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Development of neurovascular unit protection therapy for cerebral ischemia-reperfusion injury by redox nanopartices

Research Project

Project/Area Number 17K10819
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Neurosurgery
Research InstitutionUniversity of Tsukuba

Principal Investigator

Marushima Aiki  筑波大学, 医学医療系, 講師 (40722525)

Co-Investigator(Kenkyū-buntansha) プエンテス サンドラ  筑波大学, システム情報系, 助教 (00725765)
平山 暁  筑波技術大学, 保健科学部, 教授 (20323298)
鈴木 謙介  獨協医科大学, 医学部, 教授 (20400674)
鶴嶋 英夫  筑波大学, 医学医療系, 准教授 (50315470)
滝川 知司  獨協医科大学, 医学部, 准教授 (60450227)
Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywords脳梗塞 / 脳虚血再灌流障害 / 脳保護療法 / 活性酸素 / ナノ粒子 / フリーラジカル / 脳保護 / RNP / 血栓回収療法 / 神経血管ユニット保護 / 血液脳関門 / ナノ粒子化活性酸素消去剤 / 脳神経外科学 / 脳血管障害学
Outline of Final Research Achievements

In order to suppress intracranial hemorrhage and enlargement of infarct lesion due to cerebral ischemia-reperfusion injury in cerebral infarction, we conducted research and development of a novel cerebral protective therapy using nanoparticulate active oxygen scavenger (RNP). When the optimal dose of RNP was evaluated, 9 mg / kg (7 μM) had the highest survival rate, reduced cerebral infarction volume, and improved neurological symptoms. In the evaluation of the distribution of RNP in the brain, RNP was distributed in cerebral vascular endothelium and neuronal cells in the penumbra region. In a trial comparing with Edaravone, RNP significantly improved the survival rate and neurological symptoms in mice. RNP is considered as a novel neuroprotective drug that can control cerebral ischemia-reperfusion injury, and its mechanism of action is considered to be a drug with a unique mechanism.

Academic Significance and Societal Importance of the Research Achievements

脳主幹動脈閉塞による重症脳梗塞は、t-PAや血栓回収療法を行っても、依然として転帰不良は50%以上認めている。その一因は再開通後の脳虚血再灌流障害による脳梗塞拡大、脳浮腫、頭蓋内出血である。RNPを血栓回収療法時にマイクロカテーテルから脳虚血部位に直接投与する脳保護療法は、脳虚血再灌流障害を抑制できる、新たな脳保護領として期待できる。本研究課題では、マウス脳虚血再灌流障害モデルによる、RNPによる脳保護療法の有効性とその機序を秋からにすることができた。当脳保護療法を実用化が期待される成果であり、今後、RNPの有効性をヒトへ外挿するために大型動物モデルを用いたさらなる研究が期待される。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (29 results)

All 2020 2019 2018 2017

All Journal Article (16 results) (of which Peer Reviewed: 16 results,  Open Access: 3 results) Presentation (13 results) (of which Int'l Joint Research: 1 results,  Invited: 1 results)

  • [Journal Article] Novel neuroprotection using antioxidant nanoparticles in a mouse model of head trauma2020

    • Author(s)
      Takahashi Toshihide、Marushima Aiki、Nagasaki Yukio、Hirayama Aki、Muroi Ai、Puentes Sandra、Mujagic Arnela、Ishikawa Eiichi、Matsumura Akira
    • Journal Title

      Journal of Trauma and Acute Care Surgery

      Volume: - Issue: 5 Pages: 1-1

    • DOI

      10.1097/ta.0000000000002617

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Effects of Gait Treatment With a Single-Leg Hybrid Assistive Limb System After Acute Stroke: A Non-randomized Clinical Trial2020

    • Author(s)
      Watanabe H, Marushima A, Kadone H, Ueno T, Shimizu Y, Kubota S, Hino T, Sato M, Ito Y, Hayakawa M, Tsurushima H, Takada T, Tsukada A, Fujimori H, Sato N, Maruo K, Kawamoto H, Hada Y, Yamazaki M, Sankai Y, Ishikawa E, Matsumaru Y, Matsumura A
    • Journal Title

      Frontiers in Neuroscience

      Volume: 13

    • DOI

      10.3389/fnins.2019.01389

    • NAID

      120007132794

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Clinical Characteristics and Endovascular Treatment for Spinal Dural Arteriovenous Fistula in Japan: Japanese Registry of Neuroendovascular Therapy 2 and 32019

    • Author(s)
      TSURUTA Wataro、MATSUMARU Yuji、IIHARA Koji、SATOW Tetsu、SAKAI Nobuyuki、KATSUMATA Masahiro、HOSOO Hisayuki、SATO Masayuki、ITO Yoshiro、MARUSHIMA Aiki、HAYAKAWA Mikito、ISHIKAWA Eiichi、MATSUMURA Akira
    • Journal Title

      Neurologia medico-chirurgica

      Volume: 59 Issue: 12 Pages: 492-497

    • DOI

      10.2176/nmc.st.2018-0218

    • NAID

      130007761491

    • ISSN
      0470-8105, 1349-8029
    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Effectiveness of Near-Infrared Spectroscopy (NIRO-200NX, Pulse Mode) for Risk Management in Carotid Artery Stenting2019

    • Author(s)
      Terakado Toshitsugu、Marushima Aiki、Koyama Yasuaki、Tsuruta Wataro、Takigawa Tomoji、Ito Yoshiro、Hino Tenyu、Sato Masayuki、Hayakawa Mikito、Ishikawa Eiichi、Inoue Yoshiaki、Matsumaru Yuji、Matsumura Akira
    • Journal Title

      World Neurosurgery

      Volume: 131 Pages: e425-e432

    • DOI

      10.1016/j.wneu.2019.07.184

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Encapsulation of tissue plasminogen activator in pH-sensitive self-assembled antioxidant nanoparticles for ischemic stroke treatment ? Synergistic effect of thrombolysis and antioxidant ?2019

    • Author(s)
      Mei Ting、Kim Ahram、Vong Long Binh、Marushima Aiki、Puentes Sandra、Matsumaru Yuji、Matsumura Akira、Nagasaki Yukio
    • Journal Title

      Biomaterials

      Volume: 215 Pages: 119209-119209

    • DOI

      10.1016/j.biomaterials.2019.05.020

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Balanced single-vector co-delivery of VEGF/PDGF-BB improves functional collateralization in chronic cerebral ischemia2019

    • Author(s)
      Marushima Aiki、Nieminen Melina、Kremenetskaia Irina、Gianni-Barrera Roberto、Woitzik Johannes、Degenfeld Georges von、Banfi Andrea、Vajkoczy Peter、Hecht Nils
    • Journal Title

      Journal of Cerebral Blood Flow & Metabolism

      Volume: 印刷中 Issue: 2 Pages: 404-419

    • DOI

      10.1177/0271678x18818298

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] The visualization methods of occluded dural sinus for safe transvenous embolization of dural AVFs2019

    • Author(s)
      Hosoo H, Tsuruta W, Nakai Y, Shiigai M, Sato M, Ito Y, Takigawa T, Marushima A, Ishikawa E, Yamamoto T, Matsumaru Y, Matsumura A.
    • Journal Title

      World Neurosurgery

      Volume: 印刷中 Pages: e337-e345

    • DOI

      10.1016/j.wneu.2019.02.250

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] 症例 鼻出血で発症した海綿静脈洞部内頚動脈解離性動脈瘤の1例2018

    • Author(s)
      Kino H, Tsuruta W, Ito Y, Takigawa T, Shiigai M, Marushima A, Nakai Y, Yamamoto T, Matsumura A
    • Journal Title

      Neurological Surgery 脳神経外科

      Volume: 46 Issue: 9 Pages: 789-795

    • DOI

      10.11477/mf.1436203815

    • ISSN
      0301-2603, 1882-1251
    • Year and Date
      2018-09-10
    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Preliminary in vivo magnetofection data using magnetic calcium phosphate nanoparticles immobilizing DNA and iron oxide nanocrystals2018

    • Author(s)
      Shubhra Quazi T.H.、Oyane Ayako、Nakamura Maki、Puentes Sandra、Marushima Aiki、Tsurushima Hideo
    • Journal Title

      Data in Brief

      Volume: 18 Pages: 1696-1701

    • DOI

      10.1016/j.dib.2018.04.058

    • NAID

      120007128503

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Treatment Strategy Based on Plaque Vulnerability and the Treatment Risk Evaluation for Internal Carotid Artery Stenosis2018

    • Author(s)
      ITO Yoshiro、TSURUTA Wataro、NAKAI Yasunobu、TAKIGAWA Tomoji、MARUSHIMA Aiki、MASUMOTO Tomohiko、MATSUMARU Yuji、ISHIKAWA Eiichi、MATSUMURA Akira
    • Journal Title

      Neurologia medico-chirurgica

      Volume: 58 Issue: 5 Pages: 191-198

    • DOI

      10.2176/nmc.oa.2017-0228

    • NAID

      130006734354

    • ISSN
      0470-8105, 1349-8029
    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Spinal Cord Infarction in the Region of the Posterior Spinal Artery After Embolization for Vertebral Artery Dissection2018

    • Author(s)
      Tsuruta Wataro、Yamamoto Tetsuya、Ikeda Go、Sato Masayuki、Ito Yoshiro、Takigawa Tomoji、Marushima Aiki、Nakai Yasunobu、Matsumaru Yuji、Matsumura Akira
    • Journal Title

      Operative Neurosurgery

      Volume: 15 Issue: 6 Pages: 701-710

    • DOI

      10.1093/ons/opy026

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Neurovascular Unit Protection From Cerebral Ischemia-Reperfusion Injury by Radical-Containing Nanoparticles in Mice2017

    • Author(s)
      Hosoo H, Marushima A, Nagasaki Y, Hirayama A, Ito H, Puentes S, Mujagic A, Tsurushima H, Tsuruta W, Suzuki K, Matsui H, Matsumaru Y, Yamamoto T, Matsumura
    • Journal Title

      Stroke

      Volume: 48 Issue: 8 Pages: 2238-2247

    • DOI

      10.1161/strokeaha.116.016356

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Medial medullary infarction caused by antineutrophil cytoplasmic antibody-related vasculitis: Case report and review of the literature2017

    • Author(s)
      Yanagiha K, Ishii K, Ueno T, Marushima A, Tamaoka A
    • Journal Title

      Medicine (Baltimore)

      Volume: 96 Issue: 33 Pages: e7722-e7722

    • DOI

      10.1097/md.0000000000007722

    • NAID

      120007134546

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Cerebral Tissue Oxygenation Index Using Near-infrared Spectroscopy during Extracorporeal Cardio-pulmonary Resuscitation Predicted Good Neurological Recovery in a Patient with Acute Severe Anemia2017

    • Author(s)
      Koyama Y, Mizutani T, Marushima A, Sonobe A, Shimojo N, Kawano S
    • Journal Title

      Internal Medicine

      Volume: 56 Issue: 18 Pages: 2451-2453

    • DOI

      10.2169/internalmedicine.7826-16

    • NAID

      130006078614

    • ISSN
      0918-2918, 1349-7235
    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Intensive Gait Treatment Using a Robot Suit Hybrid Assistive Limb in Acute Spinal Cord Infarction: Report of Two Cases2017

    • Author(s)
      Watanabe H, Marushima A, Kawamoto H, Kadone H, Ueno T, Shimizu Y, Endo A, Hada Y, Saotome K, Abe T, Yamazaki M, Sankai Y, Ishikawa E, Matsumura A
    • Journal Title

      J Spinal Cord Med

      Volume: 9 Issue: 3 Pages: 1-7

    • DOI

      10.1080/10790268.2017.1372059

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Improving the neurological prognosis following OHCA using real-time evaluation of cerebral tissue oxygenation: a case report2017

    • Author(s)
      Koyama Y, Inoue Y, Hisago S, Marushima A, Hagiya K, Yamasaki Y, Enomoto Y, Shimojo N, Kawano S, Mizutani T
    • Journal Title

      Am J Emerg Med

      Volume: 36 Issue: 2 Pages: 344.e5-344.e7

    • DOI

      10.1016/j.ajem.2017.11.029

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Presentation] 脳梗塞急性期血栓回収療法における抗酸化ナノメディシン(RNP)による脳保護療法の開発2019

    • Author(s)
      丸島愛樹,長崎幸夫,Arnela Mujagic,松村英明,平田浩二,秋本大輔,Sandra Puentes,細尾久幸,平山暁,鈴木謙介,滝川知司,石川栄一,松丸祐司,松村明
    • Organizer
      第62回脳循環代謝学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 脳梗塞急性期再開通療法における新たな脳保護療法のトランスレーショナルリサーチ2019

    • Author(s)
      丸島愛樹、長崎幸夫、細尾久幸、Mei Ting、Arnela Mujagic、松村英明、Sandra Puentes、平山暁、鈴木謙介、滝川知司、石川栄一、井上貴昭、松丸祐司、松村明
    • Organizer
      第78回日本脳神経学会学術総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 抗酸化ナノメディシン(RNP)による脳虚血再灌流障害に対する脳保護療法2019

    • Author(s)
      丸島 愛樹、長崎 幸夫、Arnela Mujagic、細尾 久幸、平山 暁、松井 裕史、Sandra Puentes、鈴木 謙介、滝川 知司、石川 栄一、井上 貴昭、松丸 祐司、松村 明
    • Organizer
      第72回日本酸化ストレス学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 虚血性脳卒中の治療を目指した組織プラスミノーゲン活性 化因子封入型レドックスナノ粒子の開発2019

    • Author(s)
      Mei, Ting;Ahram, Kim;Long, Binh Vong;丸島, 愛樹;プエンテス, サンドラ;松丸, 祐司;松村, 明;長崎, 幸夫
    • Organizer
      高分子学会第68回年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 脳梗塞急性期再開通療法における環境応答性ナノ粒子化活性酸素消去剤(RNP)による脳保護療法の開発2018

    • Author(s)
      丸島愛樹、細尾久幸、長崎幸夫、Mujagic A、Puentes S、平山 暁、鈴木謙介、滝川知司、早川幹人、伊藤嘉朗、鶴嶋英夫、松井裕史、石川栄一、井上貴昭、松丸祐司、松村 明
    • Organizer
      第43回日本脳卒中学会学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] 脳梗塞急性期血栓回収療法におけるナノ粒子化活性酸素消去剤(RNP)による脳保護療法の開発2018

    • Author(s)
      丸島愛樹、長崎幸夫、Mujagic A、高橋利英、渡部大輔、松村英明、Ting M、Puentes S、細尾久幸、平山 暁、鈴木謙介、滝川知司、石川栄一、井上貴昭、松丸祐司、松村 明
    • Organizer
      第61回日本脳循環代謝学会学術集会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] ナノ粒子化活性酸素消去剤(RNP)による神経保護療法の実用化を目指した研究開発2018

    • Author(s)
      丸島愛樹、長崎幸夫、Mujagic A、高橋利英、渡部大輔、松村英明、Ting M、Puentes S、細尾久幸、平山暁、鈴木謙介、滝川知司、石川栄一、井上貴昭、松丸祐司、松村 明
    • Organizer
      日本脳神経外科学会第77回学術総会
    • Related Report
      2018 Research-status Report
  • [Presentation] 抗酸化ナノメディシン(RNP)による急性脳主幹動脈閉塞に対する脳保護療法の開発2018

    • Author(s)
      丸島愛樹、長崎幸夫、細尾久幸、Mujagic A、松村英明、渡部大輔、Puentes S、平山 暁、松井裕史、鈴木謙介、滝川知司、早川幹人、佐藤允之、伊藤嘉朗、石川栄一、井上貴昭、松丸祐司、松村 明
    • Organizer
      第33回日本酸化ストレス学会関東支部会
    • Related Report
      2018 Research-status Report
  • [Presentation] Neurovascular Unit Protection Using Nitroxide Radicals-containing Nanoparticles (TEMPO-RNP) for Cerebral Ischemia-reperfusion Injury in Mice2018

    • Author(s)
      Hisayuki Hosoo, Aiki Marushima, Yukio Nagasaki, Aki Hirayama, Hiromu Ito, Sandra Puentes, Arnela Mujagic, Hideo Tsurushima, Wataro, Kensuke Suzuki; Hirofumi Matsui, Yuji Matsumaru, Tetsuya Yamamoto, Akira Matsumura
    • Organizer
      International stroke conference 2018
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] 活性酸素消去剤封入ナノ粒子(RNP)による脳虚血再灌流障害に対するNeurovascular unit保護効果2017

    • Author(s)
      丸島愛樹、細尾久幸、長崎幸夫、平山暁、Sandra Puentes、Arnela Mujagic 、伊藤紘、鶴嶋英夫、鶴田和太郎、鈴木謙介、松井裕史、松丸祐司、山本哲哉、松村明
    • Organizer
      第60回脳循環代謝学会
    • Related Report
      2017 Research-status Report
  • [Presentation] 後方循環急性期再開通療法の治療成績と今後の課題2017

    • Author(s)
      丸島愛樹, 滝川知司, 早川幹人, 日野天祐, 松村英明, 渡部大輔, 池田剛, 中居康展, 上村和也, 中村和弘 谷中清之, 石川栄一, 松丸祐司, 松村明
    • Organizer
      第76回日本脳神経外科学会学術総会
    • Related Report
      2017 Research-status Report
  • [Presentation] 急性期脳梗塞に対する血栓回収療法のさらなる時間短縮-D2N 30分、D2P 60分、D2R 90分-を目指した取り組み2017

    • Author(s)
      丸島愛樹、滝川知司、早川幹人、小山泰明、榎本有希、松本佑啓、下條信威、河野了、松丸祐司、松村明、井上貴昭
    • Organizer
      第45回日本救急医学会総会・学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] 脳卒中急性期におけるロボットスーツHAL治療の効果量についての検討2017

    • Author(s)
      丸島愛樹、上野友之、河本浩明、羽田康司、清水如代、遠藤歩、鶴見一恵、門根秀樹、渡邉大貴、中井啓、松下明、山崎正志、松村明
    • Organizer
      第54回日本リハビリテーション医学会
    • Related Report
      2017 Research-status Report

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Published: 2017-04-28   Modified: 2021-02-19  

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