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Novel therapeutic strategy targeting RAGE for treatment of peripheral neuropathy and visceral pain

Research Project

Project/Area Number 17K09046
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Pain science
Research InstitutionKindai University

Principal Investigator

Kawabata Atsufumi  近畿大学, 薬学部, 教授 (20177728)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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疼痛の発生・増強機序 / RAGE / HMGB1 / 末梢神経障害 / 内蔵痛 / 薬理学 / HMGB1 / 薬学 / 疼痛 / 神経
Outline of Final Research Achievements

To develop seeds for development of medicines targeting RAGE for treatment of intractable pain, the present study first ascertained the involvement of RAGE in neuropathic and visceral pain using animal models. We then demonstrated that middle-molecular-weight-heparinylphenylalanine suppressed intractable pain possibly through selective blockade of RAGE. Our in silico analysis identified a small molecule compound that inhibits AGE-RAGE binding and is useful as a seed compound for novel RAGE blocker development. Together, our study identified both large and small molecules as RAGE blockers, which would be useful for pain treatment.

Academic Significance and Societal Importance of the Research Achievements

これまでに、アルツハイマー病の予防・治療を目的とするいくつかのRAGE拮抗薬の開発が試みられてきたが、まだ臨床応用には至っていない。本研究では、RAGEが難治性疼痛の治療標的分子になりうることを証明して、高分子および低分子のRAGE拮抗薬のシーズを得ることができた。現在、モルヒネ、プレガバリンなどが効かない難治性慢性疼痛を訴える患者が多数存在することを考慮すると、今回得られた知見は社会的にもインパクトのあるものであると考える。

Report

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

    (14 results)

All 2020 2019 2018

All Journal Article (3 results) (of which Peer Reviewed: 3 results,  Open Access: 2 results) Presentation (11 results) (of which Int'l Joint Research: 3 results,  Invited: 4 results)

  • [Journal Article] HMGB1 and its membrane receptors as therapeutic targets in an intravesical substance P-induced bladder pain syndrome mouse model2020

    • Author(s)
      Irie Yuhei、Tsubota Maho、Maeda Mariko、Hiramoto Shiori、Sekiguchi Fumiko、Ishikura Hiroyasu、Wake Hidenori、Nishibori Masahiro、Kawabata Atsufumi
    • Journal Title

      Journal of Pharmacological Sciences

      Volume: in press Issue: 2 Pages: 112-116

    • DOI

      10.1016/j.jphs.2020.03.002

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Role of high mobility group box 1 and its modulation by thrombomodulin/thrombin axis in neuropathic and inflammatory pain2020

    • Author(s)
      Tsujita, R., Tsubota, M., Sekiguchi, F., Kawabata, A.
    • Journal Title

      Br J Pharmacol

      Volume: - Issue: 4 Pages: 798-812

    • DOI

      10.1111/bph.15091

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Role of non-macrophage cell-derived HMGB1 in oxaliplatin-induced peripheral neuropathy and its prevention by the thrombin/thrombomodulin system in rodents: negative impact of anticoagulants2019

    • Author(s)
      Tsubota Maho、Fukuda Ryotaro、Hayashi Yusuke、Miyazaki Takaya、Ueda Shin、Yamashita Rika、Koike Nene、Sekiguchi Fumiko、Wake Hidenori、Wakatsuki Shuji、Ujiie Yuka、Araki Toshiyuki、Nishibori Masahiro、Kawabata Atsufumi
    • Journal Title

      Journal of Neuroinflammation

      Volume: 16 Issue: 1 Pages: 199-199

    • DOI

      10.1186/s12974-019-1581-6

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] Role of ATP/HMGB1/RAGE and H2S/Cav3.2 axes in cystitis-related bladder pain2020

    • Author(s)
      Kawabata, A.
    • Organizer
      National Institute of Physiological Sciences International Workshop on Frontiers in Defensive Survival Circuit Research(痛み研究会2019)2020
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Neuroimmune crosstalk in neuropathic and visceral pain: HMGB1 and ATP as key mediators2020

    • Author(s)
      Kawabata, A.
    • Organizer
      In Symposium “Neuroimmune crosstalk and pain”, 第93回日本薬理学会年会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] RAGE阻害活性を有する中分子ヘパリニルフェニルアラニンはマウスにおけるoxaliplatin誘発性末梢神経障害およびbutyrate誘起結腸痛を抑制する2020

    • Author(s)
      東本久瑠美、上野山桐子、西川裕之、関口富美子、坪田真帆、豊岡尚樹、川畑篤史
    • Organizer
      第93回日本薬理学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 化学療法誘発性末梢神経障害のリスク因子解析とHMGB1を標的とする予防戦略:基礎研究と臨床研究の融合による新知見とイノベーション2019

    • Author(s)
      川畑篤史
    • Organizer
      生体機能と創薬シンポジウム2019
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Role of HMGB1 and PRRs in pain processing2019

    • Author(s)
      Kawabata, A.
    • Organizer
      The 6th Asian College of Neuropsychopharmacology (AsCNP) Congress
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 中分子ヘパリニルフェニルアラニンのRAGE阻害活性とマウスにおけるoxaliplatin誘発性末梢神経障害およびbutyrate誘起結腸痛に対する抑制作用2019

    • Author(s)
      東本紅瑠美、上野山桐子、西川裕之、関口富美子、坪田真帆、岡田卓哉、豊岡尚樹、川畑篤史
    • Organizer
      第69回日本薬学会関西支部総会・大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] AzelastineはRAGEが関与する化学療法誘起末梢神経障害の発症を抑制する - ドラッグ・リプロファイリング/リポジショニング研究からの知見2018

    • Author(s)
      脇谷航平, 関口富美子, 坪田真帆, 中村真也, 仲西功, 川畑篤史
    • Organizer
      第133回日本薬理学会近畿部会
    • Related Report
      2018 Research-status Report
  • [Presentation] がん化学療法誘起末梢神経障害モデルマウスにおける中分子ヘパリニルフェニルアラニンの抗アロディニア作用2018

    • Author(s)
      西川裕之、上野山桐子、関口富美子、坪田真帆、岡田卓哉、豊岡尚樹、川畑篤史
    • Organizer
      第133回日本薬理学会近畿部会
    • Related Report
      2018 Research-status Report
  • [Presentation] RAGEを標的とした化学療法誘起末梢神経障害治療薬の探索: In silicoドラッグ・リプロファイリング/リポジショニングからのアプローチ2018

    • Author(s)
      脇谷航平, 関口富美子, 坪田真帆, 中村真也, 仲西功, 川畑篤史
    • Organizer
      第40回日本疼痛学会
    • Related Report
      2018 Research-status Report
  • [Presentation] 中分子ヘパリニルフェニルアラニンは化学療法誘起末梢神経障害を抑制する2018

    • Author(s)
      西川裕之、上野山桐子、関口富美子、坪田真帆、岡田卓哉、豊岡尚樹、川畑篤史
    • Organizer
      第40回日本疼痛学会
    • Related Report
      2018 Research-status Report
  • [Presentation] Middle molecular weight heparinylphenylalanine is an analgesic with reduced risk of hemorrhage2018

    • Author(s)
      Nishikawa, H., Uenoyama, K., Sekiguchi, F., Tsubota, M., Kawabata, A.
    • Organizer
      18th World Congress of Basic and Clinical Pharmacology
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research

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

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