| Project/Area Number |
17K08071
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Veterinary medical science
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| Research Institution | Obihiro University of Agriculture and Veterinary Medicine |
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Principal Investigator |
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2017: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
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| Keywords | パーキンソン病 / 認知障害 / MPTP / セロトニン5-HT4受容体作動薬 / Phosphodiesterase阻害薬 / 海馬歯状回 / cAMP / PKA / セロトニン5-HT4受容体 / velusetrag / prucalopride / cAMP-PKAシグナル / Phosphodiesterase IV 阻害薬 / Rolipram / 脳神経疾患 / 神経科学 / 脳・神経 / 薬理学 / 獣医学 |
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| Outline of Final Research Achievements |
We found that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson’s disease (PD) model mice (PD mice) show facilitation of hippocampal memory extinction via reduced cyclic adenosine monophosphate (cAMP)/cAMP-dependent response element-binding protein (CREB) signaling, which may cause cognitive impairment in PD. Administration of rolipram, a phosphodiesterase IV (PDE IV) inhibitor, or prucalopride and velusetrag, serotonin 5-HT4 receptor (5-HT4R) agonists restore the facilitation of memory extinction in PD mice by stimulating the cAMP/CREB pathway in the hippocampus. These results suggest that a 5-HT4R agonist and/or a PDE IV inhibitor could be potentially useful as a therapeutic drug for treating cognitive deficits in PD.
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| Academic Significance and Societal Importance of the Research Achievements |
パーキンソン病(PD)患者に高頻度に併発する難治性の認知障害の発症機構を解明し創薬の手がかりを見出すことに成功した。具体的には、PDモデルマウス(PDマウス)で認めれれる記憶の保持能力が低下が、海馬の歯状回のcAMP-PKAシグナルの減弱化に起因する活性型CREBの発現低下によることをみつけ、PD患者に併発する難治性認知障害の発症機構を明らかにした。さらに、phosphodiesterase IV阻害薬rolipramやセロトニン5-HT4受容体の選択的作動薬velusetragとprucaloprideがPDの認知障害に有効であることを発見・特許出願し、創薬の手がかりを見出すことに成功した。
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