Establishment of novel prophylaxis/treatment for cerebral infarction using SIRT1 activator

• Project/Area Number: 26640034
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: Hattori Yorito 国立研究開発法人国立循環器病研究センター, 病院, 客員研究員 (60713849)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: SIRT1 / 頸動脈狭窄症 / 血管性認知症 / 脳血流量 / 脳低還流 / 脳虚血 / 内皮型一酸化窒素合成酵素 / 脱アセチル化

Outline of Final Research Achievements

We hypothesized that SIRT1 counertacts cerebral ischemia/hypoperfusion.
We did the bilateral common carotid artery stenosis (BCAS) surgery to Sirt1 transgenic (Sirt1-Tg) mice and wild-type (WT) littermates, which induces chronic cerebral hypoperfusion. WT mice showed working memory impairment and cerebral white matter ischemic injury, but Sirt1-Tg mice preserved memory function and cerebral histologic integrity at 1 month after BCAS. For Sirt1-Tg mice showed continuously preserved cerebral blood flow after BCAS even though CBF of WT mice decreased to 70-80% of baseline after the surgery. The mechanism is that SIRT1 deacetylate endothelial nitric oxide synthase (eNOS) and activated that so that cerebral arteries dilate.
We are going to try the clinical research using SIRT1 activator.

Research Products

• [Journal Article] Gradual Carotid Artery Stenosis in Mice Closely Replicates Hypoperfusive Vascular Dementia in Humans. (2016)
  • Author(s): Hattori Y, Enmi J, Iguchi S, Saito S, Yamamoto Y, Tsuji M, Nagatsuka K, Kalaria RN, Iida H, Ihara M
  • Journal Title: Journal of the American Heart Association Volume: 5 Issue: 2
  • DOI: 10.1161/jaha.115.002757
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] SIRT1 attenuates severe ischemic damage by preserving cerebral blood flow. (2015)
  • Author(s): Hattori Y, Okamoto Y, Nagatsuka K, Takahashi R, Kalaria RN, Kinoshita M, Ihara M
  • Journal Title: NeuroReport Volume: 26 Issue: 3 Pages: 113-117
  • DOI: 10.1097/wnr.0000000000000308
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Silent Information Regulator 2 Homolog 1 Counters Cerebral Hypoperfusion Injury by Deacetylating Endothelial Nitric Oxide Synthase (2014)
  • Author(s): Hattori Y, Okamoto Y, Maki T, Yamamoto Y, Oishi N, Yamahara K, Nagatsuka K, Takahashi R, Kalaria RN, Fukuyama H, Kinoshita M, Ihara M
  • Journal Title: Stroke Volume: 45 Issue: 11 Pages: 3403-3411
  • DOI: 10.1161/strokeaha.114.006265
  • Peer Reviewed
• [Presentation] Gradual Carotid Artery Stenosis in Mice Closely Replicates Hypoperfusive Vascular Dementia in Humans (2016)
  • Author(s): Hattori Y, Enmi J, Okamoto Y, Nagatsuka K, Kalaria RN, Iida H, Ihara M
  • Organizer: International Stroke Conference 2016
  • Place of Presentation: Los Angeles
  • Year and Date: 2016-02-16
  • Int'l Joint Research
• [Presentation] 緩徐進行性の脳血流低下による血管性認知障害モデルマウスの作製 (2015)
  • Author(s): 服部頼都，圓見純一郎，長束一行，飯田秀博，猪原匡史
  • Organizer: 第27回日本脳循環代謝学会総会
  • Place of Presentation: 富山
  • Year and Date: 2015-10-30
• [Presentation] A POTENT PROTECTIVE ROLE OF SIRT1 AGAINST CHRONIC CEREBRAL HYPOPERFUSION (2014)
  • Author(s): Hattori Y, Okamoto Y, Yamamoto Y, Oishi N, Nagatsuka K, Takahashi R, Fukuyama H, Kinoshita M, Ihara M
  • Organizer: 第55回日本神経学会学術集会
  • Place of Presentation: 福岡国際会議場
  • Year and Date: 2014-05-21 – 2014-05-24
• [Book] 脳卒中―新時代の治療を求めて「SIRT1」 (2016)
  • Author(s): 服部頼都，猪原匡史
  • Total Pages: 6
  • Publisher: 日本臨牀