Pathophysiological roles of ventral striatal ROS signaling in obsessive compulsive disorder

• Project/Area Number: 19K21244
• Project/Area Number (Other): 18H06128 (2018)
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund (2019); Single-year Grants (2018)
• Review Section: 0802:Biomedical structure and function and related fields
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: Asaoka Nozomi 京都府立医科大学, 医学(系)研究科(研究院), 助教 (90826091)
• Project Period (FY): 2018-08-24 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); 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)
• Keywords: 強迫性障害 / 線条体 / 眼窩前頭皮質 / 活性酸素

Outline of Research at the Start

強迫性障害は薬物治療の奏効率が低く、有効な治療法開発には、病態メカニズムの理解とそれに沿った戦略が重要となる。これまでに、独自の強迫性障害モデルマウスを作製して病態メカニズムの検討を行った結果、モデル動物では腹側線条体(VS)内の神経細胞種選択的な可塑的変化が起こることを見出している。本研究では新たに、臨床知見とモデル動物に共通するもう一つの因子である、活性酸素種(ROS)シグナルの増加に着目し、ROSシグナルによるVS 内の可塑的変化が強迫症状の発現・治療に関与するとの仮説の下、分子生物学的、行動学的、電気生理学的な検討を行い、強迫性障害の病態解明および治療戦略の開発を目指す。

Outline of Final Research Achievements

Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder characterized by the repeated rise of concerns (obsessions) and repetitive unwanted behavior (compulsions). Although selective serotonin reuptake inhibitors (SSRIs) is the first-choice drug, response rates to SSRI treatment vary between symptom dimensions. In this study, we found a novel therapeutic target for SSRI-resilient OCD symptoms by using a newly validated OCD model mice.

Academic Significance and Societal Importance of the Research Achievements

OCDの創薬研究は、アンメットニーズの存在は認識されているものの、アプローチの方策に乏しいために難航している。本研究では、治療薬探索に適した簡便で妥当性を備えた新規のモデル動物の作製・評価を行ったのみならず、既存の治療薬であるSSRIに抵抗性の強迫性障害様行動に対しても改善作用を示す、新規の治療標的を見出すことに成功した。この成果はOCDや強迫性が問題となる類似精神疾患の新規治療法開発に繋がることが期待できる。

Research Products

• [Journal Article] An Adenosine A2A Receptor Antagonist Improves Multiple Symptoms of Repeated Quinpirole-Induced Psychosis. (2019)
  • Author(s): Asaoka N, Nishitani N, Kinoshita H, Nagai Y, Hatakama H, Nagayasu K, Shirakawa H, Nakagawa T, Kaneko S
  • Journal Title: eNeuro Volume: 6 Issue: 1 Pages: ENEURO.0366-18.2019
  • DOI: 10.1523/eneuro.0366-18.2019
  • Peer Reviewed / Open Access
• [Presentation] An adenosine A2A receptor antagonist, istradefylline, improves multiple symptoms reflecting obsessive-compulsive disorder in mice (2020)
  • Author(s): Nozomi Asaoka, Naoya Nishitani, Haruko Kinoshita, Yuma Nagai, Hikari Hatakama, Kazuki Nagayasu, Hisashi Shirakawa, Takayuki Nakagawa, Chihiro Yabe-Nishimura, Shuji Kaneko
  • Organizer: 第10回武田科学振興財団薬科学シンポジウム
• [Presentation] Nox1 deficiency alleviated behavioral abnormalities in obsessive-compulsive disorder model mice via inhibition of D2 receptor/β-arrestin pathway-mediated synaptic facilitation (2020)
  • Author(s): Nozomi Asaoka, Chihiro Yabe-Nishimura, Shuji Kaneko
  • Organizer: 第93回日本薬理学会年会
• [Presentation] Blockade of adenosine A2A receptor improves repeated dopamine D2 receptor stimulation-induced multiple abnormalities reflecting obsessive-compulsive disorder (2019)
  • Author(s): Nozomi Asaoka, Naoya Nishitani, Haruko Kinoshita, Yuma Nagai, Hikari Hatakama, Kazuki Nagayasu, Hisashi Shirakawa, Takayuki Nakagawa, Chihiro Yabe-Nishimura, Shuji Kaneko
  • Organizer: Neuro2019
• [Presentation] Developing novel treatment strategies for OCD by utilizing rodent models: a therapeutic potential of adenosine A2A receptor antagonism (2019)
  • Author(s): Nozomi Asaoka, Chihiro Yabe-Nishimura, Shuji Kaneko
  • Organizer: The 6th Asian College of Neuropsychopharmacology
  • Int'l Joint Research
• [Presentation] An adenosine A2A receptor antagonist, istradefylline, improves multiple symptoms reflecting obsessive-compulsive disorder in mice (2019)
  • Author(s): Nozomi Asaoka, Naoya Nishitani, Haruko Kinoshita, Yuma Nagai, Hikari Hatakama, Kazuki Nagayasu, Hisashi Shirakawa, Takayuki Nakagawa, Chihiro Yabe-Nishimura, Shuji Kaneko
  • Organizer: The 6th Asian College of Neuropsychopharmacology
  • Int'l Joint Research
• [Presentation] An adenosine A2A receptor antagonist improves multiple symptoms reflecting obsessive-compulsive disorder (2019)
  • Author(s): Nozomi Asaoka, Naoya Nishitani, Haruko Kinoshita, Yuma Nagai, Hikari Hatakama, Kazuki Nagayasu, Hisashi Shirakawa, Takayuki Nakagawa, Chihiro Yabe-Nishimura, Shuji Kaneko
  • Organizer: 第92回日本薬理学会年会
• [Presentation] An adenosine A2A receptor antagonist, istradefylline, improves multiple symptoms reflecting obsessive-compulsive disorder in a novel murine model (2018)
  • Author(s): Nozomi Asaoka, Naoya Nishitani, Haruko Kinoshita, Yuma Nagai, Kazuki Nagayasu, Hisashi Shirakawa, Takayuki Nakagawa, Shuji Kaneko
  • Organizer: 18th World Congress of Basic and Clinical Pharmacology
  • Int'l Joint Research