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Elucidation of the role of CGRP in migraine pathophysiology and application of oligonucleotide therapeutics to migraine treatment

Research Project

Project/Area Number 19K07849
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 51030:Pathophysiologic neuroscience-related
Research InstitutionKeio University

Principal Investigator

Shibata Mamoru  慶應義塾大学, 医学部(信濃町), 客員教授 (60286466)

Project Period (FY) 2019-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Keywords片頭痛 / カルシトニン遺伝子関連ペプチド / 三叉神経節ニューロン / 感作 / 身体活動性低下 / 光過敏 / 後発症状 / ノイロトロピン / 皮質拡延性抑制 / 三叉神経節 / mRNA / 核酸医薬 / autocrine / ニューロペプチド / カルシトニン遺伝子関連ペプチド (CGRP) / アンチセンスオリゴヌクレオチド / mRNA / 三叉神経 / CGRP / 活動性低下 / 生活の質
Outline of Research at the Start

片頭痛は中枢神経系と三叉神経系の機能異常に基づく慢性頭痛疾患である。新規片頭痛治療法としてカルシトニン遺伝子関連ペプチド(CGRP)を標的にした抗体や化合物の有効性と忍容性の高さが脚光を浴びており、特に抗体治療は海外で薬事承認を既に受けている。しかし、片頭痛病態におけるCGRPの役割や発現変化には不明な点が多く、その解明によってCGRPを標的にした治療戦略はさらに進歩することが予想される。本研究では、三叉神経支配領域での痛覚感作誘導と片頭痛前兆の発生閾値にCGRPが与える影響を検討し、病態モデルにアンチセンスオリゴヌクレオチドを投与して、CGRP発現抑制効果と病態改善効果もあわせて検討する。

Outline of Final Research Achievements

We have shown that cortical spreading depression (CSD) causes trigeminal sensitization, photophobia, and hypomotility in mice. The calcitonin gene-related peptide (CGRP) receptor blocker, olcegepant, and sumatriptan suppressed these abnormalities. The CSD-induced hypomotility outlasted trigeminal sensitization, reminiscent of migraine postdrome. This protracted hypomotility proved to be ameliorated by CGRP receptor blockade and Neurotropin. CSD did not significantly change the density of CGRP mRNA-synthesizing neurons in the ipsilateral trigeminal ganglion (TG). However, the cell sizes of CGRP mRNA-synthesizing TG neurons were significantly larger at 48 h and 72 h post-CSD. We deduce that the CSD-induced upward cell size shift of CGRP mRNA-synthesizing TG neurons might be causative of greater disease activity and/or less responsiveness to CGRP-based therapy. Our research has opened up the possibilities of nucleic acids therapeutics-based approach to migraine.

Academic Significance and Societal Importance of the Research Achievements

CGRPに対する核酸医薬の効果を検討するための片頭痛モデルを作成した。片頭痛の後発症状のモデル動物を作成し、後発症状の身体活動性の低下にノイロトロピンとCGRP受容体拮抗薬olcegepant抑制が有効である可能性を示した。CSDを用いた片頭痛モデルで、三叉神経節ニューロンでのCGRP mRNA産生状態に変化が認められたことはCGRPに対する核酸医薬が片頭痛に対する有効な治療戦略である可能性を示唆していると考えられる。また、CGRP mRNA産生を行う細胞が遅発性に変化したことは、片頭痛再発予防治療を考える上で重要な所見と考えられる。

Report

(5 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (35 results)

All 2022 2021 2020

All Journal Article (14 results) (of which Int'l Joint Research: 6 results,  Peer Reviewed: 14 results,  Open Access: 13 results) Presentation (19 results) (of which Int'l Joint Research: 1 results,  Invited: 19 results) Book (2 results)

  • [Journal Article] Galcanezumab Effects on Migraine Severity and Symptoms in Japanese Patients with Episodic Migraine: Secondary Analysis of a Phase 2 Randomized Trial2022

    • Author(s)
      Igarashi Hisaka、Shibata Mamoru、Ozeki Akichika、Matsumura Taka
    • Journal Title

      Neurology and Therapy

      Volume: 12 Issue: 1 Pages: 73-87

    • DOI

      10.1007/s40120-022-00410-3

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Sustained Effects of CGRP Blockade on Cortical Spreading Depolarization-Induced Alterations in Facial Heat Pain Threshold, Light Aversiveness, and Locomotive Activity in the Light Environment.2022

    • Author(s)
      Kitagawa S, Tang C, Unekawa M, Kayama Y, Nakahara J, Shibata M
    • Journal Title

      Int J Mol Sci

      Volume: 23 Issue: 22 Pages: 13807-13807

    • DOI

      10.3390/ijms232213807

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Real-world evidence of galcanezumab for migraine treatment in Japan: a retrospective analysis2022

    • Author(s)
      Takizawa Tsubasa、Ohtani Seiya、Watanabe Narumi、Miyazaki Naoki、Ishizuchi Kei、Sekiguchi Koji、Iba Chisato、Shibata Mamoru、Takemura Ryo、Hori Satoko、Nakahara Jin
    • Journal Title

      BMC Neurology

      Volume: 22 Issue: 1 Pages: 512-512

    • DOI

      10.1186/s12883-022-03041-1

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Painless Thyroiditis Presenting with Headache2021

    • Author(s)
      Takizawa Tsubasa、Kurihara Isao、Suzuki Norihiro、Nakahara Jin、Shibata Mamoru
    • Journal Title

      Internal Medicine

      Volume: 60 Issue: 16 Pages: 2693-2696

    • DOI

      10.2169/internalmedicine.6975-20

    • NAID

      130008074626

    • ISSN
      0918-2918, 1349-7235
    • Year and Date
      2021-08-15
    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Protracted hypomobility in the absence of trigeminal sensitization after cortical spreading depolarization: Relevance to migraine postdrome2021

    • Author(s)
      Shibata Mamoru、Kitagawa Satoshi、Tang Chunghua、Unekawa Miyuki、Kayama Yohei、Shimizu Toshihiko、Nakahara Jin、Suzuki Norihiro
    • Journal Title

      Neuroscience Research

      Volume: 172 Pages: 80-86

    • DOI

      10.1016/j.neures.2021.03.010

    • Related Report
      2021 Research-status Report 2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Incidence of headache after COVID-19 vaccination in patients with history of headache: A cross-sectional study2021

    • Author(s)
      Sekiguchi Koji、Watanabe Narumi、Miyazaki Naoki、Ishizuchi Kei、Iba Chisato、Tagashira Yu、Uno Shunsuke、Shibata Mamoru、Hasegawa Naoki、Takemura Ryo、Nakahara Jin、Takizawa Tsubasa
    • Journal Title

      Cephalalgia

      Volume: 42 Issue: 3 Pages: 266-272

    • DOI

      10.1177/03331024211038654

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Impact of the COVID-19 pandemic on migraine in Japan: a multicentre cross-sectional study.2021

    • Author(s)
      Suzuki K, Takeshima T, Igarashi H, Imai N, Danno D, Yamamoto T, Nagata E, Haruyama Y, Mitsufuji T, Suzuki S, Ito Y, Shibata M, Kowa H, Kikui S, Shiina T, Okamura M, Tatsumoto M, Hirata K
    • Journal Title

      J Headache Pain

      Volume: 22 Issue: 1 Pages: 53-53

    • DOI

      10.1186/s10194-021-01263-1

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] 21st century headache: mapping new territory2021

    • Author(s)
      Goadsby Peter J.、Lanteri-Minet Michel、Michel Martin C.、Peres Mario、Shibata Mamoru、Straube Andreas、Wijeratne Tissa、Ebel-Bitoun Caty、Constantin Luminita、Hitier Simon
    • Journal Title

      The Journal of Headache and Pain

      Volume: 22 Issue: 1 Pages: 19-19

    • DOI

      10.1186/s10194-021-01233-7

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Early Onset and Maintenance Effect of Galcanezumab in Japanese Patients with Episodic Migraine2021

    • Author(s)
      Igarashi Hisaka、Shibata Mamoru、Ozeki Akichika、Day Kathleen Ann、Matsumura Taka
    • Journal Title

      Journal of Pain Research

      Volume: Volume 14 Pages: 3555-3564

    • DOI

      10.2147/jpr.s326905

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Cortical spreading depolarisation-induced facial hyperalgesia, photophobia and hypomotility are ameliorated by sumatriptan and olcegepant2020

    • Author(s)
      Tang Chunhua、Unekawa Miyuki、Kitagawa Satoshi、Takizawa Tsubasa、Kayama Yohei、Nakahara Jin、Shibata Mamoru
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1

    • DOI

      10.1038/s41598-020-67948-w

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Characteristics of cortical spreading depression and c-Fos expression in transgenic mice having a mutation associated with familial hemiplegic migraine 22020

    • Author(s)
      Tang Chunhua、Unekawa Miyuki、Shibata Mamoru、Tomita Yutaka、Izawa Yoshikane、Sugimoto Hiroki、Ikeda Keiko、Kawakami Kiyoshi、Suzuki Norihiro、Nakahara Jin
    • Journal Title

      Cephalalgia

      Volume: 40 Issue: 11 Pages: 1177-1190

    • DOI

      10.1177/0333102420929028

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Resilience to capsaicin-induced mitochondrial damage in trigeminal ganglion neurons2020

    • Author(s)
      Shibata Mamoru、Kayama Yohei、Takizawa Tsubasa、Ibata Keiji、Shimizu Toshihiko、Yuzaki Michisuke、Suzuki Norihiro、Nakahara Jin
    • Journal Title

      Molecular Pain

      Volume: 16

    • DOI

      10.1177/1744806920960856

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] [123I]-IMP single-photon emission computed tomography imaging in visual snow syndrome: A case series2020

    • Author(s)
      Shibata Mamoru、Tsutsumi Kei、Iwabuchi Yu、Kameyama Masashi、Takizawa Tsubasa、Nakahara Tadaki、Fujiwara Hirokazu、Jinzaki Masahiro、Nakahara Jin、Dodick David W
    • Journal Title

      Cephalalgia

      Volume: 40 Issue: 14 Pages: 1671-1675

    • DOI

      10.1177/0333102420950454

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Implications of Transient Receptor Potential Cation Channels in Migraine Pathophysiology2020

    • Author(s)
      Shibata Mamoru、Tang Chunhua
    • Journal Title

      Neuroscience Bulletin

      Volume: 37 Issue: 1 Pages: 103-116

    • DOI

      10.1007/s12264-020-00569-5

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] ホットトピックス3: Galcanezumab: Evidence in Japan.2022

    • Author(s)
      柴田 護
    • Organizer
      第63回日本神経学会学術大会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 高齢者の慢性片頭痛2022

    • Author(s)
      柴田 護
    • Organizer
      第64回日本老年医学会学術集会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 片頭痛におけるCGRPの役割と新規治療開発2022

    • Author(s)
      柴田 護
    • Organizer
      第33回日本末梢神経学会学術集会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 頭痛の診療ガイドライン2021: 片頭痛診療の新しい羅針盤2022

    • Author(s)
      柴田 護
    • Organizer
      第40回日本神経治療学会学術集会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 頭痛発生のメカニズムと頭痛の鑑別診断2022

    • Author(s)
      柴田 護
    • Organizer
      日本医師会生涯教育講座
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] CGRPの構造と機能: 片頭痛病態との関連を中心に2022

    • Author(s)
      柴田 護
    • Organizer
      第50回日本頭痛学会総会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 特別セミナー. アクセプトをめざした論文作成法2022

    • Author(s)
      柴田 護
    • Organizer
      第50回日本頭痛学会総会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] Overview: How do we effectively utilize CGRP-related monoclonal antibodies in migraine prophylaxis?2022

    • Author(s)
      Mamoru Shibata
    • Organizer
      AHS 64th Annual Scientific Meeting
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 片頭痛と緊張型頭痛の病態仮説2021

    • Author(s)
      柴田 護
    • Organizer
      第62回日本神経学会学術大会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] 片頭痛の病態とカルシトニン遺伝子関連ペプチド (CGRP)2021

    • Author(s)
      柴田 護
    • Organizer
      第39回日本神経治療学会学術集会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] COVID-19と頭痛 5. 抗体療法とワクチン2021

    • Author(s)
      柴田 護
    • Organizer
      第49回日本頭痛学会総会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] 片頭痛治療におけるCGRP関連薬剤の意義2021

    • Author(s)
      柴田 護
    • Organizer
      第49回日本頭痛学会総会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] 降雪視 (Visual snow syndrome)2021

    • Author(s)
      柴田 護
    • Organizer
      第49回日本頭痛学会総会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] Gepants and Lasmiditan: novel players in acute migraine treatment.2020

    • Author(s)
      柴田 護
    • Organizer
      第61回日本神経学会学術大会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] 前庭性片頭痛 (片頭痛関連めまい)の病態と治療2020

    • Author(s)
      柴田 護
    • Organizer
      第61回日本神経学会学術大会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] 片頭痛の薬物治療2020

    • Author(s)
      柴田 護
    • Organizer
      第38回日本神経治療学会学術集会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] 経口CGRP拮抗薬gepantの開発状況2020

    • Author(s)
      柴田 護
    • Organizer
      第38回日本神経治療学会学術集会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] 光と片頭痛ー基礎研究から臨床研究へ 皮質拡延性抑制による行動変容に対するCGRP受容体阻害の影響―明暗所での比較2020

    • Author(s)
      柴田 護
    • Organizer
      第48回日本頭痛学会総会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] 片頭痛の病態2020

    • Author(s)
      柴田 護
    • Organizer
      第25回日本口腔顔面痛学会総会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Book] 最新主要文献とガイドラインでみる 脳神経内科学レビュー 2022-’232022

    • Author(s)
      鈴木則宏
    • Total Pages
      456
    • Publisher
      総合医学社
    • ISBN
      9784883784646
    • Related Report
      2021 Research-status Report
  • [Book] 頭痛の診療ガイドライン20212021

    • Author(s)
      日本神経学会、日本頭痛学会、日本神経治療学会、頭痛の診療ガイドライン作成委員会
    • Total Pages
      512
    • Publisher
      医学書院
    • ISBN
      9784260046985
    • Related Report
      2021 Research-status Report

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Published: 2019-04-18   Modified: 2024-01-30  

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