Elucidation of molecular mechanism of orexin on the brain in endotoxin shock
Project/Area Number |
16K08541
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Research Field |
General pharmacology
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Research Institution | University 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)
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Co-Investigator(Kenkyū-buntansha) |
桜井 武 筑波大学, 医学医療系, 教授 (60251055)
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Research Collaborator |
Ogawa Yasuhiro
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Project Period (FY) |
2016-04-01 – 2019-03-31
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Project Status |
Completed (Fiscal Year 2018)
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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)
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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.
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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。
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Report
(4 results)
Research Products
(16 results)
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[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.
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Journal Title
Elife.
Volume: 5
Pages: 1-18
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
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[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
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[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
Int'l Joint Research
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[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
Int'l Joint Research
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[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
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