Neuroprotective effects of ADAMTS13 against delayed brain ischemia after subarachnoid hemorrhage

• Project/Area Number: 26462170
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurosurgery
• Research Institution: Nara Medical University
• Principal Investigator: Fujioka Masayuki 奈良県立医科大学, 医学部, 非常勤講師 (20254518)
• Co-Investigator(Kenkyū-buntansha): 三島 健一 福岡大学, 薬学部, 教授 (00320309)
• Co-Investigator(Renkei-kenkyūsha): TAOKA Toshiaki 名古屋大学, 医学部, 准教授 (30305734) ; ABE Kohji 大阪大学, 医学部, 特任准教授 (80571207) ; NAKASE Hiroyuki 奈良県立医科大学, 医学部, 教授 (10217739)
• Research Collaborator: MUROI Carl, Izumi ; FUJIMURA Yoshihiro ; TSUBOI Akio
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2014: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: ADAMTS13 / クモ膜下出血 / 脳虚血 / 脳動脈瘤 / 血栓 / 炎症 / VWF / MRI / 遅発性脳虚血 / 動物モデル

Outline of Final Research Achievements

ADAMTS13 cleaves VWF and reduces its prothrombotic and proinflammatory functions. Thus, ADAMTS13 protects the brain against acute ischemia by ameliorating post-ischemic brain hypoperfusion and inflammation. We studied the effect of ADAMTS13 on delayed cerebral ischemia after aneurysmal SAH. We evaluated the mice SAH model with 7.0 Tesla MRI and histology. The effects of ADAMTS13 on delayed cerebral microthrombi, cerebral vasospasm, neuronal inflammation, and neuronal death in the cerebral cortex and hippocampus were analyzed over time after SAH by comparing the groups with and without ADAMTS13 administration. ADAMTS13 significantly reduced microthrombosis, neuroinflammation and degenerative neurons, and improved neurological performance in SAH models. Our study with ADAMTS13 knockout mice signified neuroprotective effects of ADAMTS13 in SAH models. ADAMTS13 could provide a novel therapeutic approach for delayed cerebral ischemia after SAH as well as for acute ischemic stroke.

Research Products

• [Journal Article] Goreisan Prevents Brain Edema after Cerebral Ischemic Stroke by Inhibiting Aquaporin 4 Upregulation in Mice (2018)
  • Author(s): Takafumi Nakano, Chisa Nishigami, Keiichi Irie, Yutaka Shigemori, Kazunori Sano, Yuta Yamashita, Takayuki Myose, Koji Tominaga, Koichi Matsuo, Yoshihiko Nakamura, Hiroyasu Ishikura, Hidetoshi Kamimura, Takashi Egawa, Kenichi Mishima
  • Journal Title: J Stroke Cerebrovasc Dis Volume: 27 Issue: 3 Pages: 758-763
  • DOI: 10.1016/j.jstrokecerebrovasdis.2017.10.010
  • Peer Reviewed
• [Journal Article] 三島 健一、中野貴文、入江 圭一、藤岡政行 (2018)
  • Author(s): 脳梗塞モデルマウスを用いた漢方製剤五苓散のaquaporin 4阻害作用による脳浮腫改善効果
  • Journal Title: 福岡大学産学官連携研究機関 加齢脳科学研究所 2017年度研究成果報告書 Volume: -
• [Journal Article] 脳梗塞モデルマウスに対する播種性血管内凝固症候群治療薬 トロンボモデュリン アルファの効果 (2017)
  • Author(s): 三島 健一、藤岡政行、仲村佳彦、中野貴文、入江 圭一
  • Journal Title: 福岡大学産学官連携研究機関 加齢脳科学研究所 2016年度研究成果報告書 Volume: - Pages: 53-61
• [Journal Article] Evaluation of a filament perforation model for mouse subarachnoid hemorrhage using 7.0 Tesla MRI (2016)
  • Author(s): Muroi C, Kashiwagi Y, Rokugawa T, Tonomura M, Obata A, Nevzati E, Tsuboi A, Okuchi K, Mishima K, Abe K, Fujioka M
  • Journal Title: J Clin Neurosci. Volume: 28 Pages: 141-147
  • DOI: 10.1016/j.jocn.2015.10.045
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Recombinant human soluble thrombomodulin ameliorates cerebral ischemic injury through a high-mobility group box 1 inhibitory mechanism without hemorrhagic complications in mice. (2016)
  • Author(s): Nakamura Y, Nakano T, Irie K, Sano K, Tanaka J, Yamashita Y, Satho T, Matsuo K, Fujioka M, Ishikura H, Mishima K.
  • Journal Title: J Neurol Sci. Volume: 362 Pages: 278-282
  • DOI: 10.1016/j.jns.2016.01.047
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Time Course of Diffusion Kurtosis in Cerebral Infarctions of Transient Middle Cerebral Artery Occlusion Rat Model. (2016)
  • Author(s): Taoka T, Fujioka M, Kashiwagi Y, Obata A, Rokugawa T, Hori M, Masutani Y, Aoki S, Naganawa S, Abe K.
  • Journal Title: J Stroke Cerebrovasc Dis. Volume: 25 Issue: 3 Pages: 610-617
  • DOI: 10.1016/j.jstrokecerebrovasdis.2015.11.028
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mouse model of subarachnoid hemorrhage: technical note on the filament perforation model. (2015)
  • Author(s): Muroi C, Fujioka M, Marbacher S, Fandino J, Keller E, Iwasaki K, Mishima K.
  • Journal Title: Acta Neurochir Suppl. 2015;120:315-20. Volume: 120 Pages: 315-320
  • DOI: 10.1007/978-3-319-04981-6_54
  • ISBN: 9783319049809, 9783319049816
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Utility of High-b-Value Diffusion-Weighted Magnetic Resonance Imaging in Evaluating Reversible Medial Longitudinal Fasciculus Syndrome Caused by Acute Brainstem Ischemia. (2015)
  • Author(s): Miki Y, Fujioka M, Taoka T, Tanaka H, Chitoku S, Matsuyama T, Tanaka S.
  • Journal Title: J Stroke Cerebrovasc Dis. Volume: 24 Issue: 6 Pages: 157-159
  • DOI: 10.1016/j.jstrokecerebrovasdis.2015.03.002
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Delayed treatment with ADAMTS13 ameliorates cerebral ischemic injury without hemorrhagic complication (2015)
  • Author(s): Nakano T, Irie K, Hayakawa K, Sano K, Nakamura Y, Tanaka M, Yamashita Y, Satho T, Fujioka M, Muroi C, Matsuo K, Ishikura H, Futagami K, Mishima K.
  • Journal Title: Brain Res. Volume: 1624 Pages: 330-335
  • DOI: 10.1016/j.brainres.2015.07.027
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Filament perforation model for mouse subarachnoid hemorrhage: Surgical-technical considerations (2014)
  • Author(s): Muroi C, Fujioka M, Okuchi K, Fandino J, Keller E, Sakamoto Y, Mishima K, Iwasaki K, Fujiwara M
  • Journal Title: Br J Neurosurg Volume: 28 Issue: 6 Pages: 722-732
  • DOI: 10.3109/02688697.2014.918579
  • Peer Reviewed
• [Journal Article] Effect of ADAMTS-13 on cerebrovascular microthrombosis and neuronal injury after experimental subarachnoid hemorrhage. (2014)
  • Author(s): Muroi C, Fujioka M, Mishima K, Irie K, Fujimura Y, Nakano T, Fandino J, Keller E, Iwasaki K, Fujiwara M.
  • Journal Title: J Thromb Haemost. Volume: 12(4) Issue: 4 Pages: 505-514
  • DOI: 10.1111/jth.12511
  • Peer Reviewed
• [Journal Article] Selective neuronal loss in ischemic stroke and cerebrovascular disease (2014)
  • Author(s): Baron JC, Yamauchi H, Fujioka M, Endres M
  • Journal Title: J Cereb Blood Flow Metab Volume: 34 Issue: 1 Pages: 2-18
  • DOI: 10.1038/jcbfm.2013.188
  • Peer Reviewed
• [Journal Article] Magnet Resonance Imaging in Experimental Mouse Subarachnoid Hemorrhage (2014)
  • Author(s): Muroi C, Kashiwakgi Y, Rokugawa T, Yamada T, Obata A, Fujioka M, Abe K
  • Journal Title: J Neurol Surg A Cent Eur Neurosurg Volume: 75 (S 02) Pages: 64-64
  • Peer Reviewed
• [Journal Article] クモ膜下出血後の遅発性脳虚血におけるADAMTS13の病態生理学的意義とその治療応用についての検討 (2014)
  • Author(s): 藤岡政行
  • Journal Title: 冲中記念成人病研究所年報 Volume: 40 Pages: 59-62
• [Journal Article] 私の研究 －My Research－ 第5回 ADAMTS13 (2014)
  • Author(s): 藤岡政行、藤村吉博
  • Journal Title: Angiology Frontier Volume: 13 Pages: 58-63
• [Presentation] Neuroprotective Effects of ADAMTS13 against Delayed Brain Ischemia after Aneurysmal Subarachnoid Hemorrhage (2017)
  • Author(s): Fujioka M, Muroi C, Tsuboi A, Okuchi K, Nakase H, Abe K, Mishima K
  • Organizer: XXIII World Congress of Neurology
  • Int'l Joint Research
• [Presentation] ADAMTS 13 - Microthrombosis in Subarachnoid Hemorrhage - an Update - (2017)
  • Author(s): Muroi C, Fujioka M, Abe K, Keller E, Fujimura Y, Mishima K
  • Organizer: Vasospasm 2017. The 14th International Conference on Neurovascular Events after Subarachnoid Hemorrhage
  • Int'l Joint Research / Invited
• [Presentation] Recombinant human soluble thrombomodulin ameliorates cerebral ischemic injury through a high-mobility group box 1 inhibitory mechanism without hemorrhagic complications in mice (2017)
  • Author(s): Yoshihiko Nakamura, Takafumi Nakano, Keiichi Irie, Kazunori Sano, Junichi Tanaka, Yuta Yamashita, Tomomitsu Satho, Koichi Matsuo, Masayuki Fujioka, Hiroyasu Ishikura, Kenichi Mishima
  • Organizer: Neuroscience 2017
  • Int'l Joint Research
• [Presentation] Effect of delayed treatment with ADAMTS13 on cerebral ischemic injury compared with tPAs (2017)
  • Author(s): Takafumi Nakano, Keiichi Irie, Yuta Yamashita, Takayuki Myose, Kazunori Sano, Yoshihiko Nakamura, Tomomitsu Satho, Mamiko Kai, Koji Tominaga, Hidetoshi Kamimura, Kenichi Mishima, Takashi Egawa
  • Organizer: Neuroscience 2017
  • Int'l Joint Research
• [Presentation] 脳梗塞時における酸化 LDL 誘発性炎症反応に対する thrombospondin-1 の役割 (2017)
  • Author(s): 中野貴文、入江圭一、山下郁太、明瀬孝之、高瀬友美、佐藤朝光、松尾宏一、佐野和憲、本多健治、神村英利、三島健一
  • Organizer: 日本薬学会第137年会
• [Presentation] 長時間脳虚血マウスに対する血栓溶解薬 t-PA と DIC 治療薬 thrombomodulin の有用性 (2017)
  • Author(s): 安村真子、中野貴文、仲村佳彦、入江圭一、山下郁太、明瀬孝之、佐藤朝光、三島健司、松尾宏一、佐野和憲、本多健治、石倉宏恭、三島健一
  • Organizer: 日本薬学会第137年会
• [Presentation] クモ膜下出血後の脳虚血に対するADAMTS13の神経保護効果 (2016)
  • Author(s): 藤岡 政行, 室井 カール, 坪井 昭夫, 奥地 一夫, 中瀬 裕之, 阿部 浩司, 三島 健一
  • Organizer: 第7５回日本脳神経外科学会学術総会
  • Place of Presentation: 福岡国際会議場、 福岡
  • Year and Date: 2016-09-29
• [Presentation] 脳動脈瘤破裂クモ膜下出血後の脳虚血病態に対するADAMTS13の 脳保護機能. (2015)
  • Author(s): 藤岡 政行, 室井 カール, 奥地 一夫, 中瀬 裕之, 阿部 浩司, 三島 健一.
  • Organizer: 第74回日本脳神経外科学会学術総会
  • Place of Presentation: ロイトン札幌, 札幌
  • Year and Date: 2015-10-14
• [Presentation] Filament Perforation Model for Mouse Subarachnoid Hemorrhage: Evaluation by 7.0T MRI (2015)
  • Author(s): Carl Muroi, Yuto Kashiwagi, Takemi Rokugawa, Misato Tonomura, Atsushi Obata, Edin Nevzati, Akio Tsuboi, Kenichi Mishima, Kohji Abe, Masayuki Fujioka.
  • Organizer: Vasospasm 2015. 13th International Conference on Neuromuscular Events after Subarachnoid Hemorrhage
  • Place of Presentation: Karuizawa Prince Hotel West, Karuizawa
  • Year and Date: 2015-09-17
  • Int'l Joint Research / Invited
• [Presentation] 脳虚血およびクモ膜下出血後の遅発性脳虚血病態に対するADAMTS13の脳保護機能 (2015)
  • Author(s): 藤岡 政行, 室井 カール, 松山 武, 阿部浩司、三島 健一
  • Organizer: 第40回日本脳卒中学会総会
  • Place of Presentation: リーガロイヤルホテル広島 広島
  • Year and Date: 2015-03-27
• [Presentation] 虚血‐再潅流およびクモ膜下出血後の脳虚血病態に対するADAMTS13の脳保護機能 (2014)
  • Author(s): 藤岡 政行, 室井 カール, 松山 武, 三島 健一
  • Organizer: 第７３回日本脳神経外科学会総会
  • Place of Presentation: グランドプリンスホテル新高輪 東京
  • Year and Date: 2014-10-09
• [Presentation] Magnet Resonance Imaging in Experimental Mouse Subarachnoid Hemorrhage (2014)
  • Author(s): Muroi C, Kashiwakgi Y, Rokugawa T, Yamada T, Obata A, Fujioka M, Abe K
  • Organizer: Joint Annual Meeting 2014: Swiss Society of Neurosurgery, Swiss Society of Clinical Neurophysiology, Swiss Society of Neuropediatrics
  • Place of Presentation: Zurich, Switzerland
  • Year and Date: 2014-06-12 – 2014-06-13
  • Invited