論文; https://dl.ndl.go.jp/collections/A00014
• 収集根拠: 博士論文（自動収集）
• 受理日（W3CDTF）: 2023-03-07T16:07:52+09:00
• 記録形式（IMT）: application/pdf
• オンライン閲覧公開範囲: 国立国会図書館内限定公開
• デジタル化資料送信: 図書館・個人送信対象外
• 遠隔複写可否（NDL）: 可
• 掲載誌（URI）: http://hdl.handle.net/10069/00042029
• 連携機関・データベース: 国立国会図書館 : 国立国会図書館デジタルコレクション; https://dl.ndl.go.jp