Investigation of mechanism of pathogenesis of postoperative and sepsis-associated delirium and cognitive dysfunction and development of the prophylaxis.

• Project/Area Number: 17H04319
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Anesthesiology
• Research Institution: Hirosaki University
• Principal Investigator: HIROTA KAZUYOSHI 弘前大学, 医学研究科, 教授 (20238413)
• Co-Investigator(Kenkyū-buntansha): 上野 伸哉 弘前大学, 医学研究科, 教授 (00312158) ; 櫛方 哲也 弘前大学, 医学研究科, 准教授 (80250603) ; 二階堂 義和 弘前大学, 医学研究科, 講師 (50613478) ; 橋場 英二 弘前大学, 医学部附属病院, 准教授 (10374844) ; 村上 学 弘前大学, 医学研究科, 教授 (80302090) ; 斎藤 淳一 弘前大学, 医学部附属病院, 助教 (90647413)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥16,640,000 (Direct Cost: ¥12,800,000、Indirect Cost: ¥3,840,000); Fiscal Year 2020: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2018: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2017: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
• Keywords: 譫妄 / 認知機能 / 手術侵襲 / 敗血症 / 高齢者

Outline of Final Research Achievements

Animal study: Lipopolysaccharide (LPS)-treated aged rats displayed a decreased object discrimination index, elevation of lipocalin-2 (LCN2) levels and ferrous ion levels in the hippocampus and the cortex. Pretreatment with the iron chelator deferoxamine (DFO) prevented the reduction in the object discrimination index of LPS-treated aged rats. The elevation in hippocampal and cortical LCN2 levels caused by LPS was not influenced by DFO pretreatment. The LPS-induced ferrous ion level elevation was blocked by DFO pretreatment.
Clinical Study: Plasma inflammatory markers significantly increased during radical cancer surgery in patients with esophageal or oral floor cancer. However, there was significant differences in plasma inflammatory biomarkers between patients with or without postoperative delirium (POD). Both density and ratio of α wave power were significantly higher in non-POD patients than POD patients.

Academic Significance and Societal Importance of the Research Achievements

基礎研究では、高齢敗血症ラットでの認知機能低下に鉄代謝が関与していることが分かり、鉄キレート剤で改善したことから、新たな創薬に結び付く可能性がある。臨床研究では、脳波のα波に麻酔導入直後から、術後譫妄が生じた患者では生じなかった患者より有意にα波パワー密度、相対的α波が低く、脳波により術後譫妄を予測でき、早めに介入することで譫妄を抑制できる可能性がある。また、譫妄患者も非譫妄患者も、全身炎症の程度は同様であり、炎症だけでは譫妄は生じないことが分かった。

Research Products

• [Journal Article] Lower fractional exhaled nitric oxide levels are associated with depressive symptom in males: A population-based cross-sectional study (2020)
  • Author(s): Takekawa Daiki、Kudo Takashi、Saito Junichi、Nikaido Yoshikazu、Sawada Kaori、Takanashi Shingo、Hirota Kazuyoshi
  • Journal Title: Psychiatry Research Volume: 293 Pages: 113453-113453
  • DOI: 10.1016/j.psychres.2020.113453
  • Peer Reviewed
• [Journal Article] GABA storage and release in the medial globus pallidus in L-DOPA-induced dyskinesia priming (2020)
  • Author(s): Nishijima H, Mori F, Arai A, Zhu G, Wakabayashi K, Okada M, Ueno S, Ichinohe N, Suzuki C, Kon T, Tomiyama M
  • Journal Title: Neurobiol Dis Volume: 143 Pages: 104979-104979
  • DOI: 10.1016/j.nbd.2020.104979
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sex-Related Differences in Anxiety and Functional Recovery after Spinal Cord Injury in Mice (2020)
  • Author(s): Fukutoku Tatsuhiro、Kumagai Gentaro、Fujita Taku、Sasaki Ayako、Wada Kanichiro、Liu Xizhe、Tanaka Toshihiro、Kudo Hitoshi、Asari Toru、Nikaido Yoshikazu、Ueno Shinya、Ishibashi Yasuyuki
  • Journal Title: Journal of Neurotrauma Volume: 37 Issue: 21 Pages: 2235-2243
  • DOI: 10.1089/neu.2019.6929
  • Peer Reviewed
• [Journal Article] Anti-Epileptic Effects of FABP3 Ligand MF1 through the Benzodiazepine Recognition Site of the GABAA Receptor (2020)
  • Author(s): Yabuki Yasushi、Liu Jiaqi、Kawahata Ichiro、Izumi Hisanao、Shinoda Yasuharu、Koga Kohei、Ueno Shinya、Shioda Norifumi、Fukunaga Kohji
  • Journal Title: International Journal of Molecular Sciences Volume: 21 Issue: 15 Pages: 5525-5525
  • DOI: 10.3390/ijms21155525
  • Peer Reviewed / Open Access
• [Journal Article] Decreased cardiac pacemaking and attenuated beta-adrenergic response in TRIC-A knockout mice. (2020)
  • Author(s): Murakami M, Toyama Y, Yonekura M, Ohba T, Matsuzaki Y, Sawamura D, Murakami AM, Nishi M, Itagaki S, Tomita H, Takeshima H.
  • Journal Title: Plos ONE Volume: 15 Issue: 12 Pages: 1-12
  • DOI: 10.1371/journal.pone.0244254
  • Peer Reviewed / Open Access
• [Journal Article] 術後せん妄・認知機能障害の予防と対策―最近のガイドラインから― (2020)
  • Author(s): 廣田和美
  • Journal Title: 麻酔 Volume: 69 Pages: 496-502
  • Peer Reviewed
• [Journal Article] Preoperative management and postoperative delirium: The possibility of neuroprehabilitation using virtual reality. (2020)
  • Author(s): Hirota K
  • Journal Title: J Anesth. Volume: 34 Issue: 1 Pages: 1-4
  • DOI: 10.1007/s00540-019-02660-2
  • Peer Reviewed
• [Presentation] 高齢化社会における術後譫妄・認知機能障害予防戦略～早期覚醒と周術期の患者管理・評価の重要性～ (2020)
  • Author(s): 廣田和美
  • Organizer: 日本臨床麻酔学会
  • Invited
• [Presentation] 高齢化社会における安全な周術期管理 -術後せん妄対策 (2020)
  • Author(s): 廣田和美
  • Organizer: 日本臨床モニター学会総会
  • Invited
• [Presentation] Involvement of meurodegenerative and neuroinflammatory processes in the pathogenesis of postoperative delirium in elderly mice. (2019)
  • Author(s): Nikaido Y, Tatara Y, Kushikata T, Hirota K.
  • Organizer: Hirosaki Medical Science Forum
  • Int'l Joint Research
• [Presentation] Investigation of the effect of perioperative inflammation on electroencephalogram (2019)
  • Author(s): Hirotaka Kinoshita, Tetsuya Kushikata, Daiki Takekawa, Kazuyoshi Hirota
  • Organizer: The 6th Congress of Asian Society for Neuroanesthesia and Critical Care
  • Int'l Joint Research