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Drug discovery and research for regulation of chronic inflammation caused by microglial activation

Research Project

Project/Area Number 17K17947
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Drug development chemistry
Neurochemistry/Neuropharmacology
Research InstitutionKyushu University

Principal Investigator

YAMASHITA Tomohiro  九州大学, 薬学研究院, 助教 (30645635)

Research Collaborator TSUDA Makoto  
SAITOH Hidetoshi  
Jose Caaveiro  
INOUE Kazuhide  
Project Period (FY) 2017-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2018: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Keywordsミクログリア / 医薬品探索 / サイトカイン / ATP受容体 / 慢性炎症 / P2X7受容体 / IL-1β / アカデミア創薬 / ドラッグリポジショニング
Outline of Final Research Achievements

The excess production and release of inflammatory factors from microglial cells are involved in the development and maintenance of central nervous system inflammation. Therefore, in this study, we aimed to search for compounds to regulate microglia-mediated inflammation among approved drugs libraries by high-throughput screening (HTS). We found that some compounds inhibit not only the function of P2X7R but also the release of IL-1β from microglial cells. Moreover, we succeeded that intrathecal administration of a potent compound among them produced a reversal of nerve injury-induced mechanical allodynia in a rat model of neuropathic pain. In addition, we also succeeded that a compound, which suppresses the production and release of IL-1β from microglial cells, recovered depressive-like behavior caused by chronic inflammation. These results suggest that approved drugs discovered by HTS may be able to regulate microglia-mediated inflammation.

Academic Significance and Societal Importance of the Research Achievements

現代の医薬品開発において、創薬ターゲットの枯渇が問題視されている中、安全性に関する適正な情報を有する既存薬の中から中枢のミクログリアに新たな薬効を示す化合物を見出すことを目的とした本研究は、画期的な治療戦略法となり得る。本研究成果からミクログリアを標的とした革新的な中枢疾患系疾患の治療薬につながることが期待でき、学術的意義および社会的意義は高いと考えられる。

Report

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

    (10 results)

All 2019 2018 Other

All Journal Article (2 results) (of which Peer Reviewed: 2 results,  Open Access: 1 results) Presentation (5 results) (of which Int'l Joint Research: 3 results,  Invited: 2 results) Book (1 results) Remarks (2 results)

  • [Journal Article] Green Pharma: A New Strategy for Drug Discovery in Academia by Targeting Glial Cells and ATP Receptors2018

    • Author(s)
      Yamashita Tomohiro、Tsuda Makoto、Tozaki-Saitoh Hidetoshi、Inoue Kazuhide
    • Journal Title

      YAKUGAKU ZASSHI

      Volume: 138 Issue: 8 Pages: 1027-1031

    • DOI

      10.1248/yakushi.17-00211-1

    • NAID

      130007429840

    • ISSN
      0031-6903, 1347-5231
    • Year and Date
      2018-08-01
    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] New pharmacological effect of fulvestrant to prevent oxaliplatin-induced neurodegeneration and mechanical allodynia in rats2018

    • Author(s)
      Yamamoto S, Yamashita T, Ito M, Caaveiro JMM, Egashira N, Tozaki-Saitoh H, Tsuda M
    • Journal Title

      Int J Cancer

      Volume: - Issue: 8 Pages: 2107-2113

    • DOI

      10.1002/ijc.32043

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] New pharmacological effects of approved drugs targeting P2X7 receptors against the release of IL-1β from microglial cells and neuropathic pain after peripheral nerve injury2018

    • Author(s)
      Tomohiro Yamashita, Sawako Kamikaseda, Aya Tanaka, Hidetoshi Tozaki-Saitoh, Makoto Tsuda, and Kazuhide Inoue
    • Organizer
      PURINES 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Microglial ATP receptors in neuropathic pain2018

    • Author(s)
      Kazuhide Inoue and Tomohiro Yamashita
    • Organizer
      PURINES 2018
    • Related Report
      2018 Annual Research Report 2017 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] New pharmacological effects of approved drugs targeting P2X7 receptors against the release of IL-1β from microglial cells and neuropathic pain after peripheral nerve injury2018

    • Author(s)
      Tomohiro Yamashita, Sawako Kamikaseda, Aya Tanaka, Hidetoshi Tozaki-Saitoh, Makoto Tsuda, and Kazuhide Inoue
    • Organizer
      WCP2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Drug discovery technologies to achieve pain relief through drug repositioning approaches2018

    • Author(s)
      山下智大
    • Organizer
      第92回日本薬理学会年会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] アドレナリン受容体を介したミクログリアの炎症応答調節2018

    • Author(s)
      笹木泉, 山下智大, 齊藤秀俊, 津田誠
    • Organizer
      第35回日本薬学会九州支部会
    • Related Report
      2018 Annual Research Report
  • [Book] エコファーマによる新規神経障害性疼痛治療薬の探索2019

    • Author(s)
      山下智大
    • Total Pages
      5
    • Publisher
      ファルマシア
    • Related Report
      2018 Annual Research Report
  • [Remarks] Department of Global Healthcare

    • URL

      http://global.phar.kyushu-u.ac.jp/

    • Related Report
      2018 Annual Research Report
  • [Remarks] オキサリプラチンによる神経ダメージを保護する既承認薬を発見!

    • URL

      http://www.phar.kyushu-u.ac.jp/bbs/view2.php?S_Publ_Year=2019&word=&page=1&B_Code=449

    • Related Report
      2018 Annual Research Report

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

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