Development of therapeutic agents for neuropsychiatric disorders targeting the stress-sensitive transcription factor NPAS4

• Project/Area Number: 17K08306
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pharmacology in pharmacy
• Research Institution: Nagoya City University (2018-2021); Nagoya University (2017)
• Principal Investigator: HIBI YOKO 名古屋市立大学, 大学院医学研究科, 教授 (70295616)
• Project Period (FY): 2017-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: Npas4 / ストレス / 神経分化 / Neuronal PAS domain 4 / 精神疾患 / 脳 / プロモーターアッセイ / 脳神経疾患 / 神経科学 / 薬学

Outline of Final Research Achievements

Since dysfunction of suppressive GABAergic nerves due to decreased expression of NPAS4 may cause nerve excitement / suppression imbalance, we investigated the association with seizures. Npas4-knockout mice were shown to have a lower threshold for convulsions. It was suggested that as the mechanism, Npas4 transcripts Homer1a and gives feedback to suppress nerve excitement. Regarding the search for compounds that induce Npas4 promoter activity, we found several compounds that increase Npas4 promoter activity in humans and mice from commercially available active compound libraries.

Academic Significance and Societal Importance of the Research Achievements

神経分化関連転写因子Npas4はストレス負荷により発現が低下することが見いだされており、Npas4の発現低下が神経の興奮/抑制バランスを崩すことによっててんかんなどの疾病の要因となる可能性が示された。また、このNpas4発現を誘導する化合物の探索によって、神経疾患や神経損傷の治療薬の開発の可能性にもつながる。

Research Products

• [Journal Article] Protective effects of tadalafil on damaged podocytes in an adriamycin-induced nephrotic syndrome model. (2022)
  • Author(s): Tomita N, Hotta Y, Naiki-Ito A, Sanagawa A, Kataoka T, Furukawa-Hibi Y, Takahashi S, Kimura K.
  • Journal Title: J Pharmacol Sci. Volume: 149 Issue: 2 Pages: 53-59
  • DOI: 10.1016/j.jphs.2022.03.003
  • Peer Reviewed / Open Access
• [Journal Article] Methylation analysis for postpartum depression : a case control study. (2019)
  • Author(s): Nakamura Y, Nakatochi M, Kunimoto S, Okada T, Aleksic B, Toyama M, Shiino T, Morikawa M, Yamauchi A, Yoshimi A, Furukawa-Hibi Y, Nagai T, Ohara M, Kubota C, Yamada K, Ando M, Ozaki N.
  • Journal Title: BMC Psychiatry. Volume: 19 Issue: 1 Pages: 190-199
  • DOI: 10.1186/s12888-019-2172-x
  • Peer Reviewed / Open Access
• [Journal Article] Association between CYP2C19 genotype and the additional effect of cilostazol to clopidogrel resistance in neuroendovascular therapy (2018)
  • Author(s): Tajima H, Izumi T, Miyachi S, Matsubara N, Ito M, Imai T, Nishihori M, Shintai K, Okamoto S, Araki Y, Kumakura Y, Furukawa-Hibi Y, Yamada K, Wakabayashi T.
  • Journal Title: Nagoya Journal of Medical Science Volume: 80 Issue: 2 Pages: 207-215
  • DOI: 10.18999/nagjms.80.2.207
  • NAID: 120006469000
  • ISSN: 2186-3326
  • URL: https://nagoya.repo.nii.ac.jp/records/26018
  • Peer Reviewed
• [Journal Article] Neuronal PAS domain protein 4 (Npas4) controls neuronal homeostasis in pentylenetetrazole-induced epilepsy through the induction of Homer1a. (2017)
  • Author(s): 2.Shan W, Nagai T, Tanaka M, Itoh N, Furukawa-Hibi Y, Nabeshima T, Sokabe M, Yamada K.
  • Journal Title: J Neurochem. Volume: - Issue: 1 Pages: 19-33
  • DOI: 10.1111/jnc.14274
  • Peer Reviewed / Open Access