The effects of neurotrophic factor for carbon monoxide poisoning–induced delayed encephalopathy

• Project/Area Number: 19K09436
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55060:Emergency medicine-related
• Research Institution: Ehime University
• Principal Investigator: Nishihara Tasuku 愛媛大学, 医学系研究科, 准教授 (50568912)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 一酸化炭素中毒 / 遅発性脳症 / マイクログリア / 神経栄養因子 / IGF-2 / ミエリン / 神経細胞 / 神経保護因子 / 神経前駆細胞

Outline of Research at the Start

IGF-2による一酸化炭素中毒後遅発性脳症の治療効果を示す。IGF-2の投与によりミエリンの保持が可能であるか、リアルタイムPCRやWestern Blotting法を用いて解析する。また、IGF-2以外の神経保護因子の投与でも同様に検討し、この際にはミエリンだけではなく、神経自体、もしくはマイクログリアの保護効果についても検討していく予定である。さらに、これらの神経保護因子の効果的な組み合わせを探索することで、より臨床応用が可能な治療方法を探索する計画としている。

Outline of Final Research Achievements

In caarbon monoxide (CO) poisoning, decreased in microglial cell numbers are observed and microglia (MG) with detached branches are observed. Furthermore, mRNAs encoding several neurotrophic factors expressed by MG were decreased. These findings may cause delayed encephalopathy (DE). We aimed that supplementation of Insulin-like growth factor-2(IGF-2) may prevent DE. As the results, supplementation of IGF-2 prevented demyelination but was not associated with survival of MG. Moreover, IGF-2 ameliorated CO induced behavioral abnormality. These effects are probably induced via IGF-1 receptor expressed on the neuronal cell surface. Supplementation of IGF-2 may have certain effects on DE after CO poisoning.

Academic Significance and Societal Importance of the Research Achievements

これまで一酸化炭素中毒およびその後遺症ともいえる遅発性脳症に対して、明らかに有効といえる治療方法はなかった。しかしながら、本研究により、IGF-2という神経栄養因子の補充が、中毒後に介入可能な治療方法として可能性が認められたことは、大きな進歩といえる。

Research Products

• [Journal Article] Neural precursor cells are decreased in the hippocampus of the delayed carbon monoxide encephalopathy rat model (2021)
  • Author(s): Ochi S, Sekiya K, Abe N, Funahashi Y, Kumon H, Yoshino Y, Nishihara T, Boku S, Iga J, Ueno S
  • Journal Title: Scientific Reports Volume: 18 Issue: 1 Pages: 6244-6244
  • DOI: 10.1038/s41598-021-85860-9
  • Peer Reviewed / Open Access
• [Journal Article] Microglia and Macrophages in the Pathological Central and Peripheral Nervous Systems (2020)
  • Author(s): Abe N, Nishihara T, Yorozuya T, Tanaka J
  • Journal Title: Cells Volume: 9 Issue: 9 Pages: 2132-2132
  • DOI: 10.3390/cells9092132
  • Peer Reviewed / Open Access
• [Journal Article] A Case Report of Thrombotic Complete Obstruction of the Ascending Aorta as a Complication of Venoarterial Extracorporeal Membrane Oxygenation Support: Steps to Prevent Thrombosis (2020)
  • Author(s): Nishihara T*, Kudamatsu N, Hamada T, Nakata Y, Yamamoto W, Nandate H, Namiguchi K, Nishimura T, Izutani H, Yorozuya T
  • Journal Title: Journal of Cardiothoracic Surgery Volume: 23 Issue: 1 Pages: 185-185
  • DOI: 10.1186/s13019-020-01239-3
  • Peer Reviewed / Open Access
• [Journal Article] Chronic constriction injury of the sciatic nerve in rats causes different activation modes of microglia between the anterior and posterior horns of the spinal cord (2020)
  • Author(s): Nishihara T, Tanaka J, Sekiya K, Nishikawa Y, Abe N, Hamada T, Kitamura S, Ikemune K, Ochi S, Choudhury ME, Yano H, Yorozuya T
  • Journal Title: Neurochemistry International Volume: 134 Pages: 104672-104672
  • DOI: 10.1016/j.neuint.2020.104672
  • Peer Reviewed / Open Access
• [Journal Article] Carbon monoxide poisoning-induced delayed encephalopathy accompanies decreased microglial cell numbers: Distinctive pathophysiological features from hypoxemia-induced brain damage (2019)
  • Author(s): Sekiya K, Nishihara T, Abe N, Konishi A, Nandate H, Hamada T, Ikemune K, Takasaki Y, Tanaka J, Asano M, Yorozuya T
  • Journal Title: Brain Research Volume: 1710 Pages: 22-32
  • DOI: 10.1016/j.brainres.2018.12.027
  • Peer Reviewed / Open Access
• [Journal Article] Hemolytic reaction in the washed salvaged blood of a patient with paroxysmal nocturnal hemoglobinuria (2019)
  • Author(s): Kawamoto Y, Nishihara T, Watanabe A, Nakanishi K, Hamada T, Konishi A, Abe N, Kitamura S, Ikemune K, Toda Y, Yorozuya T
  • Journal Title: BMC Anesthesiology Volume: 19(1) Issue: 1 Pages: 83-83
  • DOI: 10.1186/s12871-019-0752-4
  • Peer Reviewed / Open Access
• [Presentation] 一酸化炭素中毒後遅発性脳症に対する神経栄養因子による予防効果の検討 (2022)
  • Author(s): 西原佑、関谷慶介、阿部尚紀、濱田泰輔、萬家俊博
  • Organizer: 日本麻酔科学会第69回学術集会