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Elucidation of molecular mechanism of orexin on the brain in endotoxin shock

Research Project

Project/Area Number 16K08541
Research Category

Grant-in-Aid for Scientific Research (C)

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

Principal Investigator

Irukayama Yoko  筑波大学, 国際統合睡眠医科学研究機構, 研究員 (90312834)

Co-Investigator(Kenkyū-buntansha) 桜井 武  筑波大学, 医学医療系, 教授 (60251055)
Research Collaborator Ogawa Yasuhiro  
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywordsオレキシン / 敗血症性ショック / リポポリサッカライド / DREADD / 炎症性サイトカイン / 体温 / カテコールアミン / コルチコステロン
Outline of Final Research Achievements

Sepsis is a systemic inflammatory response to infection and can lead to a life-threating medical emergency requiring intensive care. We found that peripheral administration of orexin penetrates the blood brain barrier and improves the survival of mice with lipopolysaccharide induced endotoxin shock. Orexin restored body temperature and cardiovascular function and decreased excessive cytokine production in mice under endotoxin shock. We detected serotonergic neurons in medullary raphe as the central target region of orexin. Then we confirmed that the inhibition of these neurons by inhibitory DREADD suppressed the orexin's thermoregulatory effect in mice with endotoxin shock. Furthermore, activation of serotonergic neurons helped restore body temperature and potentiated cardiovascular function in ePET1-Cre/FloxhM3 mice with septic shock. We concluded that peripheral administration of orexin activated the serotonergic system and helps the mice to survive and recover from septic shock.

Academic Significance and Societal Importance of the Research Achievements

敗血症の治療法の開発は重要な課題である。敗血症治療は、感染症に対する感染管理と、ショックに対する循環管理を中心とした末梢からのアプローチによるもので、未だに有効性は示されていない。オレキシンによる中枢神経系を標的とした治療法は、これらの病態に対して包括的にアプローチできる可能性がある。また既存の治療法とは作用部位が根本的に異なるために、既知の治療法との併用による相加・相乗効果が期待できる。さらに、オレキシンの標的部位としてのセロトニンニューロンの役割が解明されれば、新たな治療法開発へと繋がる。また、開発中の低分子量オレキシン受容体作動薬が新たな敗血症治療薬となる可能性が期待される。

Report

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

    (16 results)

All 2019 2018 2017 2016 Other

All Journal Article (2 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 1 results,  Open Access: 1 results,  Acknowledgement Compliant: 1 results) Presentation (12 results) (of which Int'l Joint Research: 3 results) Remarks (2 results)

  • [Journal Article] Development of a Therapeutic Drug for Narcolepsy2018

    • Author(s)
      Yoko Irukayama-Tomobe and Masashi Yanagisawa
    • Journal Title

      BRAIN and NERVE

      Volume: 70 Pages: 1255-63

    • Related Report
      2018 Annual Research Report
  • [Journal Article] Peripherally administered orexin improves survival of mice with endotoxin shock.2016

    • Author(s)
      Ogawa Y, Irukayama-Tomobe Y, Murakoshi N, Kiyama M, Ishikawa Y, Hosokawa N, Tominaga H, Uchida S, Kimura S, Kanuka M, Morita M, Hamada M, Takahashi S, Hayashi Y, Yanagisawa M.
    • Journal Title

      Elife.

      Volume: 5 Pages: 1-18

    • DOI

      10.7554/elife.21055

    • NAID

      120007135042

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Presentation] 自発的なめ行動による即時的かつ定量的なストレスフリー経口投与法 (PERO法) の確立2019

    • Author(s)
      高橋恵理矢、榎本杏子、滑川由紀子、入鹿山容子、柳沢正史
    • Organizer
      第92回 日本薬理学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 新規低分子量オレキシン2型受容体作動薬、YNT-Xの薬理作用2019

    • Author(s)
      滑川由紀子、入鹿山容子、小川靖裕、石川由紀子、山口拓土、アキンデレ チト、斉藤毅、長瀬博、柳沢正史
    • Organizer
      第92回 日本薬理学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 単一細胞レベルでのカルシウム反応計測における最適化条件の確立2018

    • Author(s)
      石川有紀子、入鹿山容子、小川靖裕、斉藤毅、長瀬博、柳沢正史
    • Organizer
      日本生理学会大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Orexin agonist improves inflammation-induced immobility2018

    • Author(s)
      Shuntaro Uchida, Yoko Irukayama-Tomobe, Yasuhiro Ogawa, Takuto Yamaguchi, Yukiko Ishikawa, Shingo Soya, Tsuyoshi Saito, Hiroshi Nagase, Masashi Yanagisawa, Takeshi Sakurai
    • Organizer
      World Congress of Basic and Clinical Pharmacology
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Non-peptidic Orexin receptor type-2 agonist attenuates body weight gain of high-fat fed mice2018

    • Author(s)
      Eriya Takahashi*, Kyoko Enomoto, Takuto Yamaguchi, Yasuhiro Ogawa, Shoji Fukusumi, Akari Kawai, Masaya Araki, Tsuyoshi Saitoh, Yoshimi Nakagawa,Yoko Irukayama-Tomobe, Hitoshi Shimano, Hiroshi Nagase, Masashi Yanagisawa
    • Organizer
      The 41st Annual Meeting of the Japan Neuroscience Society
    • Related Report
      2018 Annual Research Report
  • [Presentation] A synthetic orexin agonist improves inflammation-induced immobility through activating the medullary raphe nucleus2018

    • Author(s)
      Shuntaro Uchida, Yoko Irukayama-Tomobe, Yasuhiro Ogawa, Takuto Yamaguchi, Yukiko Ishikawa, Katsuyasu Sakurai, Shingo Soya, Tsuyoshi Saito, Hiroshi Nagase, Masashi Yanagisawa, Takeshi Sakurai
    • Organizer
      Neuroscience 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 1,3,5-Trioxazatriquinane骨格を有するトリマーの合成とオレキシン受容体拮抗活性評価2018

    • Author(s)
      雨澤真櫻、堀内淳平、斉藤毅、大下隆一郎、石川有紀子、入鹿山容子、小川靖裕、長谷川恵美、南雲康行、山本直司、沓村憲樹、早川大地、渡邉友里江、合田浩明、櫻井武、柳沢正史、長瀬博
    • Organizer
      薬学会関東部会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Orexin agonist improves inflammation-induced immobility2018

    • Author(s)
      Shuntaro Uchida, Yoko Irukayama-Tomobe, Yasuhiro Ogawa, Takuto Yamaguchi, Katsuyasu Sakurai, Shingo Soya, Tsuyoshi Saito, Hiroshi Nagase, Masashi Yanagisawa, Takeshi Sakurai
    • Organizer
      WCP 2018, 18th World Congress of Basic and Clinical Pharmacology(第18回 国際薬理学・臨床薬理学会議)
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] A small molecule orexin receptor agonist promotes recovery from inflammation-induced immobility2017

    • Author(s)
      内田 俊太郎、入鹿山 容子、小川 靖裕、富永 拡、石川 ゆい、木山 麻衣子、斉藤 毅、長瀬 博、柳沢 正史
    • Organizer
      薬理学会年会(第90回)
    • 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] Histological and electrophysiological analysis of small-molecule OX2R-selective agonist YNT-1852017

    • Author(s)
      小川 靖裕、入鹿山 容子、富永 拡、細川 直人、斉藤 毅、長瀬 博、柳沢 正史
    • Organizer
      薬理学会年会(第90回)
    • 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] Transgenic overexpression of orexin improves survival after myocardial infarction in mice2017

    • Author(s)
      石川 ゆい、村越 伸行、入鹿山 容子、小川 靖裕、内田 俊太郎、富永 拡、田尻 和子、長瀬 博、柳沢 正史
    • Organizer
      薬理学会年会(第90回)
    • 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] Orexin agonist improves inflammation-induced immobility2017

    • Author(s)
      Shuntaro Uchida, Yoko Irukayama-Tomobe, Yasuhiro Ogawa, Takuto Yamaguchi, Yukiko Namekawa, Ryo Fukai, Tsuyoshi Nemoto, Hiromu Tominaga, Yukiko Ishikawa, Katsuyasu Sakurai, Shingo Soya, Tsuyoshi Saito, Hiroshi Nagase, Masashi Yanagisawa, Takeshi Sakurai.
    • Organizer
      The 6th Annual IIIS Symposium
    • Related Report
      2017 Research-status Report
  • [Remarks] 筑波大学 注目の研究

    • URL

      http://www.tsukuba.ac.jp/attention-research/p201701271147.html

    • Related Report
      2016 Research-status Report
  • [Remarks] 朝日新聞デジタル

    • URL

      http://www.asahi.com/articles/ASK2J2JNWK2JUBQU00M.html

    • Related Report
      2016 Research-status Report

URL: 

Published: 2016-04-21   Modified: 2020-03-30  

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