Drug development of novel Kir6.2 channel inhibitor target for Alzheimer'ddisease
| Project/Area Number |
15K08583
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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 |
Applied pharmacology
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| Research Institution | Tohoku University |
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Principal Investigator |
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| Co-Investigator(Renkei-kenkyūsha) |
Fukunaga Kohji 東北大学, 大学院薬学研究科, 教授 (90136721)
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| Project Period (FY) |
2015-04-01 – 2018-03-31
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| Project Status |
Completed (Fiscal Year 2017)
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| Budget Amount *help |
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | メマンチン / KATPチャンネル / アルツハイマー病 / KATPチャネル / AD脳糖尿病仮説 / 認知・精神機能 / Memantine / CaMキナーゼII / 認知機能 / うつ症状 / 新規アダマンタン誘導体 / memantine / Kir6.2チャネル / whole-cell patch-clamp法 / カルシウムイメージング法 / CaM kinase II |
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| Outline of Final Research Achievements |
We recently discovered a novel mechanism of memory improvement by memantine via inhibition of ATP-sensitive K+ (KATP) channels. Inhibition of Kir6.2 channel by memantine improved brain insulin signaling. These results relate to brain diabetes theory causative for Alzheimer’s disease. Therefore, we have searched the novel seed compounds among adamantane derivatives with blocking action of KATP channels. We successfully discovered novel adamantane derivative, TP-compound X targeting for KATP channels, which is more potent than memantine. In the pharmacological examination, we confirmed that TP-compound improves both cognitive deficits via Kir6.2 channel inhibition and behavioral and psychological symptoms of dementia (BPSD) such as depressive-like behaviors, anxiety-like behaviors and aggressive-like behaviors via Kir6.1 channel inhibition in mice.
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Report
(4 results)
Research Products
(24 results)
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[Journal Article] Reduced expression of Na+ /Ca2+ exchangers is associated with cognitive deficits seen in Alzheimer's disease model mice2018
Author(s)
Moriguchi S, Kita S, Fukaya M, Osanai M, Inagaki R, Sasaki Y, Izumi H, Horie K, Takeda J, Saito T, Sakagami H, Saido TC, Iwamoto T, Fukunaga K
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Journal Title
Neuropharmacology
Volume: 131
Pages: 291-303
DOI
Related Report
Peer Reviewed
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[Journal Article] Reduced CaM Kinase II and CaM Kinase IV Activities Underlie Cognitive Deficits in NCKX2 Heterozygous Mice.2018
Author(s)
Moriguchi S, Kita S, Yabuki Y, Inagaki R, Izumi H, Sasaki Y, Tagashira H, Horie K, Takeda J, Iwamoto T, Fukunaga K.
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Journal Title
Mol Neurobiol.
Volume: 55(5)
Pages: 3889-3900
DOI
Related Report
Peer Reviewed
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[Journal Article] Blockade of the KATP channel Kir6.2 by memantine represents a novel mechanism relevant to Alzheimer's disease therapy.2016
Author(s)
Moriguchi S, Ishizuka T, Yabuki Y, Shioda N, Sasaki Y, Tagashira H, Yawo H, Yeh JZ, Sakagami H, Narahashi T, Fukunaga K.
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Journal Title
Mol Psychiatry.
Volume: 印刷中
Issue: 2
Pages: 211-221
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Functional Genomic Analyses Identify Pathways Dysregulated in Animal Model of Autism.2016
Author(s)
Huang JY, Tian Y, Wang HJ, Shen H, Wang H, Long S, Liao MH, Liu ZR, Wang ZM, Li D, Tao RR, Cui TT, Moriguchi S, Fukunaga K, Han F, Lu YM.
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Journal Title
CNS Neurosci Ther.
Volume: 22
Issue: 10
Pages: 845-853
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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