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Research and development of novel neuroprotective drugs targeting endothelin ETB receptor

Research Project

Project/Area Number 15K07981
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Pharmacology in pharmacy
Research InstitutionKobe Pharmaceutical University (2017-2018)
Osaka Ohtani University (2015-2016)

Principal Investigator

Koyama Yutaka  神戸薬科大学, 薬学部, 教授 (00215435)

Co-Investigator(Kenkyū-buntansha) 道永 昌太郎  大阪大谷大学, 薬学部, 助教 (60624054)
Project Period (FY) 2015-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywordsエンドセリン / 脳浮腫 / アストロサイト / ETB受容体 / ETB受容体
Outline of Final Research Achievements

Pathophysiological roles of endothelin (ET) on brain edema and neurite extension was studied, and the following findings were obtained. 1) ETB receptor antagonist BQ 788 reduced the development of brain edema in mouse traumatic brain injury model. As for the mechanisms of anti-edema actions, BQ788 decreased the productions of astrocyte-derived brain edema factors including VEGF and MMP9. 2) The anti-brain edema action of BQ788 was examined, and it was found that it increases ANG-1 expression, which enhances the barrier function of cerebrovascular. 3) ET-1 reduced Ephrin-B1 and Ephrin-B3 expression, which are neurite outgrowth inhibitory molecules of astrocytes. This suggests that stimulation of ET receptors during brain injury may promote neurite outgrowth during neural regeneration.

Academic Significance and Societal Importance of the Research Achievements

脳卒中や頭挫傷などの際に生じる脳浮腫の抑制は、患者の予後の向上に重要である。また、それら脳疾患による後遺症も、患者QOL向上のための治療法の開発が急がれている。しかし現在「脳浮腫の抑制」および「後遺障害の軽減」を意図する薬物治療は確立されていない。本研究の結果は、神経細胞を取り巻くアストログリアに多く発現するETB受容体の遮断あるいは刺激で、脳浮腫の成因となる血液脳関門の破綻の抑制や、傷害後の神経突起伸長を促し得ることを示すもので、この知見を基に新たな脳機能改善薬が開発されることが期待される。

Report

(4 results)
  • 2018 Final Research Report ( PDF )
  • 2017 Annual Research Report
  • 2016 Research-status Report
  • 2015 Research-status Report
  • Research Products

    (23 results)

All 2018 2017 2016 2015 Other

All Journal Article (9 results) (of which Peer Reviewed: 9 results,  Open Access: 8 results,  Acknowledgement Compliant: 5 results) Presentation (12 results) (of which Int'l Joint Research: 1 results,  Invited: 1 results) Book (1 results) Remarks (1 results)

  • [Journal Article] Delayed Administration of BQ788, an ETB Antagonist, after Experimental Traumatic Brain Injury Promotes Recovery of Blood-Brain Barrier Function and a Reduction of Cerebral Edema in Mice.2018

    • Author(s)
      Michinaga Shotaro, Kimura Akimasa, Hatanaka Shunichi, Minami Shizuho, Asano Arisa, Ikushima Yuki, Matsui Shingo, Toriyama Yoshiya, Fujii Manami, Koyama Yutaka.
    • Journal Title

      Journal of neurotrauma

      Volume: 印刷中 Issue: 13 Pages: 1481-1494

    • DOI

      10.1089/neu.2017.5421

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Protection of the Blood–Brain Barrier as a Therapeutic Strategy for Brain Damage2017

    • Author(s)
      Shotaro Michnaga, Yutaka Koyama
    • Journal Title

      Biological and Pharmaceutical Bulletin

      Volume: 40 Issue: 5 Pages: 569-575

    • DOI

      10.1248/bpb.b16-00991

    • NAID

      130005631954

    • ISSN
      0918-6158, 1347-5215
    • Related Report
      2017 Annual Research Report 2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Dysfunctional GPR40/FFAR1 signaling exacerbates pain behavior in mice.2017

    • Author(s)
      Nakamoto K, Aizawa F, Miyagi K, Yamashita T, Mankura M, Koyama Y, Kasuya F, Hirasawa A, Kurihara T, Miyata A, Tokuyama S.
    • Journal Title

      PLoS One

      Volume: 12(7) Issue: 7 Pages: e0180610-e0180610

    • DOI

      10.1371/journal.pone.0180610

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Dexamethasone down-regulates endothelin receptors and reduces endothelin-induced production of matrix metalloproteinases in cultured rat astrocytes.2017

    • Author(s)
      Yutaka Koyama, Ayano Ukita, Kana Abe, Kuniaki Iwamae, Shogo Tokuyama, Keisuke Tanaka, Yuki Kotake
    • Journal Title

      Mol Pharmacol.

      Volume: 印刷中 Issue: 1 Pages: 57-66

    • DOI

      10.1124/mol.116.107300

    • Related Report
      2017 Annual Research Report 2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Astrocyte activation in locus coeruleus is involved in neuropathic pain exacerbation mediated by maternal separation and social isolation stress.2017

    • Author(s)
      Nakamoto K, Aizawa F, Kinoshita M, Koyama Y, Tokuyama S.
    • Journal Title

      Front Pharmacol.

      Volume: 8 Pages: 401-401

    • DOI

      10.3389/fphar.2017.00401

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Astrocytes Release Polyunsaturated Fatty Acids by Lipopolysaccharide Stimuli2016

    • Author(s)
      Aizawa F, Nishinaka T, Yamashita T, Nakamoto K, Koyama Y, Kasuya F, Tokuyama S.
    • Journal Title

      Biological and Pharmaceutical Bulletin

      Volume: 39 Issue: 7 Pages: 1100-1106

    • DOI

      10.1248/bpb.b15-01037

    • NAID

      130005160776

    • ISSN
      0918-6158, 1347-5215
    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Functional alterations of astrocytes in mental disorders: pharmacological significance as a drug target2015

    • Author(s)
      Yutaka Koyama
    • Journal Title

      Frontiers in Cellular Neuroscience

      Volume: 9 Pages: 261-261

    • DOI

      10.3389/fncel.2015.00261

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Improvement of cold injury-induced mouse brain edema by endothelin ETB antagonists is accompanied by decreases in matrixmetalloproteinase 9 and vascular endothelial growth factor-A.2015

    • Author(s)
      Shotaro Michinaga, Naoki Seno, Mayu Fuka, Yui Yamamoto, Shizuho Minami, Marina Nagase, Emi Matsuyama, Daisuke Yamanaka and Yutaka Koyama
    • Journal Title

      European Journal of Neuroscience

      Volume: 42 Issue: 6 Pages: 2356-2370

    • DOI

      10.1111/ejn.13020

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Pathogenesis of brain edema and investigation into anti-edema drugs2015

    • Author(s)
      Shotaro Michinaga and Yutaka Koyama
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 16 Issue: 5 Pages: 9949-9975

    • DOI

      10.3390/ijms16059949

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Presentation] 頭部外傷マウスにおけるBlood-brain barrierの破綻に対するエンドセリンETB受容体拮抗薬の効果2018

    • Author(s)
      道永 昌太郎、鳥山 佳勇、藤井 愛望、小山 豊
    • Organizer
      日本薬学会 第138回年会
    • Related Report
      2017 Annual Research Report
  • [Presentation] エンドセリンETB受容体遮断薬BQ788による脳挫傷後の血液脳関門破綻に対する抑制効果の機序解明―VEGF-Aおよびclaudin-5の関与―2017

    • Author(s)
      道永 昌太郎, 麻野 有沙, 生島 佑起, 松井 伸悟, 木村 章政, 畠中 駿一, 南 志津保, 小山 豊
    • Organizer
      第90回日本薬理学会年会
    • Place of Presentation
      長崎ブリックホール (長崎県、長崎市)
    • Year and Date
      2017-03-15
    • Related Report
      2016 Research-status Report
  • [Presentation] 脳挫傷後のマウス脳浮腫に対するエンドセリンETB受容体拮抗薬BQ788の効果2017

    • Author(s)
      道永 昌太郎
    • Organizer
      第67回日本薬学会近畿支部総会・大会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 脳挫傷後の脳血管障害に対するエンドセリンETB受容体拮抗薬の効果2017

    • Author(s)
      道永 昌太郎, 小山 豊
    • Organizer
      第19回応用薬理シンポジウム
    • Related Report
      2017 Annual Research Report
  • [Presentation] Amelioration of BBB disruption and brain edema by BQ788, an endothelin ETB receptor antagonist through attenuation of matrix metalloproteinase-9 in cerebral contusion mice2017

    • Author(s)
      Shotaro Michinaga, Yoshiya Toriyama, Manami Fujii and Yutaka Koyama
    • Organizer
      第40回日本神経科学学会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 小山 豊、浮田彰乃、阿部華奈、岩前邦明、田中啓介、小竹優希2017

    • Author(s)
      デキサメタゾンによる培養アストロサイトのエンドセリンETAおよびETB受容体のDown-regulation
    • Organizer
      第131回日本薬理学会近畿部会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 流体衝撃による脳傷害後のマウス脳浮腫に対するエンドセリンETB受容体遮断薬の効果 ―血管透過性亢進因子VEGF-Aの関与―2016

    • Author(s)
      道永 昌太郎, 麻野 有沙, 生島 佑起, 松井 伸悟, 木村 光克, 畠中 駿一, 南 志津保, 小山 豊
    • Organizer
      第66 回 日本薬学会近畿支部総会・大会
    • Place of Presentation
      大阪薬科大学 (大阪府、高槻市)
    • Year and Date
      2016-10-15
    • Related Report
      2016 Research-status Report
  • [Presentation] Effects of endothelin ETB receptor antagonist on acceleration of cerebral microvascular permeability and brain edema formation after fluid percussion injury in mice2016

    • Author(s)
      Shotaro Michinaga, Akimasa Kimura, Shunichi Hatanaka, Shizuho Minami, Arisa Asano, Yuki Ikushima, Shingo Matsui, Yutaka Koyama
    • Organizer
      第39回日本神経科学大会
    • Place of Presentation
      パシフィコ横浜 (神奈川県、横浜市)
    • Year and Date
      2016-07-20
    • Related Report
      2016 Research-status Report
  • [Presentation] Fluid percussion injury後のマウス脳浮腫に対するエンドセリン受容体遮断薬の効果―ETA遮断薬とETB遮断薬の異なる効果―2016

    • Author(s)
      道永 昌太郎, 木村 章政, 畠中 駿一, 南 志津保, 麻野 有沙, 生島 佑起, 松井 伸悟, 小山 豊
    • Organizer
      第129回日本薬理学会近畿部会
    • Place of Presentation
      広島県医師会館 (広島県、広島市)
    • Year and Date
      2016-06-24
    • Related Report
      2016 Research-status Report
  • [Presentation] 培養アストロサイトでのエンドセリンによるVEGF-R1の発現変化と受容体シグナル系の増強2016

    • Author(s)
      小山 豊、林 美央、小西智洋
    • Organizer
      日本薬学会第136年会
    • Place of Presentation
      パシフィコ横浜(神奈川県、横浜市)
    • Year and Date
      2016-03-27
    • Related Report
      2015 Research-status Report
  • [Presentation] Attenuation of fluid percussion injury induced-brain edema formation by BQ788, an endothelin ETB receptor antagonist, in mice2016

    • Author(s)
      Shotaro Michinaga, Akimasa Kimura, Shunichi Hatanaka, Shizuho Minami and Yutaka Koyama
    • Organizer
      第89回 日本薬理学会年会
    • Place of Presentation
      パシフィコ横浜(神奈川県、横浜市)
    • Year and Date
      2016-03-10
    • Related Report
      2015 Research-status Report
  • [Presentation] Regulation of animal behaviors through brain reward system: Mechanisms underlying pleasure and aversion2015

    • Author(s)
      Yutaka Koyama
    • Organizer
      The 25th International symposium of itch
    • Place of Presentation
      奈良春日野国際フォーラム 甍 能楽ホール(奈良県、奈良市)
    • Year and Date
      2015-09-27
    • Related Report
      2015 Research-status Report
    • Int'l Joint Research / Invited
  • [Book] New developments in astrocytes research2016

    • Author(s)
      Koyama Y., Pointer C.B., Vaz A.R., Ito J.
    • Total Pages
      147
    • Publisher
      Nova Scientific Publishers Inc.
    • Related Report
      2016 Research-status Report
  • [Remarks] World Biomedical Frontiers

    • URL

      http://biomedfrontiers.org/neuro-2016-8-1/

    • Related Report
      2016 Research-status Report

URL: 

Published: 2015-04-16   Modified: 2020-03-30  

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