Effects of fasudil on blood-brain barrier integrity

• Material Type: 博士論文
• Title: Effects of fasudil on blood-brain barrier integrity
• Author/Editor: 佐藤, 慧
• Author Heading: 佐藤, 慧
• Publication, Distribution, etc.: BioMed Central Ltd
• Publication Date: 2022-12-07
• Publication Date (W3CDTF): 2022-12-07
• Alternative Title: ファスジルの血液脳関門保護効果
• Periodical title: Fluids and Barriers of the CNS
• No. or year of volume/issue: 19
• Volume: 19
• Pages: 43-
• ISSN (Periodical Title): ISSN : 2045-8118
• Degree grantor/type: Nagasaki University (長崎大学)
• Date Granted: 2022-12-07
• Dissertation Number: 甲医歯薬第1473号
• Degree Type: 博士(医学)
• Text Language Code: eng
• Subject Heading: Acute ischemic stroke; Astrocytes; Blood–brain barrier; Fasudil; Oxygen–glucose deprivationreoxygenation; Pericytes; Rho-kinase inhibitor; Tight junction; Thromboxane A2
• Target Audience: 一般
• Note (General): 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)
• Source: https://nagasaki-u.repo.nii.ac.jp/?action=repository_action_common_download&item_id=27895&item_no=1&attribute_id=70&file_no=1 （fulltext）; https://nagasaki-u.repo.nii.ac.jp/?action=repository_action_common_download&item_id=27895&item_no=1&attribute_id=70&file_no=1
• Access Restrictions: インターネット公開
• Rights (production): © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
• Related Material: http://hdl.handle.net/10069/00041980
• Related Material (DOI): 10.1186/s12987-022-00336-w
• Data Provider (Database): 国立情報学研究所 : 学術機関リポジトリデータベース（IRDB）（機関リポジトリ）; https://irdb.nii.ac.jp
• Original Data Provider (Database): 長崎大学 : 長崎大学学術研究成果リポジトリ