Importance of histamine metabolizing enzyme in the brain

• Project/Area Number: 16K18389
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Tohoku University
• Principal Investigator: Yoshikawa Takeo 東北大学, 医学系研究科, 准教授 (70506633)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: ヒスタミン / ヒスタミン代謝酵素 / ヒスタミン神経系

Outline of Final Research Achievements

HIstamine acts as a neurotransmitter in the central nervous system. In this study,I examined the importance of a histamine metabolizing enzyme for brain functions. I revealed the essential role of this enzyme in the regulation of brain histamine and the contribution to brain functions such as sleep-wake cycle and aggression. Previous reports showed that brain histamine concentration was decreased in various brain diseases. Thus, I tried to develop new inhibitors against the histamine metabolizing enzyme to increase brain histamine concentration. I have confirmed that several compounds have sufficient inhibitory effects on the histamine metabolizing enzyme.

Research Products

• [Journal Article] Heparan sulfate in pancreatic β-cells contributes to normal glucose homeostasis by regulating insulin secretion. (2018)
  • Author(s): Matsuzawa T, Yoshikawa T, Iida T, Karpati A, Kitano H, Harada R, Nakamura T, Sugawara A, Yamaguchi Y, Yanai K.
  • Journal Title: Biochem Biophys Res Commun Volume: - Issue: 3 Pages: 688-695
  • DOI: 10.1016/j.bbrc.2018.03.213
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Histamine N-methyltransferase regulates aggression and the sleep-wake cycle (2017)
  • Author(s): Naganuma Fumito、Nakamura Tadaho、Yoshikawa Takeo、Iida Tomomitsu、Miura Yamato、Karpati Aniko、Matsuzawa Takuro、Yanai Atushi、Mogi Asuka、Mochizuki Takatoshi、Okamura Nobuyuki、Yanai Kazuhiko
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 15899-15899
  • DOI: 10.1038/s41598-017-16019-8
  • Peer Reviewed / Open Access
• [Journal Article] Activated Braf induces esophageal dilation and gastric epithelial hyperplasia in mice (2017)
  • Author(s): Inoue Shin-Ichi、Takahara Shingo、Yoshikawa Takeo、Niihori Tetsuya、Yanai Kazuhiko、Matsubara Yoichi、Aoki Yoko
  • Journal Title: Hum Mol Genet Volume: 26 Issue: 23 Pages: 4715-4727
  • DOI: 10.1093/hmg/ddx354
  • Peer Reviewed
• [Journal Article] JNJ10181457, a histamine H3 receptor inverse agonist, regulates in vivo microglial functions and improves depression-like behaviours in mice (2017)
  • Author(s): Iida Tomomitsu、Yoshikawa Takeo、Karpati Aniko、Matsuzawa Takuro、Kitano Haruna、Mogi Asuka、Harada Ryuichi、Naganuma Fumito、Nakamura Tadaho、Yanai Kazuhiko
  • Journal Title: Biochem Biophys Res Commun Volume: 488 Issue: 3 Pages: 534-540
  • DOI: 10.1016/j.bbrc.2017.05.081
  • Peer Reviewed
• [Journal Article] The clinical pharmacology of non-sedating antihistamines. (2017)
  • Author(s): Yanai K, Yoshikawa T, Yanai A, Nakamura T, Iida T, Leurs R, Tashiro M.
  • Journal Title: Pharmacol Ther. Volume: 178 Pages: 148-156
  • DOI: 10.1016/j.pharmthera.2017.04.004
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Induced histamine regulates Ni elution from an implanted Ni wire in mice by downregulating neutrophil migration. (2017)
  • Author(s): Kishimoto Y, Asakawa S, Sato T, Takano T, Nakajyo T, Mizuno N, Segawa R, Yoshikawa T, Hiratsuka M, Yanai K, Ohtsu H, Hirasawa N.
  • Journal Title: Exp Dermatol Volume: 印刷中 Issue: 10 Pages: 868-874
  • DOI: 10.1111/exd.13315
  • Peer Reviewed
• [Journal Article] Histamine clearance through polyspecific monoamine transporters in the brain (2017)
  • Author(s): Yoshikawa T and Yanaik
  • Journal Title: Handb Exp Pharmacol Volume: 印刷中 Pages: 173-187
  • DOI: 10.1007/164_2016_13
  • ISBN: 9783319581927, 9783319581941
  • Peer Reviewed
• [Journal Article] Synthesis and characterization of 18F-interleukin-8 using a cell-free translation system and 18F-fluoro-L-proline, Journal of Nuclear Medicine (2016)
  • Author(s): Ryuichi Harada, Shozo Furumoto, Takeo Yoshikawa, Yoichi Ishikawa, Katsutoshi Shibuya, Nobuyuki Okamura, Kiichi Ishiwata, Ren Iwata, Kazuhiko Yanai
  • Journal Title: Journal of Nuclear Medicine Volume: 57(4) Issue: 4 Pages: 634-639
  • DOI: 10.2967/jnumed.115.162602
  • Peer Reviewed
• [Presentation] ヒスタミン3型受容体インバースアゴニストはミクログリア機能を抑制しうつ様行動を改善する (2017)
  • Author(s): 飯田智光、吉川雄朗、谷内一彦
  • Organizer: 第21回日本ヒスタミン学会
• [Presentation] 脳内ヒスタミン神経系の過剰な興奮はH2受容体を介してマウスの攻撃性を増加させる (2017)
  • Author(s): 吉川雄朗、飯田智光、長沼史登、中村正帆、岡村信行、谷内一彦
  • Organizer: 第39回日本生物学的精神医学会・第47回日本神経精神薬理学会合同年会
• [Presentation] ヒスタミン-N-メチルトランスフェラーゼのin vivo機能解析 (2017)
  • Author(s): 中村 正帆、吉川 雄朗、岡村 信行
  • Organizer: 第68回日本薬理学会北部会
• [Presentation] 脳に効くヒスチジン摂取 (2017)
  • Author(s): 吉川雄朗
  • Organizer: 第60回日本神経化学学会
• [Presentation] 骨格筋におけるヘパラン硫酸の役割について (2017)
  • Author(s): 吉川雄朗、茂木明日香、松澤拓郎、三浦大和、中村正帆、谷内一彦
  • Organizer: 第68回日本薬理学会北部会
• [Presentation] Importance of histamine N-methyltransferase in brain functions (2016)
  • Author(s): Takeo Yoshikawa, Fumito Naganuma, Tadaho Nakamura, Takatoshi Mochizuki, Tomomitsu Iida, Aniko Karpati, Takuro Matsuzawa, Kazuhiko Yanai
  • Organizer: 第39回日本神経科学大会
  • Place of Presentation: 横浜（パシフィコ横浜）
  • Year and Date: 2016-07-20
• [Presentation] Astrocytes elevate glutamate release in response to histamine (2016)
  • Author(s): Aniko Karpati, Takeo Yoshikawa, Tadaho Nakamura, Fumito Naganuma, Tomomitsu Iida, Yamato Miura, Kazuhiko Yanai
  • Organizer: 第39回日本神経科学大会
  • Place of Presentation: 横浜（パシフィコ横浜）
  • Year and Date: 2016-07-20
• [Presentation] Histamine N-methyltransferase is important for the normal sleep-wake cycles and aggression through the regulation of brain histamine concentration. (2016)
  • Author(s): Fumito Naganuma, Takeo Yoshikawa, Tadaho Nakamura, Kazuhiko Yanai
  • Organizer: 30th CINP world congress of neuropsychopharmacology
  • Place of Presentation: 韓国 ソウル
  • Year and Date: 2016-07-03
  • Int'l Joint Research
• [Presentation] Electroencephalogram of H1KO mice under isoflurane anesthesia. (2016)
  • Author(s): Tadaho, Nakamura, Takeo Yoshikawa, Fumito Naganuma, Tomomitsu Iida, Aniko Karpati, Toru Tamii, Nobuyuki Okamura, Kazuiko Yanai
  • Organizer: European Histamine Research Society 45th annual meeting
  • Place of Presentation: イタリア Florence
  • Year and Date: 2016-05-11
  • Int'l Joint Research
• [Presentation] 神経障害性疼痛におけるヒスタミン3型受容体の役割について (2016)
  • Author(s): 松澤拓郎、Mogilevskaya Maria、吉川雄朗、中村正帆、谷内一彦
  • Organizer: 第67回日本薬理学会北部会
  • Place of Presentation: 札幌（北海道大学）