| Project/Area Number |
19K07187
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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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| Review Section |
Basic Section 47060:Clinical pharmacy-related
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| Research Institution | Tohoku University |
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Principal Investigator |
Lee Seon Hwa 東北大学, 薬学研究科, 准教授 (60519776)
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| Co-Investigator(Kenkyū-buntansha) |
大江 知行 東北大学, 薬学研究科, 教授 (10203712)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
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| Keywords | Pyridoxamine / Dopamine / Parkinson`s disease / Oxidative stress / Lipid-derived aldehyde |
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| Outline of Research at the Start |
The cytotoxic effects of dopamine (DA) involve its oxidation to DA o-quinone (DAQ), which has implications in Parkinson`s disease (PD). Pyridoxamine (PM) is a drug candidate for diabetic complications. Our recent study discovered the formation of a PM-DA adduct via the reaction with DAQ. This suggests that PM could inhibit DA-induced neurotoxicity by scarvenging DAQ and a PM-DA adduct could reflect the extent of oxidative stress/DA oxidation. Therefore, the proposed research will characterize a novel PM-DA adduct and investigate inhibition effects of PM on DA-induced neurotoxicity.
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| Outline of Final Research Achievements |
The cytotoxic effects of dopamine (DA) involve its oxidation to DA o-quinone (DAQ), which has profound implications in Parkinson’s disease (PD). Pyridoxamine (PM) is a drug candidate for diabetic complications because of its scavenging effects against reactive oxygen/carbonyl species. PM can also inhibit lipid hydroperoxide-derived protein damage by trapping lipid-derived aldehydes. In the reaction of DA and PM, pyridoxal (PL)+DA－H2O was produced. Its structure was characterized, and the reaction mechanism was proposed as follows: DA initially oxidizes to DAQ, which reacts with PM to produce PL after hydrolysis. PL then reacts with DA to form PL-DA adduct. PM was shown to scavenge DAQ in the presence of tyrosinase and glutathione. PM also inhibited DA-induced alpha-synuclein (Syn) oxidation. Therefore, PM could prevent DA-induced dopaminergic cell death and aggregation of Syn involved in PD, and the resulting PL-DA adduct can be used as a dosimeter for oxidative stress/DA oxidation.
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| Academic Significance and Societal Importance of the Research Achievements |
今回、神経毒性化合物のDA酸化体（DAQ）とPMの反応機構、反応生成物、およびは細胞内環境に近い条件でのDAQ捕捉、α-シヌクレイン酸化阻害効果を精査した。これらの知見からPMは、糖尿病、酸化・脂質化の関与する様々な慢性疾患（高脂血症、老化など）のみならず、PD予防薬としての可能性が示された。本研究の進展により、PD予防法の確立、長期的なDA補充療法に伴う問題 (ウェアリング・オフ現象やジスキネジアの発生) の解決、ドラッグデザインへの応用等が期待される。
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