Prevention of schizophrenia based on Keap1-Nrf2 system

• Project/Area Number: 17H04243
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Psychiatric science
• Research Institution: Chiba University
• Principal Investigator: Hashimoto Kenji 千葉大学, 社会精神保健教育研究センター, 教授 (10189483)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥15,860,000 (Direct Cost: ¥12,200,000、Indirect Cost: ¥3,660,000); Fiscal Year 2020: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2019: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2018: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2017: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
• Keywords: 統合失調症 / うつ病 / 炎症 / 栄養学 / 脳-腸相関 / 予防 / 酸化的ストレス / 自閉症 / 脳・神経疾患

Outline of Final Research Achievements

A number of epidemiological studies suggest that maternal immune activation can increase the risk of autism spectrum disorder and schizophrenia in offspring. In this study, we reported that dietary intake of Nrf2 activator glucoraphanin during pregnancy and lactation can prevent the onset of behavioral abnormalities in offspring. Furthermore, We found that maternal exposure of glyphosate can cause behavioral abnormalities in offspring of mouse, and that administration of soluble epoxide hydrolase inhibitor TPPU could prevented the onset of behavioral abnormalities in offspring. In this study, we proposed that maternal nutrition plays an important role in the mental health of offspring.

Academic Significance and Societal Importance of the Research Achievements

妊娠期のストレス等による母体の免疫活性化が、子供のメンタルヘルスに影響を及ぼすことが知られている。今回、マウスを用いた研究において、妊娠期の栄養、すなわち抗炎症作用を有する食事が、生まれてくる子供のメンタルヘルスの異常を予防できる可能性を示唆した。
2019年末からの新型コロナウイルス感染の猛威によるストレスが大きな社会問題になっており、栄養学の視点から、ストレスに対するレジリエンスな体にすることが、子供のメンタルヘルスに好影響を与える可能性を示唆しており、社会的意義のある研究成果である。

Research Products

• [Int'l Joint Research] カリフォルニア大学デービス校(米国)
• [Int'l Joint Research] Jinan University(中国)
• [Int'l Joint Research] University of California at Davis(米国)
• [Journal Article] Activation of BDNF by transcription factor Nrf2 contributes to antidepressant-like actions in rodents (2021)
  • Author(s): Yao W, Lin S, Su J, Cao Q, Chen Y, Chen J, Zhang Z, Hashimoto K, Qi Q, Zhang J.
  • Journal Title: Trans Psychiatry Volume: 11 Issue: 1 Pages: 140-140
  • DOI: 10.1038/s41398-021-01261-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Repurposing of CNS drugs to treat COVID-19 infection: targeting the sigma-1 receptor (2021)
  • Author(s): Hashimoto K
  • Journal Title: Eur Arch Psychiatry Clin Neurosci Volume: 271 Issue: 2 Pages: 249-258
  • DOI: 10.1007/s00406-020-01231-x
  • Peer Reviewed / Open Access
• [Journal Article] Risk of neuropsychiatric disorders in offspring of COVID-19-infected pregnant women and nutritional intervention (2021)
  • Author(s): Hashimoto K
  • Journal Title: Eur Arch Psychiatry Clin Neurosci Volume: 271 Issue: 2 Pages: 387-389
  • DOI: 10.1007/s00406-020-01148-5
  • Peer Reviewed / Open Access
• [Journal Article] Dietary intake of glucoraphanin during pregnancy and lactation prevents the behavioral abnormalities in the offspring after maternal immune activation (2020)
  • Author(s): Fujita Y, Hashimoto K
  • Journal Title: Neuropsychopharmacol Rep Volume: 40 Issue: 3 Pages: 268-274
  • DOI: 10.1002/npr2.12112
  • Peer Reviewed / Open Access
• [Journal Article] Maternal glyphosate exposure causes autism-like behaviors in offspring through increased expression of soluble epoxide hydrolase (2020)
  • Author(s): Pu Y, Yang J, Chang L, Qu Y, Wang S, Zhang K, Xiong Z, Zhang J, Tan Y, Wang X, Fujita Y, Ishima T, Wan D, Hwang SH, Hammock BD, Hashimoto K
  • Journal Title: Proc Natl Acad Sci USA Volume: 117 Issue: 21 Pages: 11753-11759
  • DOI: 10.1073/pnas.1922287117
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Current status of potential therapeutic candidates for the COVID-19 crisis (2020)
  • Author(s): Zhang J, Xie B, Hashimoto K
  • Journal Title: Brain Behav Immun Volume: 87 Pages: 59-73
  • DOI: 10.1016/j.bbi.2020.04.046
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Recent advances in the eraly intervention in schizophrenia: future direction from preclinical findings. (2019)
  • Author(s): Hashimoto K.
  • Journal Title: Current Psychiatry Reports Volume: 21 Issue: 8 Pages: 75-75
  • DOI: 10.1007/s11920-019-1063-7
  • Peer Reviewed
• [Journal Article] Dietary intake of glucoraphanin prevents the reduction of dopamine transporter in the mouse striatum after repeated administration of MPTP (2019)
  • Author(s): Pu Y, Qu Y, Chang L, Wang S, Zhang K, Ushida Y, Suganuma H, Hashimoto K
  • Journal Title: Neuropsychopharmacology Report Volume: 39 Issue: 3 Pages: 247-251
  • DOI: 10.1002/npr2.12060
  • Peer Reviewed / Open Access
• [Journal Article] Key role of soluble epoxide hydrolase in the neurodevelopmental disorders of offspring after maternal immune activation (2019)
  • Author(s): Ma Min、Ren Qian、Yang Jun、Zhang Kai、Xiong Zhongwei、Ishima Tamaki、Pu Yaoyu、Hwang Sung Hee、Toyoshima Manabu、Iwayama Yoshimi、Hisano Yasuko、Yoshikawa Takeo、Hammock Bruce D.、Hashimoto Kenji
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 116 Issue: 14 Pages: 7083-7088
  • DOI: 10.1073/pnas.1819234116
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Keap1-Nrf2 signaling pathway confers resilience versus susceptibility to inescapable electric stress. (2018)
  • Author(s): Zhang JC, Yao W, Dong C, Han M, Shirayama Y, Hashimoto K
  • Journal Title: Eur ARch psychiatry Clin Neurosci Volume: 268(8) Issue: 8 Pages: 865-870
  • DOI: 10.1007/s00406-017-0848-0
  • Peer Reviewed
• [Journal Article] Essential Role of Keap1-Nrf2 Signaling in Mood Disorders: Overview and Future Perspective. (2018)
  • Author(s): Hashimoto K
  • Journal Title: Front Pharmacol Volume: 9 Pages: 1182-1182
  • DOI: 10.3389/fphar.2018.01182
  • Peer Reviewed / Open Access
• [Journal Article] Soluble epoxide hydrolase plays a key role in the pathogenesis of Parkinson’s disease (2018)
  • Author(s): Ren Qian、Ma Min、Yang Jun、Nonaka Risa、Yamaguchi Akihiro、Ishikawa Kei-ichi、Kobayashi Kenta、Murayama Shigeo、Hwang Sung Hee、Saiki Shinji、Akamatsu Wado、Hattori Nobutaka、Hammock Bruce D.、Hashimoto Kenji
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 115 Issue: 25
  • DOI: 10.1073/pnas.1802179115
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dietary glucoraphanin prevents the onset of psychosis in the adult offspring after maternal immune activation (2018)
  • Author(s): Matsuura Akiko、Ishima Tamaki、Fujita Yuko、Iwayama Yoshimi、Hasegawa Shunsuke、Kawahara-Miki Ryouka、Maekawa Motoko、Toyoshima Manabu、Ushida Yusuke、Suganuma Hiroyuki、Kida Satoshi、Yoshikawa Takeo、Iyo Masaomi、Hashimoto Kenji
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 2158-2158
  • DOI: 10.1038/s41598-018-20538-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Sulforaphane: A prophylactic natural compound for psychiatric disorders. (2018)
  • Author(s): Kenji Hashimoto
  • Organizer: The 8th Mind-Body Interface International Symposium
  • Int'l Joint Research / Invited
• [Presentation] Sulforaphane as prophylactic compound for the onset of depression and psychosis (2017)
  • Author(s): Kenji Hashimoto
  • Organizer: ISNPR2017
  • Int'l Joint Research
• [Remarks] 千葉大学社会精神保健教育研究センター
  • URL: https://www.m.chiba-u.ac.jp/class/shakai/jp/index.html