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Neuroprotective effects of P7C3 through activation of sirtuin gene and its application for optic nerve diseases.

Research Project

Project/Area Number 16K11336
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Ophthalmology
Research InstitutionOsaka Medical College

Principal Investigator

Oku Hidehiro  大阪医科大学, 医学部, 准教授 (90177163)

Co-Investigator(Kenkyū-buntansha) 小嶌 祥太  大阪医科大学, 医学部, 講師 (10388259)
小林 崇俊  大阪医科大学, 医学部, 講師 (10567093)
池田 恒彦  大阪医科大学, 医学部, 教授 (70222891)
高井 真司  大阪医科大学, 医学研究科, 教授 (80288703)
喜田 照代  大阪医科大学, 医学部, 講師 (90610105)
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
KeywordsP7C3 / mTOR / NAD / sirtuin / 視神経挫滅モデル / 網膜神経節細胞 / CD68 / TNF-α / rapamycin / neuroinflammation / 小胞体ストレス / NAMPT / SIRT-1 / 軸索変性 / サーチュイン
Outline of Final Research Achievements

Neuroprotective effects of P7C3 on retinal ganglion cells (RGCs) were determined using optic nerve crush (ONC) model of rats. The left optic nerve was crushed, and 5.0 mg/kg/d of P7C3 or its vehicle was injected intraperitoneally for 3 consecutive days beginning 1 day before the ONC. P7C3 significantly preserved the density of RGCs on days 7 and 14 after the ONC. ONC decreased the NAD levels as well as mRNA levels of Nampt and Sirt-1 genes in the optic nerves, while P7C3 significantly restored the levels. In addition, ONC increased the level of phosphorylated mTOR and P7C3 significantly lowered the level. There was an accumulation of CD68+ cells that were immunoreactive to TNF-α at the crush site. Inflammatory genes including the CD68, TNF-α, MCP-1, and iNOS were upregulated after the ONC and these inflammatory events were suppressed by P7C3. Thus, effects of P7C3 may involve NAD metabolisms and anti-inflammatory properties through suppression of mTOR pathways.

Academic Significance and Societal Importance of the Research Achievements

P7C3は神経再生を目的としたin vivo包括的スクリーングで抽出された薬剤で、神経保護作用が期待されている。その作用機序としてNAD合成を促進することが報告されている。NADはワーラー変性遅延遺伝子の機能も担っている。本研究でも傷害視神経でNAD量の減少が抑制された。さらにNADはmTOR系を阻害する可能性が示唆されている。mTOR kinaseはグリアの活性化に深く関与し、neuroinflammationを惹起する。P7C3は傷害視神経でリン酸化mTORの発現を抑制し、neuroinflammation を抑制した。P7C3は広く神経変性疾患に応用できる可能性があると考えられる。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (10 results)

All 2019 2018 2017 2016

All Journal Article (6 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 6 results,  Open Access: 2 results,  Acknowledgement Compliant: 2 results) Presentation (4 results) (of which Int'l Joint Research: 2 results)

  • [Journal Article] Immunohistological Study of Monkey Foveal Retina2019

    • Author(s)
      Ikeda Tsunehiko、Nakamura Kimitoshi、Oku Hidehiro、Horie Taeko、Kida Teruyo、Takai Shinji
    • Journal Title

      Scientific Reports

      Volume: 9 Issue: 1 Pages: 5258-5258

    • DOI

      10.1038/s41598-019-41793-y

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Vasoactivity of retinal veins: A potential involvement of endothelin-1 (ET-1) in the pathogenesis of retinal vein occlusion (RVO).2018

    • Author(s)
      Kida T, Flammer J, Oku H, Konieczka K, Morishita S, Horie T, Ikeda T.
    • Journal Title

      Exp Eye Res

      Volume: 176 Pages: 207-209

    • DOI

      10.1016/j.exer.2018.07.016

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Neuroprotective effects of inhibitors of Acid-Sensing ion channels (ASICs) in optic nerve crush model in rodents.2018

    • Author(s)
      Stankowska DL, Mueller BH 2nd, Oku H, Ikeda T, Dibas A.
    • Journal Title

      Curr Eye Res.

      Volume: 43 Issue: 1 Pages: 84-95

    • DOI

      10.1080/02713683.2017.1383442

    • Related Report
      2018 Annual Research Report 2017 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] P7C3 Suppresses Neuroinflammation and Protects Retinal Ganglion Cells of Rats from Optic Nerve Crush.2017

    • Author(s)
      Oku H, Morishita S, Horie T, Kida T, Mimura M, Kojima S, Ikeda T.
    • Journal Title

      Investigative Ophthalmology & Visual Science

      Volume: 58 Issue: 11 Pages: 4877-4888

    • DOI

      10.1167/iovs.17-22179

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Protective effect of P7C3 on retinal ganglion cells from optic nerve injury.2017

    • Author(s)
      Oku H, Morishita S, Horie T, Nishikawa Y, Kida T, Mimura M, Kojima S, Ikeda T.
    • Journal Title

      Jpn J Ophthalmol

      Volume: 61 Issue: 2 Pages: 195-203

    • DOI

      10.1007/s10384-016-0493-6

    • NAID

      210000165803

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Implication of VEGF and AQP4 mediating Muller cell swelling to diabetic retinal edema.2017

    • Author(s)
      Kida T, Oku H, Horie T, Fukumoto M, Okuda Y, Morishita S, Ikeda T.
    • Journal Title

      Graefes Arch Clin Exp Ophthalmol

      Volume: 印刷中 Issue: 6 Pages: 1149-1157

    • DOI

      10.1007/s00417-017-3631-z

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Presentation] P7C3 Suppresses Neuroinflammation and Protects Retinal Ganglion Cells of Rats from Optic Nerve Crush.2018

    • Author(s)
      Oku H、Horie T、Kida T, Ikeda T.
    • Organizer
      90th Annual Meeting of ARVO
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] P7C3 Suppresses Neuroinflammation and Protects Retinal Ganglion Cells of Rats from Optic Nerve Crush.2017

    • Author(s)
      Oku H, Kida T, Hoorie T, Ikeda T.
    • Organizer
      The Association for Research in Vision and Ophthalmology
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] mTOR阻害剤の小胞体ストレス、オートファジーを介した神経保護作用の検討2017

    • Author(s)
      奥 英弘、喜田照代、堀江妙子、池田恒彦
    • Organizer
      日本眼科学会総会
    • Related Report
      2017 Research-status Report
  • [Presentation] P7C3 による神経保護作用の検討2016

    • Author(s)
      奥 英弘、堀江妙子、西川優子、喜田照代、池田恒彦
    • Organizer
      第120回日本眼科学会総会
    • Place of Presentation
      仙台
    • Year and Date
      2016-04-07
    • Related Report
      2016 Research-status Report

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Published: 2016-04-21   Modified: 2020-03-30  

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