A possible neuroprotective role of ADAMTS13 by ameliorating post-ischemic hypoperfusion

2013 Fiscal Year Final Research Report

• Project/Area Number: 23590654
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Applied pharmacology
• Research Institution: Fukuoka University
• Principal Investigator: MISHIMA Kenichi 福岡大学, 薬学部, 准教授 (00320309)
• Co-Investigator(Kenkyū-buntansha): FUJIWARA Michihiro 福岡大学, 薬学部, 教授 (10091331) ; IRIE Keiichi 福岡大学, 加齢脳科学研究所, 研究員 (50509669)
• Project Period (FY): 2011 – 2013
• Keywords: ADAMTS13 / 脳虚血 / VWF / t-PA / Tsp-1

Research Abstract

Tissue plasminogen activator (t-PA) sometimes causes hemorrhagic complications in ischemic stroke. ADAMTS13, vWF-cleaving protease, maintains a physiologic balance between hemostasis and thrombolysis via regulation of vWF function. However, the pathophysiological role of ADAMTS13 in cerebral ischemia has not been investigated. In this study, we used ADAMTS13 knockout (KO) and Wild type (WT) mice subjected to 30 min of middle cerebral artery occlusion (MCAO). Infarct volume and plasma HMGB1 , inflammatory cytokine, was significantly increased at 24 hours after the reperfusion in KO mice. Further, ADAMTS13 protein significantly reduced the infarct volume without hemorrhagic complications using a 4hr-MCAO in WT mice. But, t-PA caused massive bleeding. These results indicate that ADAMTS13 would become a new therapeutic approach for ischemic stroke by regulating blood flow and inflammation without hemorrhagic complications.

Research Products

• [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) Pages: 505-14
  • Peer Reviewed
• [Journal Article] Allogeneic Transplantation of Fetal Membrane-Derived Mesenchymal Stem Cell Sheets Increases Neovascularization and Improves Cardiac Function after Myocardial Infarction in Rats (2013)
  • Author(s): Ishikane S, Hosoda H, Yamahara K, Akitake Y, Kyoungsook J, Mishima K, Iwasaki K, Fujiwara M, Miyazato M, Kangawa K, Ikeda T
  • Journal Title: Transplantation Volume: 96(8) Pages: 697-706
  • Peer Reviewed
• [Journal Article] Correlation among systemic inflammatory parameter, occurrence of delayed neurological deficits, and outcome after aneurysmal subarachnoid hemorrhage (2013)
  • Author(s): Muroi C, Hugelshofer M, Seule M, Tastan I, Fujioka M, Mishima K, Keller E
  • Journal Title: Neurosurgery Volume: 72(3) Pages: 367-375
  • Peer Reviewed
• [Journal Article] Bioimaging application of highly luminescent silica-coated ZnO-nanoparticle quantum dots with biotin (2013)
  • Author(s): Matsuyama K, Ihsan N, Irie K, Mishima K, Okuyama T, Muto H
  • Journal Title: J Colloid Interface Sci Volume: 399 Pages: 19-25
  • Peer Reviewed
• [Journal Article] Novel treatments for vasospasm after subarachnoid hemorrhage (2012)
  • Author(s): Muroi C, Seule M, Mishima K, Keller E
  • Journal Title: Curr Opin Crit Care Volume: 18(2) Pages: 119-126
  • Peer Reviewed
• [Journal Article] Preferential involvement of Na(+)/Ca(2+) exchanger type-1 in the brain damage caused by transient focal cerebral ischemia in mice (2012)
  • Author(s): Morimoto N, Kita S, Shimazawa M, Namimatsu H, Tsuruma K, Hayakawa K, Mishima K, Egashira N, Iyoda T, Horie I, Gotoh Y, Iwasaki K, Fujiwara M, Matsuda T, Baba A, Komuro I, Horie K, Takeda J, Iwamoto T, Hara H
  • Journal Title: Biochem Biophys Res Commun Volume: 429(3-4) Pages: 186-190
  • Peer Reviewed
• [Journal Article] Ameliorative effects of telmisartan on the inflammatory response and impaired spatial memory in a rat model of Alzheimer's disease incorporating additional cerebrovascular disease factors (2012)
  • Author(s): Shindo T, Takasaki K, Uchida K, Onimura R, Kubota K, Uchida N, Irie K, Katsurabayashi S, Mishima K, Nishimura R, Fujiwara M, Iwasaki K
  • Journal Title: Biol Pharm Bull Volume: 35(12) Pages: 2141-7
  • Peer Reviewed
• [Journal Article] Magnesium and the inflammatory response : potential pathophysiological implications in the management of patients with aneurysmal subarachnoid hemorrhage? (2012)
  • Author(s): Muroi C, Burkhardt JK, Hugelshofer M, Seule M, Mishima K, Keller E
  • Journal Title: Magnes Res Volume: 25(2) Pages: 64-71
  • Peer Reviewed
• [Journal Article] Correlation between Systemic Inflammatory Parameter, Occurrence of Delayed Neurological Deficits and Outcome after Aneurysmal Subarachnoid Hemorrhage (2012)
  • Author(s): Muroi C, Hugelshofer M, Seule M, Tastan I, Fujioka M, Mishima K, Keller E
  • Journal Title: Neurosurgery Volume: 72(3) Pages: 367-375
  • Peer Reviewed
• [Journal Article] Transparent polymeric hybrid film of ZnO nanoparticle quantum dots and PMMA with high luminescence and tunable emission color (2012)
  • Author(s): Matsuyama K, Mishima K, Kato T, Irie K, Mishima K
  • Journal Title: J Colloid Interface Sci Volume: 367(1) Pages: 171-177
  • Peer Reviewed
• [Journal Article] ADAMTS13 gene deletion enhances plasma high-mobility group box1 elevation and neuroinflammation in brain ischemia-reperfusion injury (2012)
  • Author(s): Fujioka M, Nakano T, Hayakawa K, Irie K, Akitake Y, Sakamoto Y, Mishima K, Muroi C, Yonekawa Y, Banno F, Kokame K, Miyata T, Nishio K, Okuchi K, Iwasaki K, Fujiwara M, Siesjö BK
  • Journal Title: Neurol Sci Volume: 33(5) Pages: 1107-1115
  • Peer Reviewed
• [Journal Article] Neuroprotective effects of citidine-5-diphosphocholine on impaired spatial memory in a rat model of cerebrovascular dementia (2011)
  • Author(s): Takasaki K, Uchida K, Fujikawa R, Nogami A, Nakamura K, Kawasaki C, Yamaguchi K, Morita M, Morishita K, Kubota K, Katsurabayashi S, Mishima K, Fujiwara M, Iwasaki K
  • Journal Title: J Pharmacol Sci Volume: 116(2) Pages: 232-7
  • Peer Reviewed
• [Journal Article] Effects of yokukansan on anxiety- like behavior in a rat model of cerebrovascular dementia (2011)
  • Author(s): Nogami A, Sakata Y, Uchida N, Yamaguchi K, Kawasaki C, Shindo T, Kubota K, Katsurabayashi S, Takasaki K, Mishima K, Nishimura R, Fujiwara M, Iwasaki K
  • Journal Title: J Nat Med Volume: 65(2) Pages: 275-281
• [Presentation] 脳梗塞における多機能サイトカインであるOncostatin M受容体の発現変化 (2014)
  • Author(s): 大石悠加, 入江圭一, 中野貴文, 楢崎友里, 田中雅彬, 佐藤朝光, 二神幸次郎, 三島健一, 岩崎克典
  • Organizer: 第134回年会日本薬学会年会
  • Place of Presentation: 熊本
  • Year and Date: 20140327-30
• [Presentation] 新生児低酸素性虚血性脳症モデルラットの脳損傷に対する内因性カンナビノイドを介したデキサメタゾンの脳保護作用 (2013)
  • Author(s): 宮澤秋子, 坂元佑哉, 入江圭一, 三島健一, 宮崎蓉子, 栫千恵, 中村裕司, 窪田香織, 桂林秀太郎, 高崎浩太郎, 岩崎克典, 藤原道弘
  • Organizer: 第133回年会日本薬学会年会
  • Place of Presentation: 横浜
  • Year and Date: 20130327-30
• [Presentation] 脳虚血障害に対する血液凝固制御因子ADAMTS13の脳保護作用におけるtrombospondin 1の関与 (2013)
  • Author(s): 田中雅彬, 入江圭一, 中野貴文, 窪田香織, 桂林秀太郎, 高崎浩太郎, 二神幸次郎, 三島健一, 岩崎克典
  • Organizer: 第87回日本薬理学会年会
  • Place of Presentation: 仙台
  • Year and Date: 20130319-21
• [Presentation] 長時間脳虚血モデルマウスに対する血液凝固制御因子ADAMTS13の脳保護効果-新規血栓溶解薬への応用- (2013)
  • Author(s): 中野貴文, 田中雅彬, 入江圭一, 仲村佳彦, 石倉宏恭, 二神幸次郎, 三島健一, 岩崎克典
  • Organizer: 第66回日本薬理学会西南部会
  • Place of Presentation: 福岡
  • Year and Date: 2013-11-16
• [Presentation] ADAMTS13: A Novel Therapeutic Drug Candidate for Acute and for Delayed Brain Ischemia (2013)
  • Author(s): Fujioka M., Muroi C., Mishima K., Fujiwara M., Okuchi K., Siesjo B.K
  • Organizer: 57th Annual Meeting of Thrombosis and Haemostasis Research
  • Place of Presentation: Munich, Germany
  • Year and Date: 2013-02-23
• [Presentation] 新生児低酸素性虚血性脳症モデルラットにおけるドーパミン神経障害誘発性回転行動に対する脳血管新生病変形成の関与 (2012)
  • Author(s): 坂元佑哉, 入江圭一, 三島健一, 秋武義治, 宮澤秋子, 栫千恵, 中村裕司, 窪田香織, 桂林秀太郎, 高崎浩太郎, 岩崎克典, 藤原道弘
  • Organizer: 第65回日本薬理学会西南部会
  • Place of Presentation: 熊本
  • Year and Date: 2012-11-23
• [Presentation] ADAMTS13:急性脳虚血に対する治療応用の可能性 (2012)
  • Author(s): 藤岡政行, Muroi Carl, 三島健一, 藤村吉博, 奥地一夫, 藤原道弘, Siesjo Bo
  • Organizer: 第71回日本脳神経外科学会学術総会
  • Place of Presentation: 大阪
  • Year and Date: 2012-10-17
• [Presentation] ADAMTS13: A Novel Therapeutic Drug Candidate for Acute Ischemic Stroke (2012)
  • Author(s): Masayuki Fujioka, Kazuhide Hayakawa, Carl Muroi, Keiichi Irie, Kenichi Mishima, Yoshihiro Fujimura, Michihiro Fujiwara, Kazuo Okuchi, Bo K. Siesjo
  • Organizer: Asia Pacific Stroke Conference 2012
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 2012-09-10
• [Presentation] 脳梗塞モデルマウスを用いたプログラニュリンの発現変化とミクログリアの活性化に関する研究 (2012)
  • Author(s): 古川歩, 入江圭一, 三島健一, 高崎浩太郎, 桂林秀太郎, 窪田香織, 岩崎克典, 藤原道弘
  • Organizer: 第89回日本生理学会大会
  • Place of Presentation: 松本
  • Year and Date: 2012-03-30
• [Presentation] 新生児低酸素性虚血性脳症モデルラットにおける脳損傷に対するドパミン神経系の関与 (2011)
  • Author(s): 坂元佑哉, 秋武義治, 入江圭一, 宮﨑蓉子, 栫千恵, 中村裕司, 窪田香織, 桂林秀太郎, 高崎浩太郎, 三島健一, 岩崎克典, 藤原道弘
  • Organizer: 第39回薬物活性シンポジウム
  • Place of Presentation: 福岡
  • Year and Date: 2011-11-21
• [Patent(Industrial Property Rights)] 血栓形成予防薬として利用されるADAMTS13誘導剤 (2011)
  • Inventor(s): 入江圭一, 藤原道弘, 岩橋克典, 三島健一, 中野貴文, 片岡泰文, 山内淳史, 佐藤朝光, 坂元佑哉, 平松征洋, 川崎圭祐
  • Industrial Property Rights Holder: 福岡大学
  • Industrial Property Rights Type: 特許特開2013-056861
  • Patent Publication Number: 特開2013-056861
  • Filing Date: 2011-09-09
  • Overseas