Development of functional molecule-targeted diagnostic and therapeutic agents for attention deficit hyperactivity disorder

• Project/Area Number: 16K10195
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Psychiatric science
• Research Institution: Fujita Health University
• Principal Investigator: Mouri Akihiro 藤田医科大学, 保健学研究科, 准教授 (20597851)
• Co-Investigator(Kenkyū-buntansha): 鍋島 俊隆 藤田医科大学, 保健学研究科, 客員教授 (70076751)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 注意欠如多動性障害 / 機能性分子 / プロスタグランディン / NMDA受容体 / Hispidulin / ADHD / NR1 / ドパミン / 前頭皮質 / AD/HD / ノルアドレナリン / モデル動物 / 機能分子 / 注意欠陥・多動性障害（ADHD） / プロスタグランジン / メチルフェニデート / アトモキセチン / 細胞外シグナル調節キナーゼ / 注意欠陥・多動性障害 / バイオマーカー

Outline of Final Research Achievements

Attention defect hyperactivity disorder (ADHD) is characterized by inattention, hyperactivity, impulsivity, and social deficit. But there are few ADHD model animals for development of therapeutic agents. In this study, We evaluated the phencyclidine (PCP)-treated mouse and EP1 knockout mouse as ADHD animal model and developed the anti-ADHD drug. Based on the behavioral and neurological experiments, anti-ADHD drug responsibility, PCP-treated mouse and the EP1 knockout mouse have good validities for ADHD animal model. We clarify that Hispidulin, which is a flavone isolated from Clerodendrum inerme (L.) Gaertn (CI), is effective for behavioral abnormalities in the PCP-treated mice.

Academic Significance and Societal Importance of the Research Achievements

これまでの注意欠如多動性障害（ADHD）の治療薬（メチルフェニデートとアトモキセチン）は前頭前皮質のドパミンやノルアドレナリンによる神経伝達を活性化させる。しかし、対症療法になるため、根本的なADHDの治療には至っていない。本研究では、ADHDの発症や病態に関与が示唆されているホルモンやサイトカインなどの機能分子を標的とし、分子生物学、神経化学および行動薬理学を駆使し、分子から神経細胞、さらに個体に至るまで包括的にADHDの発症機序と病態の解明を行った。その結果、ADHDの発症や病態に関連した機能分子（プロスタグランディン・NMDA受容体）を標的とした根本的な新規治療薬の開発を目指した。

Research Products

• [Int'l Joint Research] 国立台湾大学(その他の国・地域)
• [Journal Article] 5-HT1A receptor agonist 8-OH-DPAT induces serotonergic behaviors in mice via interaction between PKCδ and p47phox (2019)
  • Author(s): Tran Hai-Quyen、Shin Eun-Joo、Hoai Nguyen Bao-Chau、Phan Dieu-Hien、Kang Min-Ji、Jang Choon-Gon、Jeong Ji Hoon、Nah Seung-Yeol、Mouri Akihiro、Saito Kuniaki、Nabeshima Toshitaka、Kim Hyoung-Chun
  • Journal Title: Food and Chemical Toxicology Volume: 123 Pages: 125-141
  • DOI: 10.1016/j.fct.2018.10.049
  • Peer Reviewed / Open Access
• [Journal Article] Acute administration of ketamine attenuates the impairment of social behaviors induced by social defeat stress exposure as juveniles via activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (2019)
  • Author(s): Hasegawa Sho、Yoshimi Akira、Mouri Akihiro、Uchida Yoji、Hida Hirotake、Mishina Masayoshi、Yamada Kiyofumi、Ozaki Norio、Nabeshima Toshitaka、Noda Yukihiro
  • Journal Title: Neuropharmacology Volume: 148 Pages: 107-116
  • DOI: 10.1016/j.neuropharm.2018.12.020
  • Peer Reviewed
• [Journal Article] Linking phencyclidine intoxication to the tryptophan-kynurenine pathway: Therapeutic implications for schizophrenia (2019)
  • Author(s): Fujigaki Hidetsugu、Mouri Akihiro、Yamamoto Yasuko、Nabeshima Toshitaka、Saito Kuniaki
  • Journal Title: Neurochemistry International Volume: 125 Pages: 1-6
  • DOI: 10.1016/j.neuint.2019.02.001
  • Peer Reviewed
• [Journal Article] Juvenile social defeat stress exposure persistently impairs social behaviors and neurogenesis. (2018)
  • Author(s): Mouri A, Ukai M, Uchida M, Hasegawa S, Taniguchi M, Ito T, Hida H, Yoshimi A, Yamada K, Kunimoto S, Ozaki N, Nabeshima T, Noda Y.
  • Journal Title: Neuropharmacology. Volume: 133 Pages: 23-37
  • DOI: 10.1016/j.neuropharm.2018.01.016
  • Peer Reviewed / Open Access
• [Journal Article] Astroglial major histocompatibility complex class I following immune activation leads to behavioral and neuropathological changes. (2018)
  • Author(s): A Sobue, N Ito, T Nagai, W Shan, K Hada, Nakajima A, Y Murakami, A Mouri, Y Yamamoto, T Nabeshima, K Saito, K Yamada
  • Journal Title: Glia Volume: 66 Issue: 5 Pages: 1034-52
  • DOI: 10.1002/glia.23299
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Excess maternal fructose consumption impairs hippocampal function in offspring via epigenetic modification of BDNF promoter. (2018)
  • Author(s): Yamazaki M, Yamada H, Munetsuna E, Ishikawa H, Mizuno G, Mukuda T, Mouri A, Nabeshima T, Saito K, Suzuki K, Hashimoto S, Ohashi K.
  • Journal Title: FASEB J. Volume: 32 Issue: 5 Pages: 2549-2562
  • DOI: 10.1096/fj.201700783rr
  • Peer Reviewed / Open Access
• [Journal Article] Cerebellar α6 subunit-containing GABAA receptors: A novel therapeutic target for disrupted prepulse inhibition in neuropsychiatric disorders. Chiou LC, Lee HJ, Ernst M, Huang WJ, Chou JF, Chen HL, Mou (2018)
  • Author(s): Chiou LC, Lee HJ, Ernst M, Huang WJ, Chou JF, Chen HL, Mouri A, Chen LC, Treven M, Mamiya T, Fan PC, Knutson DE, Witzigmann C, Cook J, Sieghart W, Nabeshima T.
  • Journal Title: Br J Pharmacol. Volume: 印刷中 Issue: 12 Pages: 2414-2427
  • DOI: 10.1111/bph.14198
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Dysfunction of serotoninergic and dopaminergic neuronal systems in the antidepressant-resistant impairment of social behaviors induced by social defeat stress exposure as juveniles. (2018)
  • Author(s): Hasegawa S, Miyake Y, Yoshimi A, Mouri A, Hida H, Yamada K, Ozaki N, Nabeshima T, Noda Y.
  • Journal Title: Int J Neuropsychopharmacol. Volume: 印刷中 Issue: 9 Pages: 837-846
  • DOI: 10.1093/ijnp/pyy038
  • Peer Reviewed / Open Access
• [Journal Article] PKCδ Knockout Mice Are Protected from Dextromethorphan-Induced Serotonergic Behaviors in Mice: Involvements of Downregulation of 5-HT1A Receptor and Upregulation of Nrf2-Dependent GSH Synthesis. (2018)
  • Author(s): Tran HQ, Lee Y, Shin EJ, Jang CG, Jeong JH, Mouri A, Saito K, Nabeshima T, Kim HC.
  • Journal Title: Mol Neurobiol. Volume: 印刷中 Issue: 10 Pages: 7802-7821
  • DOI: 10.1007/s12035-018-0938-7
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Lipopolysaccharide shock reveals the immune function of indoleamine 2,3-dioxygenase 2 through the regulation of IL-6/stat3 signalling (2018)
  • Author(s): Yamamoto Yasuko、Yamasuge Wakana、Imai Shinjiro、Kunisawa Kazuo、Hoshi Masato、Fujigaki Hidetsugu、Mouri Akihiro、Nabeshima Toshitaka、Saito Kuniaki
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 15917-15917
  • DOI: 10.1038/s41598-018-34166-4
  • Peer Reviewed / Open Access
• [Journal Article] Human neutrophils show decreased survival upon long-term exposure to clozapine (2017)
  • Author(s): Aya Goto, Akira Yoshimi, Tomoko Nagai, Mako Ukigai, Akihiro Mouri, Norio Ozaki, Yukihiro Noda
  • Journal Title: Human Psychopharmacology: Clinical and Experimental Volume: － Issue: 6
  • DOI: 10.1002/hup.2629
  • Peer Reviewed
• [Journal Article] Adolescent stress leads to glutamatergic disturbance through dopaminergic abnormalities in the prefrontal cortex of genetically vulnerable mice (2017)
  • Author(s): Yurie Matsumoto, Minae Niwa, Akihiro Mouri, Yukihiro Noda, Takeshi Fukushima, Norio Ozaki, Toshitaka Nabeshima
  • Journal Title: Psychopharmacology Volume: 234 Issue: 20 Pages: 3055-3074
  • DOI: 10.1007/s00213-017-4704-8
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The involvement of brain-derived neurotrophic factor in 3,4-methylenedioxymethamphetamine-induced place preference and behavioral sensitization (2017)
  • Author(s): Akihiro Mouri, Yukihiro Noda, Minae Niwa, Yurie Matsumoto, Takayoshi Mamiya, Atsumi Nitta, Kiyofumi Yamada, Shoei Furukawa, Tatsunori Iwamura, Toshitaka Nabeshima
  • Journal Title: Behavioural Brain Research Volume: 329 Pages: 157-165
  • DOI: 10.1016/j.bbr.2017.04.052
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Kynurenine 3-monooxygenase is implicated in antidepressants-responsive depressive-like behaviors and monoaminergic dysfunctions (2017)
  • Author(s): Tashiro T , Murakami Y , Mouri A , Imamura Y, Nabeshima T, Yamamoto, Y , Saito, K
  • Journal Title: BEHAVIOURAL BRAIN RESEARCH Volume: 317 Pages: 279-285
  • DOI: 10.1016/j.bbr.2016.09.050
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Absence of kynurenine 3-monooxygenase reduces mortality of acute viral myocarditis in mice (2017)
  • Author(s): Kubo H, Hoshi M, Mouri A, Tashita C, Yamamoto Y, Nabeshima T, Saito K.
  • Journal Title: IMMUNOLOGY LETTERS Volume: 181 Pages: 94-100
  • DOI: 10.1016/j.imlet.2016.11.012
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The ubiquitination of serotonin transporter in lymphoblasts derived from fluvoxamine-resistant depression patients. (2016)
  • Author(s): Mouri A, Ikeda M, Koseki T, Iwata N, Nabeshima T.
  • Journal Title: Neurosci Lett. Volume: 617 Pages: 22-6
  • DOI: 10.1016/j.neulet.2016.01.064
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Prenatal phencyclidine treatment induces behavioral deficits through impairment of GABAergic interneurons in the prefrontal cortex. (2016)
  • Author(s): Toriumi K, Oki M, Muto E, Tanaka J, Mouri A, Mamiya T, Kim HC, Nabeshima T
  • Journal Title: Psychopharmacology (Berl) Volume: 233 Issue: 12 Pages: 2373-2378
  • DOI: 10.1007/s00213-016-4288-8
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Involvement of the histamine H4 receptor in clozapine-induced hematopoietic toxicity: vulnerability under granulocytic differentiation of HL-60 cells (2016)
  • Author(s): Aya Goto, Akihiro Mouri, Tomoko Nagai, Akira Yoshimi, Mako Ukigai, Tomomi Tsubai, Hirotake Hida, Norio Ozaki, Yukihiro Noda
  • Journal Title: Toxicol. Appl. Pharmacol. Volume: 306 Pages: 8-16
  • DOI: 10.1016/j.taap.2016.06.028
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Development of animal models and biomarker for depression focused on serotonergic systems (2018)
  • Author(s): Akihiro Mouri
  • Organizer: 15th International Society for Tryptophan Research (ISTRY) Conference
  • Int'l Joint Research
• [Presentation] MAGE-D1 Regurates Expression of Depression-like Begavior Through Serotonin Transporter Ubiquitylation (2018)
  • Author(s): Akihiro Mouri, Kazuo Kunisawa, Mami Hirakawa, Yuko Mori, Ken Watanabe, Hidetsugu Fujigaki, Yasuko Yamamoto, Yukihiro Noda, Kuniaki Saito, Toshitaka Nabeshima
  • Organizer: 15th International Society for Tryptophan Research (ISTRY) Conference
  • Int'l Joint Research
• [Presentation] Prostaglandin E receptor subtype EP1 deficiency elicits AD/HD-like behavior correlated with a dysfunction of dopamine D1 receptor-ERK signaling in the prefrontal cortex (2018)
  • Author(s): Akihiro Mouri, Tomoyuki Furuyashiki, Kazuo Kunisawa, Yasuko Yamamoto, Kiyofumi Yamada, Yukihiro Noda, Kuniaki Saito, Shu Narumiya, Toshitaka Nabeshima
  • Organizer: 18th World Congress of Basic and Clinical Pharmacology
  • Int'l Joint Research
• [Presentation] The ubiquitination of serotonin transporter in lymphoblasts derived from fluvoxamine-resistant depression patients (2017)
  • Author(s): Akihiro Mouri, Masashi Ikeda, Takenao Koseki, Kuniaki Saito, Nakao Iwata, Toshitaka Nabeshima
  • Organizer: 5th Asian College of Neuropsychopharmacology (AsCNP)
  • Int'l Joint Research
• [Presentation] 周産期の抑うつにおけるユビキチン化セロトニントランスポーターの変化 (2016)
  • Author(s): 毛利彰宏、椎野智子、勅使河原知明、山本康子、野田幸裕、尾崎紀夫、齋藤邦明、鍋島俊隆
  • Organizer: 第56回日本臨床化学会年次学術集会
  • Place of Presentation: くまもと県民交流館パレア（熊本）
  • Year and Date: 2016-12-02
• [Presentation] 周産期における抑うつとトリプトファン代謝関連分子 (2016)
  • Author(s): 勅使河原知明、久保緋紗子、毛利彰宏、鍋島俊隆、尾崎紀夫、山本康子、齋藤邦明
  • Organizer: 第56回日本臨床化学会年次学術集会
  • Place of Presentation: くまもと県民交流館パレア（熊本）
  • Year and Date: 2016-12-02
• [Presentation] 口腔内慢性疼痛疾患における 末梢血中ユビキチン化セロトニントランスポーターの発現変化 (2016)
  • Author(s): 毛利彰宏、近藤麻生 、木村真理 、柳本佳南、横山美里、椿井朋、後藤綾、 肥田祐丈、木村宏之、岩本邦弘、吉見陽、徳倉達也 、齋藤邦明 、尾崎紀夫 、 鍋島俊隆 、野田幸裕
  • Organizer: 第13回日本うつ病学会総会
  • Place of Presentation: ウインクあいち（名古屋）
  • Year and Date: 2016-08-05
• [Book] Neuropathology of Drug Addictions and Substance Misuse Volume 2 (2016)
  • Author(s): Akihiro Mouri, Hirotake Hida, Yukihiro Noda
  • Total Pages: 11
  • Publisher: Elsevier