New hypothermia therapy by the glial microenvironment for the neonatal hypoxic ischemic encephalopathy

• Project/Area Number: 18K07832
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Aichi Medical University
• Principal Investigator: Hiroki Kakita 愛知医科大学, 医学部, 講師 (40528949)
• Co-Investigator(Kenkyū-buntansha): 山田 恭聖 愛知医科大学, 医学部, 教授 (60405165) ; 青山 峰芳 名古屋市立大学, 医薬学総合研究院(薬学), 教授 (70363918)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 新生児低酸素性虚血性脳症 / グリア / アストロサイト / ミクログリア / 低体温療法 / 新生児脳障害 / エリスロポエチン / 低酸素性虚血性脳症 / ニューロン / 新生児仮死

Outline of Final Research Achievements

Hypoxic-ischemic encephalopathy (HIE) has a high morbidity rate and involves severe neurologic deficits, including cerebral palsy. Therapeutic hypothermia (TH) has been shown to decrease the mortality rate and provide neuroprotection in infants with HIE. We demonstrated that hypothermia after oxygen/glucose deprivation stabilized HIF-EPO signaling in astrocytes, and upregulated EPO expression could suppress neuronal apoptosis. In addition, we demonstrated that, under hypothermic conditions, expression of pro-inflammatory cytokines and inducible nitric oxide synthase (iNOS) was suppressed. In addition, phagocytosis of latex beads was significantly suppressed in BV-2 cells under hypothermic conditions.Investigating the neuroprotective effect of EPO from astrocytes and microglia function under hypothermic conditions may contribute to the development of novel neuroprotection-based therapies for HIE

Academic Significance and Societal Importance of the Research Achievements

新生児の後遺症なき生存を阻む大きな壁は脳障害である。近年、低体温療法が新生児低酸素性虚血脳症における治療法として確立している。しかし、その効果は限定的である。今回の検討で低体温療法の脳保護メカニズムの一部をグリアの機能制御という観点で明らかにできた。本研究はグリアに注目した基礎研究で、低体温療法の脳保護メカニズムのさらなる解明、新規補完治療法の開発につながると期待できる。さらにグリアの機能を制御することで低体温療法が施行困難な早産児の脳室周囲白質軟化症も含めた包括的な新生児脳障害の治療成績を向上させることにもつながると考えられる

Research Products

• [Journal Article] Hypothermia Attenuates Neuronal Damage via Inhibition of Microglial Activation, Including Suppression of Microglial Cytokine Production and Phagocytosis (2021)
  • Author(s): Kimura Tomoka、Toriuchi Kohki、Kakita Hiroki、Tamura Tetsuya、Takeshita Satoru、Yamada Yasumasa、Aoyama Mineyoshi
  • Journal Title: Cellular and Molecular Neurobiology Volume: 41 Issue: 3 Pages: 459-468
  • DOI: 10.1007/s10571-020-00860-z
  • Peer Reviewed / Open Access
• [Journal Article] Prolonged astrocyte-derived erythropoietin expression attenuates neuronal damage under hypothermic conditions (2020)
  • Author(s): Kohki Toriuchi,1 Hiroki Kakita,1,2 Tetsuya Tamura,3 Satoru Takeshita,1,2 Yasumasa Yamada,2 and Mineyoshi Aoyamacorresponding author1
  • Journal Title: J Neuroinflammation. Volume: 17 Issue: 1 Pages: 141-141
  • DOI: 10.1186/s12974-020-01831-3
  • Peer Reviewed / Open Access
• [Journal Article] IL-6 promotes cell adhesion in human endothelial cells via microRNA-126?3p suppression (2020)
  • Author(s): Ohta Momoka、Kihara Toshie、Toriuchi Kohki、Aoki Hiromasa、Iwaki Soichiro、Kakita Hiroki、Yamada Yasumasa、Aoyama Mineyoshi
  • Journal Title: Experimental Cell Research Volume: 393 Issue: 2 Pages: 112094-112094
  • DOI: 10.1016/j.yexcr.2020.112094
  • Peer Reviewed / Open Access
• [Journal Article] 新生児低酸素性虚血性脳症の治療 低体温療法を中心に(総説) (2019)
  • Author(s): 垣田博樹
  • Journal Title: 東海産科婦人科学会雑誌 Volume: 55 Pages: 9-16
• [Journal Article] 新生児低酸素性虚血性脳症の治療 ;低体温療法を中心に (2018)
  • Author(s): 垣田博樹
  • Journal Title: 東海産科婦人科学会誌 Volume: 55 Pages: 9-16
• [Presentation] 低温状態においてアストロサイトが分泌するエリスロポエチンを介した神経保護効果 (2019)
  • Author(s): 垣田博樹
  • Organizer: 第64回日本新生児成育医学会 学術集会