Experimental study on functional pathology of L-DOPA-induced dyskinesia in Parkinson's disease.
| Project/Area Number |
17K07096
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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 |
Nerve anatomy/Neuropathology
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| Research Institution | The University of Tokushima |
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Principal Investigator |
GOTO Satoshi 徳島大学, 大学院医歯薬学研究部(医学域), 特任教授 (50240916)
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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 |
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | パーキンソン病 / ジスキネジア / 線条体 / ドパミンシグナル / グルタミン酸受容体 / 脳内インフュージョン / G-タンパク質 / G蛋白質 / 脳神経疾患 / ドパミン |
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| Outline of Final Research Achievements |
In a line of our experiments using a mouse model of hemiparkinsonism with 6-hydrodopamine-induced nigral lesion, we have shown that repeated and pulsatile administration of levodopa might cause a usage-induced degradation of Gαolf proteins in striatal medium spiny neurons (MSNs) causes increased and decreased levels of Gαolf protein in the striatonigral and striatopallidal MSNs, respectively, leading to the occurrence of levodopa-induced dyskinesias. As a principal cause for generating LID, this might induce an increased responsiveness to levodopa exposure in both striatonigral and striatopallidal MSNs. We also found that continuous intrastriatal infusion of NMDA receptor antagonist memantine, which can reduce use-dependent degradation of Gαolf proteins, attenuates LIDs and parkinsonian signs. Our results suggest that a an intrastriatal memantine infusion can be beneficial for the management of Parkinson's disease with LIDs.
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| Academic Significance and Societal Importance of the Research Achievements |
パーキンソン病治療の第一選択肢はレボドパの経口投与であるが、レボドパ長期投与は難治性の薬物誘発性ジスキネジアを 惹起する。本研究において、LIDはグルタミン酸シグナル過剰刺激に伴う線条体中型有棘細胞でのGαolf蛋白の発現異常に起因する示された。また、グルタミン酸NMDA受容体拮抗薬であるメマンチンの線条体内持続投与によってパーキンソン症状と同時にLID が改善されることが判明した。本研究で得られた知見は、LIDの発現メカニズムの解明に重要であり、LIDを有するパーキンソン病患者に対する新規治療法の開発に寄与する。
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Report
(4 results)
Research Products
(23 results)
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[Journal Article] Phenotype variability and allelic heterogeneity in KMT2B-Associated disease.2018
Author(s)
Kawarai T, Miyamoto R, Nakagawa E, Koichihara R, Sakamoto T, Mure H, Morigaki R, Koizumi H, Oki R, Montecchiani C, Caltagirone C, Orlacchio A, Hattori A, Mashimo H, Izumi Y, Mezaki T, Kumada S, Taniguchi M, Yokochi F, Saitoh S, Goto S, Kaji R
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Journal Title
Parkinsonism Relat Disord.
Volume: 18
Pages: 30137-30138
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Phenotype variability and allelic heterogeneity in KMT2B-Associated disease2018
Author(s)
Kawarai T, Miyamoto R, Nakagawa E, Koichihara R, Sakamoto T, Mure H, Morigaki R, Koizumi H, Oki R, Montecchiani C, Caltagirone C, Orlacchio A, Hattori A, Mashimo H, Izumi Y, Mezaki T, Kumada S, Taniguchi M, Yokochi F, Saitoh S, Goto S, Kaji R
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Journal Title
Parkinsonism Relat Disord
Volume: 印刷中
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Presentation] Haploinsufficiency of KMT2B causes myoclonus-dystonia with impaired psychomotor ability,2017
Author(s)
Toshitaka Kawarai, Ryosuke Miyamoto, Hideo Mure, Ryoma Morigaki, Ryosuke Oki, Antonio Orlacchio, Reiko Koichihara, Eiji Nakagawa, Takashi Sakamoto, Yuishin Izumi, Satoshi Goto, Ryuji Kaji
Organizer
The MDS 21th International Congress of Parkinsons Disease and Movement Disorders
Related Report
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