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

• Project/Area Number: 17K16404
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Psychiatric science
• Research Institution: Hyogo 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: ¥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。

Research Products

• [Journal Article] Interleukin-18-deficient mice develop hippocampal abnormalities related to possible depressive-like behaviors (2019)
  • 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
  • Peer Reviewed
• [Journal Article] Analysis of genes linked to depressive-like behaviors in interleukin?18?deficient mice: Gene expression profiles in the brain (2019)
  • 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
  • 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
• [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
  • 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
  • Int'l Joint Research
• [Presentation] Neurogenesis and histone acetylation are associated with hippocampal abnormalities and depression-like behavioral changes in interleukin-18-deficient mice (2019)
  • 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
  • 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
• [Presentation] An investigation regarding the causal effect of interleukin-18-deficient condition on hippocampal abnormalities and depression-like behavioral changes (2018)
  • 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
  • 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
  • Int'l Joint Research
• [Presentation] Interleukin-18-deficient mice develop dysfunction of hippocampus resulting in depression-like behavior (2017)
  • 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
  • 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
• [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