Elucidation of the anti-inflammatory mechanism of anesthetic through peroxisome proliferator-activated receptor gamma activation

• Project/Area Number: 17K17248
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Surgical dentistry
• Research Institution: Okayama University
• Principal Investigator: Wakasugi Yuka 岡山大学, 医歯薬学総合研究科, 助教 (00749210)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 歯学 / 薬理学 / デクスメデトミジン / PPARγ / 15d-PGJ2 / ペルオキシソーム増殖因子活性化受容体γ / 抗炎症作用

Outline of Final Research Achievements

This study aimed to elucidate the mechanism of anti-inflammatory effect of dexmedetomidine (DEX). Anti-inflammatory effect of DEX in Raw264.7 mouse macrophages was examined. We hypothesized that the production of 15-deoxy-delta-12,14-prostaglandin J2 (15d-PGJ2), which are known to have anti-inflammatory effect, increased via the arachidonic acid cascade by DEX, leading to anti-inflammatory effect. DEX inhibited inflammatory cytokine production, and increased 15d-PGJ2 production and PPARγ mRNA expression in the cells. These results suggest that DEX inhibits LPS-induced inflammatory responses through 15d-PGJ2 production and PPARγ activation.

Academic Significance and Societal Importance of the Research Achievements

口腔内疾患の多くは炎症を併発し、外科処置後、炎症がさらに惹起され、腫脹、疼痛が主な術後合併症になる。術後NSAIDsが使用されるが、臨床投与量では必ずしも炎症症状を完全に抑制することはできない。当教室では、鎮静薬であるデクスメデトミジン（DEX）を局所投与することで、抗浮腫・炎症性疼痛抑制作用を示すことを証明してきた。本研究の目的はその機序を解明し、麻酔薬の抗炎症作用を臨床応用に繋げることである。

Research Products

• [Journal Article] Dexmedetomidine inhibits LPS-induced inflammatory responses through peroxisome proliferator-activated receptor gamma (PPARγ) activation following binding to α2 adrenoceptors (2021)
  • Author(s): Fujimoto Maki、Higuchi Hitoshi、Honda-Wakasugi Yuka、Miyake Saki、Nishioka Yukiko、Yabuki-Kawase Akiko、Maeda Shigeru、Miyawaki Takuya
  • Journal Title: European Journal of Pharmacology Volume: 892 Pages: 173733-173733
  • DOI: 10.1016/j.ejphar.2020.173733
  • Peer Reviewed / Open Access
• [Journal Article] Intellectual disability is a risk factor for delayed emergence from total intravenous anaesthesia. (2018)
  • Author(s): Higuchi H*, Maeda S, Ishii-Maruhama M, Honda-Wakasugi Y, Yabuki-Kawase A, Miyawaki T.
  • Journal Title: Journal of Intellectual Disability Research Volume: 62 Issue: 3 Pages: 217-224
  • DOI: 10.1111/jir.12448
• [Journal Article] Capnography prevents hypoxia during sedation for dental treatment: a randomized controlled trial. (2017)
  • Author(s): Takaya K, Higuchi H*, Ishii-Maruhama M, Yabuki-Kawase A, Honda Y, Tomoyasu Y, Maeda S, Miyawaki T.
  • Journal Title: JDR Clinical & translational research Volume: 2 Pages: 158-167
• [Journal Article] Clinical analysis of analgesics and steroids use for extraction of teeth in patients with intellectual disability under general anesthesia. (2017)
  • Author(s): Maeda S*, Honda Y, Tanimura H, Tomoyasu Y, Higuchi H, Murata N, Egusa M, Miyawaki T.
  • Journal Title: The Open Dentistry Journal Volume: 31 Issue: 1 Pages: 181-186
  • DOI: 10.2174/1874210601711010181
• [Presentation] デクスメデトミジンはペルオキシソーム増殖因子活性化受容体γ（PPARγ）活性を介してLPS誘発性炎症反応を抑制する (2020)
  • Author(s): 藤本磨希，若杉優花，三宅沙紀，樋口仁，前田茂，宮脇卓也
  • Organizer: 第48回日本歯科麻酔学会総会・学術集会
• [Presentation] Dexmedetomidine increases expression of peroxisome proliferator-activated receptor gamma (PPAR-gamma) in LPS-stimulated mouse macrophage-like cells. (2019)
  • Author(s): Fujimoto M, Miyake S, Honda-Wakasugi Y, Hitoshi H, Maeda S, Miyawaki T.
  • Organizer: Euroanaesthesia
  • Int'l Joint Research
• [Presentation] マウスマクロファージ由来株細胞 (Raw264.7) におけるデクスメデトミジンによるIL-6産生抑制効果 (2017)
  • Author(s): 若杉優花, 三宅沙紀, 藤本磨希, 栗田恵理佳, 川瀬明子, 樋口仁, 前田茂, 宮脇卓也
  • Organizer: 第45回日本歯科麻酔学会総会・学術集会
• [Presentation] Effect of dexmedetomidine on brain ischemia. (2017)
  • Author(s): Maeda S, Onishi R, Honda-Wakasugi Y, Yabuki-Kawase A, Higuchi H, Miyawaki T.
  • Organizer: 47th Society for Neuroscience
  • Int'l Joint Research
• [Presentation] Liposome-encapsulation increase the bioavailability of midazolam on oral administration. (2017)
  • Author(s): Tanimura H, Mori-Yoshioka M, Honda-Wakasugi Y, Higuchi H , Maeda S, Miyawaki T.
  • Organizer: Euroanaesthesia
  • Int'l Joint Research
• [Presentation] Ivabradine inhibits LPS-stimulated inflammatory cytokyne production via hyperpolarization-activated cyclic-nucleotide-gated channeld in the mouse macrophage-like cell line Raw264.7. (2017)
  • Author(s): Miyake S, Honda-Wakasugi Y, Yabuki-Kawase A, Hitoshi H, Maeda S, Miyawaki T.
  • Organizer: Euroanaesthesia
  • Int'l Joint Research