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Reactive oxygen species; physiological role in the brain

Research Project

Project/Area Number 19K22834
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 59:Sports sciences, physical education, health sciences, and related fields
Research InstitutionTokyo Metropolitan Geriatric Hospital and Institute of Gerontology

Principal Investigator

Endo Shogo  地方独立行政法人東京都健康長寿医療センター(東京都健康長寿医療センター研究所), 東京都健康長寿医療センター研究所, 研究部長 (60192514)

Co-Investigator(Kenkyū-buntansha) 柿澤 昌  京都大学, 薬学研究科, 准教授 (40291059)
Project Period (FY) 2019-06-28 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2020: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Fiscal Year 2019: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
KeywordsROS / 8-nitro-cGMP / 小脳 / 運動記憶 / 神経可塑性 / LTP/LTD / NO / 活性酸素種 / 記憶 / プルキンエ細胞 / cGMP / 一酸化窒素
Outline of Research at the Start

スポーツや日常の活動に伴い発生する活性酸素種は、生体分子の酸化修飾を介してガン化、細胞死、老化を招く「悪玉」であるとされている。一方で、生体は活性酸素種を積極的に産生する酵素を有しており、活性酸素種が何らかの生理的な役割を担うことが考えられる。そこで本研究では、活性酸素種の「善玉」としての役割に着目し、特に小脳を介した運動記憶および神経可塑性への活性酸素種の関与を解明する。

Outline of Final Research Achievements

Reactive Oxygen Species (ROS) damages DNA and proteins through their chemical modifications. Because these lead to cell death, cancer and aging-related physiological issues in our body, ROS is thought to be “harmful molecule” in our common knowledge. On the other hand, recent studies suggest ROS plays physiological roles in cells and tissues. In this study, using biochemical and electrophysiological techniques, and behavioral and imaging analyses, we examined ROS's roles in cerebellum and found followings; 1) ROS generated by physiological patterns of neuronal activities; 2) ROS is involved in cerebellum-dependent motor memory and neuronal plasticity; 3) ROS-8-nitro-cGMP pathway affects the neuronal plasticity direction in a calcium-dependent manner in Purkinje cells. The results indicate that ROS is “physiological messenger” and is involved in higher brain functions. Future studies may clarify mechanism of ROS production and ROS-dependent long-term memory based on this study.

Academic Significance and Societal Importance of the Research Achievements

抗酸化物質(ビタミンC やEなど)は、ROSが招く老化やガンなどの悪玉作用を抑制するとして抗加齢や健康増進のために補助食品として広く一般に用いられている。一方で、通常の食事を摂ればこの様な補助食品は不要であるとも報告されている。本研究では、脳においてROSが神経可塑性、運動記憶に重要であることを示した。そして、過剰なビタミンC/EやROSを除去する物質の投与が可塑性や記憶を阻害することも示した。したがって、ROSは必ずしも除去すれば良いわけでは無く、抗酸化物質の利用や過剰摂取に注意を要することが考えられる。

Report

(3 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • Research Products

    (39 results)

All 2021 2020 2019 Other

All Int'l Joint Research (2 results) Journal Article (14 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 10 results,  Open Access: 8 results) Presentation (20 results) (of which Int'l Joint Research: 2 results,  Invited: 1 results) Remarks (2 results) Patent(Industrial Property Rights) (1 results)

  • [Int'l Joint Research] University of Munster(ドイツ)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] Catholic University of Argentina/Universidad Nacional de Quilmes(アルゼンチン)

    • Related Report
      2020 Annual Research Report
  • [Journal Article] Role of G-Substrate in the NO/cGMP/PKG Signal Transduction Pathway for Photic Entrainment of the Hamster Circadian Clock2021

    • Author(s)
      Plano Santiago Andr?s、Alessandro Mar?a Soledad、Trebucq Laura Luc?a、Endo Shogo、Golombek Diego Andr?s、Chiesa Juan Jos?
    • Journal Title

      ASN Neuro

      Volume: 13 Issue: 1 Pages: 175909142098492-175909142098492

    • DOI

      10.1177/1759091420984920

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Apelin2021

    • Author(s)
      Kakizawa S
    • Journal Title

      Handbook of Hormones (2nd Ed.)" (eds Ando H, Ukena K, Nagata S). Elsevier (Tokyo)

      Volume: 2

    • Related Report
      2020 Annual Research Report
  • [Journal Article] Functional maintenance of calcium store by ShcB adaptor protein in cerebellar Purkinje cells2020

    • Author(s)
      Kakizawa Sho、Kishimoto Yasushi、Yamamoto Shinichiro、Onga Kazuko、Yasuda Kunihiko、Miyamoto Yoshiaki、Watanabe Masahiko、Sakai Ryuichi、Mori Nozomu
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1 Pages: 1-16

    • DOI

      10.1038/s41598-020-71414-y

    • NAID

      120006988535

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Precise Regulation of the Basal PKCγ Activity by DGKγ Is Crucial for Motor Coordination2020

    • Author(s)
      Tsumagari Ryosuke、Maruo Kenta、Kakizawa Sho、Ueda Shuji、Yamanoue Minoru、Saito Hiromitsu、Suzuki Noboru、Shirai Yasuhito
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 21 Issue: 21 Pages: 21217866-21217866

    • DOI

      10.3390/ijms21217866

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] DGKγ Knock-Out Mice Show Impairments in Cerebellar Motor Coordination, LTD, and the Dendritic Development of Purkinje Cells through the Activation of PKCγ2020

    • Author(s)
      Tsumagari Ryosuke、Kakizawa Sho、Kikunaga Sakiko、Fujihara Yoshitaka、Ueda Shuji、Yamanoue Minoru、Saito Naoaki、Ikawa Masahito、Shirai Yasuhito
    • Journal Title

      eneuro

      Volume: 7 Issue: 2 Pages: 0319-19

    • DOI

      10.1523/eneuro.0319-19.2020

    • Related Report
      2020 Annual Research Report 2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Induction of ICER is superseded by smICER, challenging the impact of ICER under chronic beta‐adrenergic stimulation2020

    • Author(s)
      Seidl Matthias D.、Fels Benedikt、Kranick Daniel、Sternberg Alexandra、Grimm Kristina、St?mpel Frank T.、Pluteanu Florentina、Schulte Jan S.、Heinick Alexander、Kojima Nobuhiko、Endo Shogo、Huge Andreas、Stoll Monika、M?ller Frank U.
    • Journal Title

      The FASEB Journal

      Volume: 34 Issue: 8 Pages: 11272-11291

    • DOI

      10.1096/fj.201902301rr

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] 神経細胞レベルのシナプス可塑性(海馬と小脳におけるシナプス可塑性)2020

    • Author(s)
      遠藤昌吾
    • Journal Title

      ヒトの動きの神経科学シリーズ-IV- 運動学習の脳・神経科学(大築、鈴木、柳原編集)

      Volume: 4 Pages: 20-39

    • Related Report
      2020 Annual Research Report
  • [Journal Article] 認知症と老化に伴う記憶低下の予防と制御―細胞内シグナル伝達系を標的として―2020

    • Author(s)
      柳井修一・遠藤昌吾
    • Journal Title

      医学のあゆみ

      Volume: 273 Pages: 1095-1101

    • Related Report
      2020 Annual Research Report
  • [Journal Article] 記憶を守る2020

    • Author(s)
      遠藤昌吾
    • Journal Title

      内藤財団時報

      Volume: 105 Pages: 37-37

    • Related Report
      2019 Research-status Report
  • [Journal Article] Vitamin C and vitamin E double-deficiency increased neuroinflammation and impaired conditioned fear memory2019

    • Author(s)
      Takahashi Keita、Yanai Shuichi、Takisawa Shoko、Kono Nozomu、Arai Hiroyuki、Nishida Yoichiro、Yokota Takanori、Endo Shogo、Ishigami Akihito
    • Journal Title

      Archives of Biochemistry and Biophysics

      Volume: 663 Pages: 120

    • DOI

      10.1016/j.abb.2019.01.003

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] 8-Nitro-cGMP attenuates context-dependent fear memory in mice.2019

    • Author(s)
      Kishimoto Y, Kasamatsu S, Yanai S, Endo S, Akaike T, Ihara H.
    • Journal Title

      Biochem Biophys Res Commun

      Volume: 511 Issue: 1 Pages: 141-147

    • DOI

      10.1016/j.bbrc.2019.01.138

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] JunB plays a crucial role in development of regulatory T cells by promoting IL-2 signaling2019

    • Author(s)
      Katagiri Takaharu、Yamazaki Soh、Fukui Yuto、Aoki Kotaro、Yagita Hideo、Nishina Takashi、Mikami Tetuo、Katagiri Sayaka、Shiraishi Ayako、Kimura Soichiro、Tateda Kazuhiro、Sumimoto Hideki、Endo Shogo、Kameda Hideto、Nakano Hiroyasu
    • Journal Title

      Mucosal Immunology

      Volume: 12 Issue: 5 Pages: 1104-1117

    • DOI

      10.1038/s41385-019-0182-0

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] モデルマウスを用いた記憶障害メカニズムの解析2019

    • Author(s)
      遠藤昌吾
    • Journal Title

      ファルマシア

      Volume: 55 Pages: 859-863

    • NAID

      130007700026

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] TRPM7 channels mediate spontaneous Ca2+ fluctuations in growth plate chondrocytes that promote bone development.2019

    • Author(s)
      Qian N, Ichimura A, Takei D, Sakaguchi R, Kitani A, Nagaoka R, Tomizawa M, Miyazaki Y, Miyachi H, Numata T, Kakizawa S, Nishi M, Mori Y, Takeshima H.
    • Journal Title

      Science signaling

      Volume: 12 Issue: 576 Pages: 4847-4847

    • DOI

      10.1126/scisignal.aaw4847

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Ca2+とレドックスシグナルによる小脳シナプス可塑性の極性決定.2020

    • Author(s)
      柿澤 昌, 遠藤 昌吾.
    • Organizer
      生理学研究所 研究会「細胞システム理解のためのシグナル応答原理解明の最前線」, Web開催
    • Related Report
      2020 Annual Research Report
  • [Presentation] 活性酸素依存的なカルシウム恒常性システムの調節を介した小脳機能制御2020

    • Author(s)
      柿澤 昌
    • Organizer
      第94回日本薬理学会年会シンポジウム
    • Related Report
      2020 Annual Research Report
  • [Presentation] MAP kinase:ERK1/2遺伝子改変マウスを用いた小脳依存性記憶の解2020

    • Author(s)
      吉田彩乃、宮本武典、新崎智子、遠藤昌吾
    • Organizer
      第72回日本動物学会・関東支部大会, Web開催
    • Related Report
      2020 Annual Research Report
  • [Presentation] Involvement of reactive oxygen species (ROS) - 8-nitro-cGMP signals in cerebellar long-term depression.2020

    • Author(s)
      Kakizawa S., Endo S
    • Organizer
      The 12th Forum of European Neuroscience, Web開催
    • Related Report
      2020 Annual Research Report
  • [Presentation] Amelioration of age-related spatial memory impairment by concurrent administration of sub-effective doses of donepezil and cilostazol.2020

    • Author(s)
      S. Yanai, T. Arasaki, S. Endo
    • Organizer
      第43回日本基礎老化学会大会,誌上開催
    • Related Report
      2020 Annual Research Report
  • [Presentation] Inhibitory effect of tocotrienols on weight gain in different mouse models.2020

    • Author(s)
      Y. Kato, S. Endo, S. Yanai, K. Fukui.
    • Organizer
      第43回日本基礎老化学会大会,誌上開催
    • Related Report
      2020 Annual Research Report
  • [Presentation] Cilostazol, a phosphodiesterase 3 inhibitor, ameliorates spatial memory in APP knock-in mouse model of Alzheimer’s disease.2020

    • Author(s)
      S. Yanai, T. Arasaki, T. Saito, T. Saido, & S. Endo
    • Organizer
      第43回日本神経科学大会, Web開催
    • Related Report
      2020 Annual Research Report
  • [Presentation] PDE3阻害剤シロスタゾール:抗血小板薬から認知症治療薬へのドラッグ・リポジショニング2020

    • Author(s)
      柳井修一・新崎智子・遠藤昌吾
    • Organizer
      日本心理学会第84回大会,2020.9.8-11.2,Web開催
    • Related Report
      2020 Annual Research Report
  • [Presentation] 18F-標識ネオペンチルスチリルピリジンアミロイド-β PETプローブの生物学的評価.2020

    • Author(s)
      多胡哲郎・豊原潤・ソウエイソウ・龍田真帆・新崎智子・柳井修一・遠藤昌吾・斉藤貴志・西道隆臣・田中浩士
    • Organizer
      第60回日本核医学会学術総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] MAP kinase:ERK1/2遺伝子改変マウスを用いた小脳依存性記憶の解析2020

    • Author(s)
      吉田彩乃、宮本武典、新崎智子、遠藤昌吾
    • Organizer
      第72回日本動物学会・関東支部大会
    • Related Report
      2019 Research-status Report
  • [Presentation] PDE3阻害剤シロスタゾールによる血液脳関門・記憶機能の改善2019

    • Author(s)
      柳井修一、新崎智子、遠藤昌吾
    • Organizer
      第8回 TOBIRA研究交流フォーラム
    • Related Report
      2019 Research-status Report
  • [Presentation] 細胞外シグナル制御キナーゼ(ERK)5の疼痛シグナル制御における役割2019

    • Author(s)
      松浦史博, 板倉紗也子, 川口慎憲, 遠藤昌吾, 佐藤泰司, 石塚俊晶, 池田健彦
    • Organizer
      第53回日本ペインクリニック学会
    • Related Report
      2019 Research-status Report
  • [Presentation] Involvement of ROS - 8-nitro-cGMP signals in cerebellar long-term depression.2019

    • Author(s)
      Sho Kakizawa, Shogo Endo
    • Organizer
      第42回日本神経科学大会
    • Related Report
      2019 Research-status Report
  • [Presentation] Concurrent administration of sub-effective doses of donepezil and phosphodiesterase 3 inhibitor cilostazol restores memory impairment in aged mice.2019

    • Author(s)
      Shuichi YANAI, Tomoko Arasaki, Shogo Endo
    • Organizer
      第42回日本神経科学大会
    • Related Report
      2019 Research-status Report
  • [Presentation] レドックスシグナルによる小脳機能制御2019

    • Author(s)
      柿澤昌, 遠藤昌吾
    • Organizer
      生理学研究所 研究会「シグナル動態の可視化と操作に基づく多階層機能解析の新展開」
    • Related Report
      2019 Research-status Report
  • [Presentation] Cilostazol, a phosphodiesterase 3 inhibitor, improves blood-brain barrier integrity and ameliorates memory decline in senescence-accelerated mouse prone 8 (SAMP8).2019

    • Author(s)
      S.Yanai, T.Arasaki & S.Endo
    • Organizer
      「次世代脳」プロジェクト 冬のシンポジウム
    • Related Report
      2019 Research-status Report
  • [Presentation] Possible Involvement ROS in Physiological Aging through Inhibition of Protein S-nitrosylation of calcium channel2019

    • Author(s)
      Kakizawa Sho
    • Organizer
      The 19th Korea-Japan Joint Symposium for Basic Gerontology
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Construction and integration of the All-in-One type single double-conditional shRNA expression vectors for spatio-temporal gene and/or cell targeting2019

    • Author(s)
      Oyamada H, Ao Y, Kudo Y, Matsuoka T, Okamoto R, Murayama T, Yamazawa T, Kakizawa S, Oguchi T, Kimura A, Yasumoto T, Mori Y, Tsuji M, Oguchi K, Kiuchi Y
    • Organizer
      NEURO2019 第42回日本神経科学大会
    • Related Report
      2019 Research-status Report
  • [Presentation] 有酸素トレーニングが老齢マウス脳内のインスリン分解酵素のS-ニトロソ化に及ぼす影響2019

    • Author(s)
      張碩文・篠崎昇平・柳井修一・松本綾子・中本英子・小林裕幸・金木正夫・遠藤昌吾・後藤佐多良・内藤久士
    • Organizer
      第74回 日本体力医学会大会
    • Related Report
      2019 Research-status Report
  • [Presentation] Amelioration of potentially harmful oxidative and nitrosative protein modifications by regular exercise in aged animals: A molecular mechanism of the beneficial effects2019

    • Author(s)
      Sataro Goto, Shuo-wen Chang, Shohei Shinozaki, Shuichi Yanai, Hideko Nakamoto, Ayako Matsumoto, Hisashi Naito, Hiroyuki Kobayshi, Masao Kaneki, Shogo Endo, & Zsolt Radak
    • Organizer
      11th International Association of Gerontology and Geriatrics Asia/Oceania Regional Congress
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Remarks] 記憶神経化学、東京都老人研

    • URL

      https://www2.tmig.or.jp/Mn_B/Japanese/index.html

    • Related Report
      2020 Annual Research Report
  • [Remarks] 記憶神経科学、東京都老人研

    • URL

      https://www2.tmig.or.jp/Mn_B/Japanese/index.html

    • Related Report
      2019 Research-status Report
  • [Patent(Industrial Property Rights)] 加齢に伴う認知機能の低下予防又は改善用の組成物2020

    • Inventor(s)
      遠藤・柳井・飯田・新谷
    • Industrial Property Rights Holder
      遠藤・柳井・飯田・新谷
    • Industrial Property Rights Type
      特許
    • Filing Date
      2020
    • Related Report
      2020 Annual Research Report

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Published: 2019-07-04   Modified: 2022-01-27  

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