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The effects of the augmented non-neuronal cardiac cholinergic system on the central nervous system

Research Project

Project/Area Number 16K08560
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field General pharmacology
Research InstitutionNippon Medical School

Principal Investigator

Kakinuma Yoshihiko  日本医科大学, 大学院医学研究科, 大学院教授 (40233944)

Research Collaborator Muramoto Kazuyo  
Nemoto Takahiro  
Sugama Shuei  
Mano Asuka  
Ohata Hisayuki  
Tsuda Masayuki  
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: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywordsアセチルコリン / 心臓 / 心筋細胞 / エネルギー代謝 / 中枢神経系 / ACh / 非神経性心臓コリン作動系 / 迷走神経 / 抗うつ効果 / 中枢神経 / 非中枢性非神経性アセチルコリン産生系 / 抗うつ・抗ストレス / 非神経性コリン作動系(NNCCS) / acetylcholine (ACh) / 抗うつ作用 / 抗不安作用 / 抗ストレス作用 / 抗痙攣作用 / 非神経性コリン作働系
Outline of Final Research Achievements

Augmentation of the non-neuronal cardiac cholinergic system (NNCCS) plays a role in modifying the central nervous system (CNS) through the ascending vagus nerve, which is triggered to be activated by increased NO production in the heart. The CNS effects of NNCCS includes anti-anxiety like, anti-depression like, and anti-stress like effects as well as anti-convulsive effect. These effects induced by activated NNCCS means that the heart-brain axis, not the brain-to axis, exists when the NNCCS is activated. Therefore, NNCCS can be a crucial player to modify the CNS function. The ChAT gene overexpressing mice (ChAT tg) are considered to be mice, which seem to be subjected to vagus nerve stimulation.

Academic Significance and Societal Importance of the Research Achievements

心筋細胞でアセチルコリン(ACh)を産生するSystem(NNCCS)が、心臓のみならず中枢神経系にも大きな効果(抗不安、抗うつ、抗ストレス、抗痙攣誘発性)を引き起こすことが、明らかとなった。このことは、このシステムを亢進させると、現代病でもある、ストレスをより感じにくくし余計な負荷を中枢神経系にかけなくてすむことを示唆している。したがって、心臓のこのシステムを鍛えることが、健康増進させる手段となることを物語っている。

Report

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

    (30 results)

All 2019 2018 2017 2016 Other

All Int'l Joint Research (1 results) Journal Article (15 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 15 results,  Open Access: 3 results,  Acknowledgement Compliant: 4 results) Presentation (10 results) (of which Int'l Joint Research: 1 results,  Invited: 6 results) Book (1 results) Patent(Industrial Property Rights) (3 results)

  • [Int'l Joint Research] University of Otago(New Zealand)

    • Related Report
      2016 Research-status Report
  • [Journal Article] Evaluation of Teneligliptin Effects on Transcriptional Activity of PPARγ in Cell-Based Assays2018

    • Author(s)
      Takenaka Yasuhiro、Inoue Ikuo、Nakano Takanari、Ikeda Masaaki、Kakinuma Yoshihiko、Ikegami Yuichi、Shimada Akira、Noda Mitsuhiko
    • Journal Title

      Journal of Nippon Medical School

      Volume: 85 Issue: 2 Pages: 95-101

    • DOI

      10.1272/jnms.2018_85-15

    • NAID

      130006731178

    • ISSN
      1345-4676, 1347-3409
    • Year and Date
      2018-04-15
    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Murine remote preconditioning increases glucose uptake and suppresses gluconeogenesis in hepatocytes via a brain-liver neurocircuit, leading to counteracting glucose intolerance2018

    • Author(s)
      Kurabayashi Atsushi、Tanaka Chiharu、Matsumoto Waka、Naganuma Seiji、Furihata Mutsuo、Inoue Keiji、Kakinuma Yoshihiko
    • Journal Title

      Diabetes Research and Clinical Practice

      Volume: 139 Pages: 288-299

    • DOI

      10.1016/j.diabres.2018.03.009

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Involvement of Noncoding RNAs in Stress-Related Neuropsychiatric Diseases Caused by DOHaD Theory2018

    • Author(s)
      Nemoto Takahiro、Kakinuma Yoshihiko
    • Journal Title

      Adv Exp Med Biol

      Volume: 1012 Pages: 49-59

    • DOI

      10.1007/978-981-10-5526-3_6

    • ISBN
      9789811055256, 9789811055263
    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The non-neuronal cholinergic system in the heart: A comprehensive review2018

    • Author(s)
      Saw Eng Leng、Kakinuma Yoshihiko、Fronius Martin、Katare Rajesh
    • Journal Title

      Journal of Molecular and Cellular Cardiology

      Volume: 125 Pages: 129-139

    • DOI

      10.1016/j.yjmcc.2018.10.013

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Lack of interleukin-13 receptor α1 delays the loss of dopaminergic neurons during chronic stress.2017

    • Author(s)
      Mori S, Sugama S, Nguyen W, Michel T, Sanna MG, Sanchez-Alavez M, Cintron-Colon R, Moroncini G, Kakinuma Y, Maher P, Conti B.
    • Journal Title

      J Neuroinflammation

      Volume: 14 Issue: 1 Pages: 88-88

    • DOI

      10.1186/s12974-017-0862-1

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Various Regulatory Modes for Circadian Rhythmicity and Sexual Dimorphism in the Non-Neuronal Cardiac Cholinergic System.2017

    • Author(s)
      Oikawa S, Kai Y, Mano A, Ohata H, Nemoto T, Kakinuma Y.
    • Journal Title

      J Cardiovasc Transl Res

      Volume: 10 Issue: 4 Pages: 411-422

    • DOI

      10.1007/s12265-017-9750-4

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Novel channel-mediated choline transport in cholinergic neurons of the mouse retina.2017

    • Author(s)
      Ishii T, Homma K, Mano A, Akagi T, Shigematsu Y, Shimoda Y, Inoue H, Kakinuma Y, Kaneda M.
    • Journal Title

      J Neurophysiol.

      Volume: 118 Issue: 4 Pages: 1952-1961

    • DOI

      10.1152/jn.00506.2016

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Erratum to: Various Regulatory Modes for Circadian Rhythmicity and Sexual Dimorphism in the Non-Neuronal Cardiac Cholinergic System.2017

    • Author(s)
      Oikawa S, Kai Y, Mano A, Ohata H, Nemoto T, Kakinuma Y.
    • Journal Title

      J Cardiovasc Transl Res.

      Volume: 10 Issue: 4 Pages: 435-435

    • DOI

      10.1007/s12265-017-9760-2

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Corrigendum to "Chronic restraint stress triggers dopaminergic and noradrenergic neurodegeneration: Possible role of chronic stress in the onset of Parkinson's disease" [Brain Behav. Immun. 51 (2016) 39-46].2017

    • Author(s)
      Sugama S, Sekiyama K, Kodama T, Takamatsu Y, Takenouchi T, Hashimoto M, Conti B, Kakinuma Y.
    • Journal Title

      Brain Behav Immun.

      Volume: 61 Pages: 389-389

    • DOI

      10.1016/j.bbi.2016.12.009

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Letter to the Editor Re:"Reconsidering the role of glial cells in chronic stress-induced dopaminergic neurons loss within the substantia nigra? Friend of foe?" by Ong et al. Brain Behavior and Immunity, 2016.2017

    • Author(s)
      Sugama S, Kakinuma Y
    • Journal Title

      Brain Behav Immun

      Volume: 60 Pages: 383-383

    • DOI

      10.1016/j.bbi.2016.11.028

    • Related Report
      2017 Research-status Report 2016 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Non-neuronal cardiac cholinergic system influences CNS via the vagus nerve to acquire a stress-refractory propensity.2016

    • Author(s)
      Oikawa S, Kai Y, Tsuda M, Ohata H, Mano A, Mizoguchi N, Sugama S, Nemoto T, Suzuki K, Kurabayashi A, Muramoto K, Kaneda M, and Kakinuma Y.
    • Journal Title

      Clinical Science

      Volume: 130(21) Issue: 21 Pages: 1913-1928

    • DOI

      10.1042/cs20160277

    • Related Report
      2016 Research-status Report
    • Peer Reviewed
  • [Journal Article] Donepezil, an acetylcholinesterase inhibitor, attenuates LPS-induced inflammatory response in murine macrophage cell line RAW 264.7 through inhibition of nuclear factor kappa B translocation.2016

    • Author(s)
      Arikawa M, Kakinuma Y, Noguchi T, Todaka H, Sato T.
    • Journal Title

      Eur J Pharmacol.

      Volume: 789 Pages: 17-26

    • DOI

      10.1016/j.ejphar.2016.06.053

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Chronic restraint stress triggers dopaminergic and noradrenergic neurodegeneration: Possible role of chronic stress in the onset of Parkinson's disease2016

    • Author(s)
      Sugama S, Sekiyama K, Kodama T, Takamatsu Y, Takenouchi T, Hashimoto M, Conti B, Kakinuma Y
    • Journal Title

      Brain Behav Immun

      Volume: 51 Pages: 39-46

    • DOI

      10.1016/j.bbi.2015.08.015

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Loss of dopaminergic neurons occurs in the ventral tegmental area and hypothalamus of rats following chronic stress: Possible pathogenetic loci for depression involved in Parkinson's disease2016

    • Author(s)
      Sugama S, Kakinuma Y
    • Journal Title

      Neurosci Res

      Volume: 111 Pages: 48-55

    • DOI

      10.1016/j.neures.2016.04.008

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Distribution of Corticotrophin-Releasing Factor Type 1 Receptor-Like Immunoreactivity in the Rat Pituitary.2016

    • Author(s)
      Mano-Otagiri A, Nemoto T, Yamauchi N, Kakinuma Y, Shibasaki T.
    • Journal Title

      Journal of Neuroendocrinology

      Volume: 28 Issue: 12

    • DOI

      10.1111/jne.12440

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Remote ischemic preconditioning affects gluconeogenesis via the brain-liver route to improve glucose intolerance2019

    • Author(s)
      Kurabayashi A, Kakinuma Y
    • Organizer
      9th Federation of the Asian and Oceanian Physiological Societies
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 心臓非神経性ACh産生システムの臓器間クロストークとその生理機能学的意味2018

    • Author(s)
      柿沼 由彦
    • Organizer
      第28回日本病態生理学会大会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Modified regulation in the non-neuronal acetylcholine in the heart (NNCCS) by circadian rhythmicity and sexual dimorphism2018

    • Author(s)
      Kakinuma Y, Oikawa S, Kai Y, Mano A, Ohata H, Nemoto K
    • Organizer
      第95回日本生理学会大会
    • Related Report
      2018 Annual Research Report 2017 Research-status Report
  • [Presentation] 心筋自らがもつACh産生系 non-neuronal cardiac cholinergic systemとその脳心連関のもつ意義2017

    • Author(s)
      柿沼 由彦
    • Organizer
      第137回 日本薬理学会関東部会
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] 心筋自らがもつACh産生系 non-neuronal cardiac cholinergic systemとその脳心連関のもつ意義2017

    • Author(s)
      柿沼 由彦
    • Organizer
      横浜市立大学大学院医学セミナー
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] A stress-refractory propensity in the CNS is provided by augmented non-neuronal cardiac cholinergic system via the vagus nerve to acquire.2017

    • Author(s)
      Kakinuma Y, Oikawa S, Kaki Y, Tsuda M, Ohata H, Mano A, Mizoguchi N, Sugama S, Nemoto T, Suzuki K, Kurabayashi A, Muramoto K, Kaneda M.
    • Organizer
      第81回日本循環器学会学術集会
    • Place of Presentation
      石川県立音楽堂他
    • Related Report
      2016 Research-status Report
  • [Presentation] Non-neuronal cardiac cholinergic system induces central anti-stress responses.2017

    • Author(s)
      Kakinuma Y, Oikawa S, Kaki Y, Tsuda M, Ohata H, Mano A, Mizoguchi N, Sugama S, Nemoto T, Suzuki K, Kurabayashi A, Muramoto K, Kaneda M.
    • Organizer
      第94回日本生理学会大会
    • Place of Presentation
      浜松アクトシティコングレスセンター
    • Related Report
      2016 Research-status Report
  • [Presentation] 循環器領域においてa non-neuronal cholinergic systemが意味するもの2016

    • Author(s)
      柿沼由彦
    • Organizer
      長崎循環器疾患連携セミナー
    • Place of Presentation
      長崎ワシントンホテル
    • Related Report
      2016 Research-status Report
    • Invited
  • [Presentation] a non-neuronal cardiac cholinergic system (NNCCS)のモデルマウス から見えてきたもの2016

    • Author(s)
      柿沼由彦
    • Organizer
      第18回旭川心血管リモデリング研究会学術講演会
    • Place of Presentation
      旭川医科大学
    • Related Report
      2016 Research-status Report
    • Invited
  • [Presentation] 心臓自らが作り出すAChとは何か(a non-neuronal cardiac cholinergic system NNCCSの発見)2016

    • Author(s)
      柿沼由彦
    • Organizer
      第4回取手・守谷地区循環器講演会
    • Place of Presentation
      デュープレックスセミナーホテル
    • Related Report
      2016 Research-status Report
    • Invited
  • [Book] 心臓の力2016

    • Author(s)
      柿沼由彦
    • Total Pages
      221
    • Publisher
      講談社(ブルーバックス)
    • Related Report
      2016 Research-status Report
  • [Patent(Industrial Property Rights)] 生体内NO産生装置2018

    • Inventor(s)
      柿沼由彦、人見雄一、渡辺正広、長尾佳文
    • Industrial Property Rights Holder
      柿沼由彦、人見雄一、渡辺正広、長尾佳文
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2018-034042
    • Filing Date
      2018
    • Related Report
      2018 Annual Research Report
  • [Patent(Industrial Property Rights)] 心臓アセチルコリン産生能誘導薬2018

    • Inventor(s)
      柿沼由彦、中村成夫
    • Industrial Property Rights Holder
      柿沼由彦、中村成夫
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2018-185112
    • Filing Date
      2018
    • Related Report
      2018 Annual Research Report
  • [Patent(Industrial Property Rights)] 生体内NO産生装置2018

    • Inventor(s)
      柿沼 由彦
    • Industrial Property Rights Holder
      柿沼 由彦
    • Industrial Property Rights Type
      特許
    • Filing Date
      2018
    • Related Report
      2017 Research-status Report

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

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