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The investigation between depression and interleukin 18 targeting for new therapy.

Research Project

Project/Area Number 17K16404
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Psychiatric science
Research InstitutionHyogo Medical University

Principal Investigator

Yamanishi Kyosuke  兵庫医科大学, 医学部, 特任助教 (50626786)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2019: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywordsインターロイキン18 / IL-18 / depression / mitochondria / hippocampas / neurogenesis / learning and memory / hippocampus / interleukin-18 / 精神医学 / うつ病 / 海馬 / 神経科学
Outline of Final Research Achievements

IL-18-deficient (Il18-/-) male mice were generated and Il18+/+ mice were used as controls. Compared with Il18+/+ mice, Il18-/- mice had impaired learning and memory and exhibited lower motivation. In the Il18-/- mice, degenerated mitochondria were detected in synaptic terminals in the molecular layer, the polymorphic layer, and in mossy fibers in the dentate gyrus, suggesting mitochondrial abnormalities. Because of the degeneration of mitochondria, in which pro-apoptotic molecules were upregulated and anti-apoptotic factors were decreased, apoptosis inducers were not cleaved, indicating inhibition of apoptosis. In addition, neurogenesis in the dentate gyrus and the maturity of neuronal cells were decreased in the Il18-/- mice, while intracerebral administration of recombinant IL-18 promoted significant recovery of neurogenesis. Our findings suggested that IL-18 was indispensable for mitochondrial homeostasis, normal neuronal maturation and hippocampal function.

Academic Significance and Societal Importance of the Research Achievements

炎症性サイトカインのインターロイキン18(IL-18)は、免疫機能に深く関与しているが、近年うつ病との関連も言われている。本研究よりIL-18が中枢神経細胞に深い関わりがあり、IL-18が欠損する事で海馬機能不全を呈し、記銘力障害、抑うつ様行動変化等の精神症状を呈し、IL-18を補うことで一部の改善を認めた事を報告した。抑うつやストレスが関わる精神疾患に対するIL-18の治療標的の可能性を探る目的で行い、治療満足度の低いうつ病に新たな治療法につながる可能性を示唆した。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (12 results)

All 2019 2018 2017

All Journal Article (2 results) (of which Peer Reviewed: 2 results,  Open Access: 1 results) Presentation (10 results) (of which Int'l Joint Research: 6 results)

  • [Journal Article] Interleukin-18-deficient mice develop hippocampal abnormalities related to possible depressive-like behaviors2019

    • Author(s)
      Yamanishi Kyosuke, Doe Nobutaka, Mukai Keiichiro, Ikubo Kaoru, Hashimoto Takuya, Uwa Noriko, Sumida Miho, El-Darawish Yosif, Gamachi Naomi, Li Wen, Kuwahara-Otani Sachi, Maeda Seishi, Watanabe Yuko, Hayakawa Tetsu, Yamanishi Hiromichi, Matsuyama Tomohiro, Yagi Hideshi, Okamura Haruki, & Matsunaga Hisato
    • Journal Title

      Neuroscience

      Volume: 408 Pages: 147-160

    • DOI

      10.1016/j.neuroscience.2019.04.003

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Analysis of genes linked to depressive-like behaviors in interleukin?18?deficient mice: Gene expression profiles in the brain2019

    • Author(s)
      Yamanishi Kyosuke、Hashimoto Takuya、Miyauchi Masahiro、Mukai Keiichiro、Ikubo Kaoru、Uwa Noriko、Watanabe Yuko、Ikawa Takashi、Okuzaki Daisuke、Okamura Haruki、Yamanishi Hiromichi、Matsunaga Hisato
    • Journal Title

      Biomedical Reports

      Volume: 12(1) Pages: 3-10

    • DOI

      10.3892/br.2019.1259

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] IL-18 の欠損状態がうつ病など精神症状発現に及ぼす影響について~神経再生と Epigenetics な 視点から~2019

    • Author(s)
      山西 恭輔、土江 伸誉、橋本 卓也、井窪 薫、向井 馨一郎、李 文、渡辺 優子、 宇和 典子、山西 博道、岡村 春樹、松永 寿人
    • Organizer
      第115回日本精神神経学会学術総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Epigenetic analysis of depression-like behavior in interleukin-18-deficient mice.2019

    • Author(s)
      K. Yamanishi, K. Mukai, T. Hashimoto, M. Miyauchi, K. Ikubo, N. Uwa, Y. Watanabe, C. Yamanishi, H. Okamura, H. Matsunaga
    • Organizer
      24th International Symposium on Molecular Medicine
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Molecular analysis causing depressive-like behaviors in interleukin-18-deficient mice: Gene expression profiles in the brain.2019

    • Author(s)
      T. Ikawa, K. Yamanishi, K. Mukai, T. Hashimoto, M. Miyauchi, K. Ikubo, N. Uwa, Y. Watanabe, C. Yamanishi, H. Okamura, H. Matsunaga
    • Organizer
      24th International Symposium on Molecular Medicine
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Neurogenesis and histone acetylation are associated with hippocampal abnormalities and depression-like behavioral changes in interleukin-18-deficient mice2019

    • Author(s)
      Kyosuke Yamanishi, Takuya Hashimoto, Kaoru Ikubo, Keiichiro Mukai, Noriko Uwa, Wen Li, Yuko Watanabe, Hiromichi Yamanishi, Haruki Okamura, and Hisato Matsunaga
    • Organizer
      14th World Congress of Biological Psychiatry
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] インターロイキン18 (IL-18) の欠損状態がうつ病など精神症状発現に及ぼす影響について~免疫と精神のクロストーク~2018

    • Author(s)
      山西恭輔、土江伸誉、橋本卓也、井窪薫、澄田美保、大谷(桑原)佐知、前田誠司、李文、渡辺優子、宇和典子、早川徹、山西博道、岡村春樹、松永寿人
    • Organizer
      第114回日本精神神経学会学術総会
    • Related Report
      2018 Research-status Report
  • [Presentation] An investigation regarding the causal effect of interleukin-18-deficient condition on hippocampal abnormalities and depression-like behavioral changes2018

    • Author(s)
      Kyosuke Yamanishi, Nobutaka Doe, Keiichiro Mukai, Kaoru Ikubo, Takuya Hashimoto, Noriko Uwa, Miho Sumida, Haruki Okamura, and Hisato Matsunaga
    • Organizer
      WFSBP 2018 KOBE
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Histone acetylation and neurogenesis are associated with hippocampal abnormalities in interleukin-18-deficient mice.2018

    • Author(s)
      Kyosuke Yamanishi, Nobutaka Doe, Kaoru Ikubo, Miho Sumida, Sachi Kuwahara-Otani, Seishi Maeda, Yuko Watanabe, Momoko Yoshida, Wen Li, Tetsu Hayakawa, Haruki Okamura, Hiromichi Yamanishi, Hisato Matsunaga
    • Organizer
      22nd International Symposium on Molecular Medicine
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Interleukin-18-deficient mice develop dysfunction of hippocampus resulting in depression-like behavior2017

    • Author(s)
      Kyosuke Yamanishi, Nobutaka Doe, Kaoru Ikubo, Miho Sumida, Sachi Kuwahara-Otani, Seishi Maeda, Yuko Watanabe, Momoko Yoshida, Wen Li, Tetsu Hayakawa, Haruki Okamura, Hiromichi Yamanishi, Hisato Matsunaga
    • Organizer
      WPA XVII World Congress of Psychiatry
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] 山西恭輔、松永寿人、土江伸誉、橋本卓也、井窪薫、澄田美保、大谷(桑原)佐知、前田誠司、李文、渡辺優子、宇和典子、早川徹、 山西博道、岡村春樹2017

    • Author(s)
      IL18 の欠損状態がうつ病など精神症状発現に及ぼす影響について~IL18 欠損 マウスを用いた多角的検討~
    • Organizer
      第113回日本精神神経学会学術総会
    • Related Report
      2017 Research-status Report
  • [Presentation] 山西恭輔、松永寿人、土江伸誉、橋本卓也、井窪薫、澄田美保、大谷(桑原)佐知、前田誠司、李文、渡辺優子、宇和典子、早川徹、 山西博道、岡村春樹2017

    • Author(s)
      IL18 の欠損状態がうつ病など精神症状発現に及ぼす影響について~IL18 欠損 マウスを用いた多角的検討~
    • Organizer
      医療心理懇話会 第2回
    • Related Report
      2017 Research-status Report

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Published: 2017-04-28   Modified: 2021-02-19  

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