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Pyridoxamine could be a candidate drug for Parkinson`s disease: Mechanistic study to reduce dopamine-induced toxicity

Research Project

Project/Area Number 19K07187
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 47060:Clinical pharmacy-related
Research InstitutionTohoku University

Principal Investigator

Lee Seon Hwa  東北大学, 薬学研究科, 准教授 (60519776)

Co-Investigator(Kenkyū-buntansha) 大江 知行  東北大学, 薬学研究科, 教授 (10203712)
Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
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)
KeywordsPyridoxamine / Dopamine / Parkinson`s disease / Oxidative stress / Lipid-derived aldehyde
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.

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.

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。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (23 results)

All 2021 2020 2019 Other

All Journal Article (6 results) (of which Peer Reviewed: 6 results) Presentation (13 results) (of which Int'l Joint Research: 1 results,  Invited: 1 results) Remarks (4 results)

  • [Journal Article] Robust analysis of angiotensin peptides in human plasma: Column switching-parallel LC/ESI-SRM/MS without adsorption or enzymatic decomposition2021

    • Author(s)
      Suzuki Shinsaku、Goto Takaaki、Lee Seon Hwa、Oe Tomoyuki
    • Journal Title

      Analytical Biochemistry

      Volume: 630 Pages: 114327-114327

    • DOI

      10.1016/j.ab.2021.114327

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Alternative LC/ESI-MS/MS approach to screen hemoglobin N-terminal modifications2021

    • Author(s)
      Usuzawa Go、Lee Seon Hwa、Oe Tomoyuki
    • Journal Title

      International Journal of Mass Spectrometry

      Volume: 468 Pages: 116651-116651

    • DOI

      10.1016/j.ijms.2021.116651

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Screening of chemical modifications in human skin keratins by mass spectrometry-based proteomic analysis via noninvasive sampling and on-tape digestion2020

    • Author(s)
      Seon Hwa Lee, Jiei Kawase, Yusuke Hiroshima, Tomoyuki Oe
    • Journal Title

      Journal of Proteome Research

      Volume: 19 Issue: 9 Pages: 3837-3845

    • DOI

      10.1021/acs.jproteome.0c00406

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Carnosine and anserine in chicken can quench toxic acrylamide under cooking conditions: Mass spectrometric studies on adduct formation and characterization2020

    • Author(s)
      Aoi Takama, Hiroko Matsubara, Seon Hwa Lee, Tomoyuki Oe
    • Journal Title

      Food Chemistry

      Volume: 333 Pages: 127480-127480

    • DOI

      10.1016/j.foodchem.2020.127480

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Angiotensin II-induced oxidative stress in human endothelial cells: Modification of cellular molecules through lipid peroxidation2019

    • Author(s)
      Seon Hwa Lee, Shuhei Fujioka, Ryo Takahashi, and Tomoyuki Oe
    • Journal Title

      Chemical Research in Toxicology

      Volume: 32 Issue: 7 Pages: 1412-1422

    • DOI

      10.1021/acs.chemrestox.9b00110

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] LC-MS analyses of <i>N</i>-acetyl-<i>p</i>-benzoquinone imine-adducts of glutathione, cysteine, <i>N</i>-acetylcysteine, and albumin in a plasma sample: A case study from a patient with a rare acetaminophen-induced acute swelling rash2019

    • Author(s)
      Masashi Ozawa, Takashi Kubo, Seon Hwa Lee, and Tomoyuki Oe
    • Journal Title

      The Journal of Toxicological Sciences

      Volume: 44 Issue: 8 Pages: 559-563

    • DOI

      10.2131/jts.44.559

    • NAID

      130007687322

    • ISSN
      0388-1350, 1880-3989
    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Presentation] LC/MSによる毛髪ケラチンの化学修飾解析法の開発2021

    • Author(s)
      保栖大暉、幡川祐資、李宣和、大江知行
    • Organizer
      第81回分析化学討論会
    • Related Report
      2021 Annual Research Report
  • [Presentation] N 末端α-ケトアミド型アンジオテンシンⅡのLC/ESI/SRM/MS 法の開発2021

    • Author(s)
      妻木拓人、池田真人、李宣和、大江知行
    • Organizer
      第18回次世代を担う若手のためのフィジカル・ファーマフォーラム/PPF2020/2021
    • Related Report
      2021 Annual Research Report
  • [Presentation] LC-MSによる毛髪ケラチンの化学修飾解析2021

    • Author(s)
      保栖大暉、幡川祐資、李宣和、大江知行
    • Organizer
      新アミノ酸分析研究会第11回学術講演会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 過酸化脂質由来の反応性アルデヒドによるグルタチオンペルオキシダーゼの活性阻害機構の解明2021

    • Author(s)
      高橋和之、幡川祐資、李宣和、大江知行
    • Organizer
      新アミノ酸分析研究会第11回学術講演会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 細胞内脂質過酸化機構の解明を目的とした水酸化脂肪酸のキラルLC/EC-APCI/SRM/MS分析2021

    • Author(s)
      中川秀斗、幡川祐資、李宣和、大江知行
    • Organizer
      第32回クロマトグラフィー科学会議
    • Related Report
      2021 Annual Research Report
  • [Presentation] 非置換型 etheno-DNA付加体のUHPLC/ESI-SRM/MS法の開発2021

    • Author(s)
      南雲悠真、幡川祐資、李宣和、大江知行
    • Organizer
      第32回クロマトグラフィー科学会議
    • Related Report
      2021 Annual Research Report
  • [Presentation] 食肉中イミダゾールジペプチドによるアクリルアミドの捕捉2020

    • Author(s)
      松原 寛子、髙間 葵、李 宣和、大江 知行
    • Organizer
      第59回日本薬学会東北支部大会
    • Related Report
      2020 Research-status Report
  • [Presentation] 脂質過酸化物由来のアルデヒド 4,5-epoxy-2(E)-decenal と DNA 塩基の反応 性に関する研究2020

    • Author(s)
      宍戸 菜々子、李 宣和、大江 知行
    • Organizer
      第59回日本薬学会東北支部大会
    • Related Report
      2020 Research-status Report
  • [Presentation] 神経毒性を有するドパミン酸化体のピリドキサミンによる捕捉:LC-MSによる反応メカニズム解析2019

    • Author(s)
      松本直也、李宣和、大江知行
    • Organizer
      みちのく分析科学シンポジウム2019
    • Related Report
      2019 Research-status Report
  • [Presentation] 過酸化脂質由来のインスリン抵抗性発現機構の解明2019

    • Author(s)
      筒井瑞紀、松永淳、李宣和、大江知行
    • Organizer
      みちのく分析科学シンポジウム2019
    • Related Report
      2019 Research-status Report
  • [Presentation] Pyridoxamine as a potential scavenger of neurotoxic dopamine quinone2019

    • Author(s)
      Naoya Matsumoto, Seon Hwa Lee, Tomoyuki Oe
    • Organizer
      2019年度 化学系学協会東北大会
    • Related Report
      2019 Research-status Report
  • [Presentation] Lipid hydroperoxide-derived insulin resistance in L6 skeletal muscle cells2019

    • Author(s)
      Mizuki Tsutsui, Atsushi Matsunaga, Seon Hwa Lee, Tomoyuki Oe
    • Organizer
      2019年度 化学系学協会東北大会
    • Related Report
      2019 Research-status Report
  • [Presentation] Alternative approach for biomarker discovery through chemical modificomics2019

    • Author(s)
      Seon Hwa Lee
    • Organizer
      2nd Tohoku University-Sichuan University Pharmaceutical Sciences Collaboration Symposium
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Remarks] researchmap マイポータル

    • URL

      https://researchmap.jp/LSH6835

    • Related Report
      2021 Annual Research Report 2020 Research-status Report 2019 Research-status Report
  • [Remarks] 東北大学大学院薬学研究科臨床分析化学分野ホームページ

    • URL

      http://www.pharm.tohoku.ac.jp/~bunseki/bunseki.html

    • Related Report
      2021 Annual Research Report 2020 Research-status Report 2019 Research-status Report
  • [Remarks] 東北大学研究者紹介

    • URL

      https://www.r-info.tohoku.ac.jp/index.php?action=pages_view_main&active_action=cvclient_view_main_init&cvid=LSH6835&display_type=cv&block_id=442#_442

    • Related Report
      2021 Annual Research Report
  • [Remarks] 東北大学研究者紹介

    • URL

      http://db.tohoku.ac.jp/whois/detail/a63434da0ba1befd3ff395e655af195e.html

    • Related Report
      2020 Research-status Report 2019 Research-status Report

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Published: 2019-04-18   Modified: 2023-01-30  

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