2018 Fiscal Year Final Research Report

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

Research Project

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Project/Area Number	16K11336
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Research Field	Ophthalmology
Research Institution	Osaka 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
Keywords	P7C3 / mTOR / NAD / sirtuin / 視神経挫滅モデル / 網膜神経節細胞 / CD68 / TNF-α
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.
Free Research Field	眼科学
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。