PACAP-PAC1 signal-targeted drug development for stress-induced disorders

• Project/Area Number: 19K07121
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47040:Pharmacology-related
• Research Institution: Osaka University
• Principal Investigator: Hayata-Takano Atsuko 大阪大学, 大学院歯学研究科, 准教授 (70390812)
• Co-Investigator(Kenkyū-buntansha): 橋本 均 大阪大学, 大学院薬学研究科, 教授 (30240849)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: PACAP / 精神疾患 / ストレス / 治療薬開発

Outline of Research at the Start

本研究では、精神行動の調節や同疾患のリスクとの関連が示唆されている神経ペプチドPACAPのシグナルを標的とした薬理学研究を実施し、うつ病などのストレス性精神疾患の新たな神経基盤に基づく治療薬としての可能性を見出す。
また、PACAPが関わる神経活動を全脳細胞レベルで解析することで、重要な神経回路や細胞種を同定し、未だ明らかではないストレスが引き起こす発症機序や治療機序の手掛かりを見出すことを目指す。

Outline of Final Research Achievements

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a highly conserved pleiotropic neuropeptide, implicated in emotional stress responses and anxiety-related disorders. We recently developed novel small-molecule non-peptide antagonists of the PACAP receptor (PAC1) using docking-based in silico screening. In the present study, we aimed to examine the effects of the PAC1 antagonists on acute emotional stress-induced anxiety-like behaviors or repeated social defeat stress (RSDS)-induced depression-like behaviors.
The antagonists significantly improved anxiety-like behaviors in mice subjected to acute restraint stress. A single dose of the antagonist significantly ameliorated depression-like behaviors in RSDS mice, and this effect lasted 8 weeks. The antagonist also attenuated anxiety-like behaviors and cognitive deficits in RSDS mice. These results suggest that our novel PAC1 antagonist would be a new class of antidepressant with strong efficacy and high safety profile.

Academic Significance and Societal Importance of the Research Achievements

本研究成果は、治療満足度や寛解率が十分ではないうつ病や不安障害などの精神疾患の既存薬とは異なる作用機序をもつPACAP受容体アンタゴニストが、単回投与することで即効性かつ持続的な抗うつ・抗不安作用や記憶障害の改善を示すものである。このことは、本拮抗薬が不安障害・うつ病に対して、安全で有効な新規治療薬の候補となることを示している。また、本研究の成果は、ストレス関連性精神疾患の病態解明や、さらなる治療薬の開発の手がかりを得ることにも繋がるものであり、その学術的意義は極めて高いと考えられる。

Research Products

• [Journal Article] Vasoactive intestinal peptide receptor 2 signaling promotes breast cancer cell proliferation by enhancing the ERK pathway (2023)
  • Author(s): Asano Satoshi、Ono Ami、Sakamoto Kotaro、Hayata-Takano Atsuko、Nakazawa Takanobu、Tanimoto Kotaro、Hashimoto Hitoshi、Ago Yukio
  • Journal Title: Peptides Volume: 161 Pages: 170940-170940
  • DOI: 10.1016/j.peptides.2023.170940
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Small-molecule non-peptide antagonists of the PACAP receptor attenuate acute restraint stress-induced anxiety-like behaviors in mice (2022)
  • Author(s): Shintani Yusuke、Hayata-Takano Atsuko、Yamano Yui、Ikuta Mankato、Takeuchi Rei、Takuma Kazuhiro、Okada Takuya、Toyooka Naoki、Takasaki Ichiro、Miyata Atsuro、Kurihara Takashi、Hashimoto Hitoshi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 631 Pages: 146-151
  • DOI: 10.1016/j.bbrc.2022.09.079
  • Peer Reviewed / Open Access
• [Journal Article] Vasoactive intestinal peptide?VIPR2 signaling regulates tumor cell migration (2022)
  • Author(s): Asano Satoshi、Yamasaka Misa、Ozasa Kairi、Sakamoto Kotaro、Hayata-Takano Atsuko、Nakazawa Takanobu、Hashimoto Hitoshi、Waschek James A.、Ago Yukio
  • Journal Title: Frontiers in Oncology Volume: 12 Pages: 852358-852358
  • DOI: 10.3389/fonc.2022.852358
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] PACAP-PAC1 Signaling Regulates Serotonin 2A Receptor Internalization (2021)
  • Author(s): Hayata-Takano A et al.
  • Journal Title: Frontiers in Endocrinology Volume: 12 Pages: 732456-732456
  • DOI: 10.3389/fendo.2021.732456
  • Peer Reviewed / Open Access
• [Journal Article] 発達障がいモデルマウスを用いた脳の発達や社会性に変化をもたらす分子メカニズム解明～全脳イメージング解析から，シナプス機能解析まで (2021)
  • Author(s): 早田敦子、勢力薫、中澤敬信、橋本均
  • Journal Title: The Journal of Child & Brain Development Volume: 12 Issue: 1 Pages: 17-25
  • DOI: 10.34572/jcbd.12.1_17
  • NAID: 130008104073
  • ISSN: 2185-1417, 2435-8819
• [Journal Article] 概日リズムに関わる時計遺伝子とストレス感受性・抵抗性 (2021)
  • Author(s): 早田敦子、内匠透
  • Journal Title: Clinical Neuroscience Volume: 39(6) Pages: 780-783
• [Journal Article] 概日リズムのクロノタイプと気分障害に関わるストレスレジリエンス (2021)
  • Author(s): 早田敦子、内匠透
  • Journal Title: 生物学的精神医学会誌 Volume: 32(4) Pages: 174-178
• [Journal Article] Intranasal oxytocin administration ameliorates social behavioral deficits in a POGZWT/Q1038R mouse model of autism spectrum disorder (2021)
  • Author(s): Kitagawa Kohei、Matsumura Kensuke、Baba Masayuki、Kondo Momoka、Takemoto Tomoya、Nagayasu Kazuki、Ago Yukio、Seiriki Kaoru、Hayata-Takano Atsuko、Kasai Atsushi、Takuma Kazuhiro、Hashimoto Ryota、Hashimoto Hitoshi、Nakazawa Takanobu
  • Journal Title: Molecular Brain Volume: 14 Issue: 1 Pages: 56-56
  • DOI: 10.1186/s13041-021-00769-8
  • Peer Reviewed / Open Access
• [Journal Article] Lipocalin-type prostaglandin D synthase regulates light-induced phase advance of the central circadian rhythm in mice (2020)
  • Author(s): Kawaguchi, C., Shintani, N., Hayata-Takano, A., Hatanaka, M., Kuromi, A., Nakamura, R., Yamano, Y., Shintani, Y., Nagai, K., Tsuchiya, S., Sugimoto, Y., Ichikawa, A., Okuno, Y., Urade, Y., Hirai, H., Nagata, K., Nakamura, M., Narumiya, S., Nakazawa, T., Kasai, A., Ago, Y., Takuma, K., Baba, A., and Hashimoto, H.
  • Journal Title: Communications Biology Volume: 3 Issue: 1 Pages: 557-557
  • DOI: 10.1038/s42003-020-01281-w
  • Peer Reviewed / Open Access
• [Journal Article] Activation of the VPAC2 Receptor Impairs Axon Outgrowth and Decreases Dendritic Arborization in Mouse Cortical Neurons by a PKA-Dependent Mechanism (2020)
  • Author(s): Takeuchi Shuto、Kawanai Takuya、Yamauchi Ryosuke、Chen Lu、Miyaoka Tatsunori、Yamada Mei、Asano Satoshi、Hayata-Takano Atsuko、Nakazawa Takanobu、Yano Koji、Horiguchi Naotaka、Nakagawa Shinsaku、Takuma Kazuhiro、Waschek James A.、Hashimoto Hitoshi、Ago Yukio
  • Journal Title: Frontiers in Neuroscience Volume: 14 Pages: 521-532
  • DOI: 10.3389/fnins.2020.00521
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] PACAPシグナル系を介したストレスが誘発する精神疾患の発症機序の解明と治療薬の開発 (2020)
  • Author(s): 早田敦子、吾郷由希夫、橋本均
  • Journal Title: Medical Science Digest Volume: 46(6) Pages: 340-343
  • NAID: 40022470686
• [Journal Article] Pituitary adenylate cyclase-activating polypeptide modulates dendritic spine maturation and morphogenesis via microRNA-132 upregulation. (2019)
  • Author(s): Hayata-Takano A, Kamo T, Kijima H, Seiriki K, Ogata K, Ago Y, Nakazawa T, Shintani Y, Higashino K, Nagayasu K, Shintani N, Kasai A, Waschek JA, Hashimoto H.
  • Journal Title: J Neurosci. Volume: 印刷中 Issue: 22 Pages: 4208-4220
  • DOI: 10.1523/jneurosci.2468-18.2019
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Autism-associated protein kinase D2 regulates embryonic cortical neuron development. (2019)
  • Author(s): Matsumura K, Baba M, Nagayasu K, Yamamoto K, Kondo M, Kitagawa K, Takemoto T, Seiriki K, Kasai A, Ago Y, Hayata-Takano A, Shintani N, Kuriu T, Iguchi T, Sato M, Takuma K, Hashimoto R, Hashimoto H.
  • Journal Title: Biochem Biophys Res Commun Volume: 519(3) Issue: 3 Pages: 626-632
  • DOI: 10.1016/j.bbrc.2019.09.048
  • Peer Reviewed / Open Access
• [Presentation] Fast and lasting antidepressant-like effect of small molecule PACAP receptor PAC1 antagonist (2022)
  • Author(s): Yusuke Shintani, Atsuko Hayata-Takano, Yui Yamano, Manato Ikuta, Rei Takeshita, Kenichiro Murata, Ichiro Takasaki, Takashi Kurihara, Hitoshi Hashimoto
  • Organizer: VPAC ISBAP2022
  • Int'l Joint Research
• [Presentation] Chemogenetic inhibition of PACAP neurons projecting to the mPFC exerts antidepressant-like effects (2022)
  • Author(s): Yui Yamano, Atsuko Hayata-Takano, Yusuke Shintani, Manato Ikuta, Rei Takeshita, Kenichiro Murata, Hitoshi Hashimoto
  • Organizer: VPAC ISBAP2022
  • Int'l Joint Research
• [Presentation] A single oral administration of small-molecule PAC1 antagonist attenuates repeated stress-induced depressive-like behaviors in mice (2022)
  • Author(s): Manato Ikuta, Atsuko Hayata-Takano, Yusuke Shintani, Yui Yamano, Rei Takeshita, Kenichiro Murata, Ichiro Takasaki, Takashi Kurihara, Hitoshi Hashimoto
  • Organizer: VPAC ISBAP2022
  • Int'l Joint Research
• [Presentation] Social defeat stress induces activation of PACAP-expressing neurons in thermoregulatory systems (2022)
  • Author(s): Yuzuka Fujimoto, Kaoru Seiriki, Shunsuke Maeda, Taiyou Baba, Atsuko Hayata-Takano, Atsushi Kasai, Hitoshi Hahimoto
  • Organizer: VPAC ISBAP2022
  • Int'l Joint Research
• [Presentation] PACAP受容体PAC1の低分子遮断薬の抗うつ効果と関連する脳領域の解析 (2022)
  • Author(s): 早田敦子、新谷勇介、山野結衣、生田学登、竹下黎、田熊一敞、髙崎一朗、栗原崇、橋本均
  • Organizer: BPCNPNPPP2022
• [Presentation] 新規ストレス関連障害の治療薬創成を目指した非ペプチドで低分子なPACAP受容体PAC1 遮断薬の行動薬理学研究 (2022)
  • Author(s): 新谷勇介、早田敦子、山野結衣、生田学登、竹下黎、髙崎一朗、栗原崇、橋本均
  • Organizer: 生体機能と創薬シンポジウム2022
• [Presentation] 新規PACAP受容体PAC1遮断薬による即効性、持続性の抗うつ作用 (2022)
  • Author(s): 新谷勇介、早田敦子、山野結衣、生田学登、竹下黎、髙﨑一朗、栗原崇、橋本均
  • Organizer: 第95回日本薬理学会年会
• [Presentation] 時計遺伝子PER2のリン酸化と精神的ストレス応答との関連 (2021)
  • Author(s): Hayata-Takano A., Yamawaki Y, Imamura K, Takumi T.
  • Organizer: 第94回日本生化学会
• [Presentation] Maternal separation with early weaning induced anxiety-like behavior and morphological changes in mouse mPFC neurons. (2021)
  • Author(s): 山野結衣、早田敦子、橋本均
  • Organizer: 第51回日本神経精神薬理学会
• [Presentation] Overexpression of VIPR2 in neurons causes defects in dendritic growth and cognitive impairment (2021)
  • Author(s): Tatsunori Miyaoka, Lu Chen, Mei Yamada, Daichi Koan, Satoshi Asano, Kenji Ishimoto, Shinsaku Nakagawa, Atsuko Hayata, Takanobu Nakazawa, Akihiro Harada, Hitoshi Hashimoto, James A. Waschek, Yukio Ago
  • Organizer: AsCNP2021
  • Int'l Joint Research
• [Presentation] 胎児期におけるPGD2シグナル活性化による社会性行動や神経細胞形態への影響 (2021)
  • Author(s): 菊池泰河，早田敦子，毛利育子，橘雅弥，谷池雅子，橋本均
  • Organizer: 第140回日本薬理学会近畿部会
• [Presentation] 慢性社会的敗北ストレスモデルマウスにおける新規低分子性PACAP受容体PAC1遮断薬の行動薬理学研究 (2021)
  • Author(s): 新谷勇介、早田敦子、山野結衣、生田学登、竹下黎、髙﨑一朗、栗原崇、橋本均
  • Organizer: 第16回GPCR研究会
• [Presentation] PACAP attenuates 5-HTR2A mediated hallucinations. (2021)
  • Author(s): Shintani Y., Hayata-Takano A., Moriguchi K., Hashimoto H.
  • Organizer: CINP2021
  • Int'l Joint Research
• [Presentation] 脳神経細胞でのVPAC2受容体の過剰発現は認知機能障害を引き起こす (2021)
  • Author(s): 古庵 大地、今戸 瑛二、浅野 智志、Chen Lu、宮岡 辰典、山田 めゐ、石本 憲司、中川 晋作、早田 敦子、中澤 敬信、原田 彰宏、橋本 均、Waschek James、吾郷 由希夫
  • Organizer: 日本薬学会第141年会
• [Presentation] VPAC2受容体の制御する細胞遊走メカニズム (2021)
  • Author(s): 山坂 美紗、浅野 智志、早田 敦子、中澤 敬信、橋本 均、Waschek James、吾郷 由希夫
  • Organizer: 日本薬学会第141年会
• [Presentation] 睡眠相前進を示す時計遺伝子変異マウスは慢性ストレスに抵抗性をもつ (2020)
  • Author(s): Hayata-Takano A., Yamawaki Y, Imamura K, Takumi T.
  • Organizer: NPBPPP2020
• [Presentation] PACAP Increases Functional Synapses In The Primary Hippocampal Neurons (2019)
  • Author(s): Hayata-Takano A., Kijima H, Shintani Y, Nakazawa T, Hashimoto H.
  • Organizer: AsCNP2019
  • Int'l Joint Research
• [Presentation] Analysis of PACAP signaling for functional synapse formation in the hippocampal neurons (2019)
  • Author(s): Hayata-Takano A., Kijima H, Kamo T, Seiriki K, Shintani Y, Nakazawa T, Hashimoto H.
  • Organizer: The Akira Arimura Memorial VIP/PACAP and Related Peptides Symposium
  • Int'l Joint Research
• [Presentation] Differential regulation of PACAP-PAC1 signaling by two isoforms of β-arrestin (2019)
  • Author(s): Shintani Y., Hayata-Takano A., Moriguchi K., Kijima H, Kikuchi T, Hashimoto H.
  • Organizer: The Akira Arimura Memorial VIP/PACAP and Related Peptides Symposium
  • Int'l Joint Research
• [Presentation] Prostaglandin D2 modulates neuronal morphological development via activation of DP1 receptor (2019)
  • Author(s): Hayata-Takano A, Mohri I, Okuda K, Tachibana M, Kikuchi T, Shintani Y, Nakazawa T, Taniike M, HashimotoH
  • Organizer: NEURO2019
• [Presentation] PACAP-provoked PAC1 receptor signaling and internalization through two isoform of β-arrestins dependent mechanisms (2019)
  • Author(s): Shintani Y., Hayata-Takano A., Moriguchi K., Hashimoto H.
  • Organizer: NEURO2019
• [Presentation] Mice neonatally treated with the VPAC2 receptor agonist present cognitive dysfunction specifically reverted by clozapine (2019)
  • Author(s): Takeuchi S, Yamauchi R, Kawanai T, Miyaoka T, Chen L, Hayata-takano A, Waschek JA, Nakazawa T, Takuma K, Nakagawa S, Hashimoto H, Ago Y.
  • Organizer: NEURO2019
• [Presentation] 神経ペプチドPACAPの機能的シナプス調節機構の解析 (2019)
  • Author(s): 貴島春衣、早田敦子、新谷勇介、中澤敬信、橋本均
  • Organizer: 次世代を担う創薬・医療薬理シンポジウム2019
• [Remarks] 大阪大学大学院薬学研究科神経薬理学分野ホームページ
  • URL: http://molpharm.umin.jp/
• [Remarks] 大阪大学大学院 連合小児発達学研究科 附属子どものこころの分子統御機構研究センター
  • URL: http://www.med.osaka-u.ac.jp/pub/kokoro/
• [Remarks] 大阪大学大学院歯学研究科薬理学教室ホームページ
  • URL: https://web.dent.osaka-u.ac.jp/pharm/
• [Remarks] 大阪大学大学院 連合小児発達学研究科 附属子どものこころの分子統御機構研究センター
  • URL: http://www.med.osaka-u.ac.jp/pub/kokoro/top.htm
• [Patent(Industrial Property Rights)] ＰＡＣ１受容体拮抗薬を用いた抗うつ・抗不安薬 (2021)
  • Inventor(s): 栗原崇，髙﨑一朗，橋本均，早田敦子，新谷勇介
  • Industrial Property Rights Holder: 栗原崇，髙﨑一朗，橋本均，早田敦子，新谷勇介
  • Industrial Property Rights Type: 特許
  • Filing Date: 2021
  • Acquisition Date: 2022
• [Patent(Industrial Property Rights)] ＰＡＣ１受容体拮抗薬を用いた抗うつ・抗不安薬 (2020)
  • Inventor(s): 栗原崇，髙﨑一朗，橋本均，早田敦子，新谷勇介
  • Industrial Property Rights Holder: 栗原崇，髙﨑一朗，橋本均，早田敦子，新谷勇介
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2020-082465
  • Filing Date: 2020