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Contribution of activated microglia in epileptogenesis after status epilepticus

Research Project

Project/Area Number 16K19634
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Pediatrics
Research InstitutionUniversity of Yamanashi

Principal Investigator

Fumikazu SANO  山梨大学, 大学院総合研究部, 特任助教 (00622375)

Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywordsてんかん / ミクログリア / アストロサイト / 神経炎症 / 脳神経疾患 / 神経科学
Outline of Final Research Achievements

The aim of this study is to test our hypothesis that early microglial activation after status epilepticus (SE) lead to reactive astrocytes which can cause epileptogenesis.
We detected a significant increase in the area of Iba1-positive microglia, mRNA of TNF-α in the hippocampus at 1 day after SE which was followed by the increase in the area of GFAP-positive astrocyte in CA1 from 7 to 28 days after SE. Astrocytes displayed significantly larger and longer Ca2+ signals from 25 to 32 days after SE. In addition, less dose of pilocarpine was required for the induction of the second SE at 28 days after the first SE. Microglia inhibition with minocycline reduced astrogliosis, Ca2+ signals of astrocytes, and rescued the increased seizure-susceptibility. These results suggest that reactive astrocytes triggered by activated microglia undergo a part of physiological changes which can cause epilepstogenesis.

Academic Significance and Societal Importance of the Research Achievements

本研究を通じて、てんかん原生獲得の分子病態におけるグリア相互作用(活性化ミクログリアが誘導するアストロサイトの活性化)の関与が明らかとなったことで、既存のてんかん治療薬とは全く異なる、グリア細胞を標的とした新たなてんかん治療薬開発の基盤となる成果となりうる。また、これらの結果は、従来の難治てんかんに対する「単にてんかん発作を抑制する」という対症療法的な治療戦略と異なりてんかん原生そのものを予防・消失させるという「てんかんに対する病態修飾治療」という新たな治療戦略の基礎的概念の確立と、臨床応用にむけた萌芽的な研究成果となりうる。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (10 results)

All 2019 2018 2017 2016 Other

All Presentation (9 results) (of which Int'l Joint Research: 3 results) Remarks (1 results)

  • [Presentation] Astrocytic Ca2+ signals via IP3 receptor type2 mediate reactive astrocytes after status epilepticus2019

    • Author(s)
      佐野史和
    • Organizer
      The 9th Federation of the Asian and Oceanian Physiological Societies Congress
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Microglial VNUT derived ATP mediates astrogliosis-dependent epileptogenesis after status epilepticus2018

    • Author(s)
      佐野史和
    • Organizer
      第60回日本小児神経学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Contribution of activated glial cells in epileptogenesis after status epilepticus2018

    • Author(s)
      佐野史和
    • Organizer
      18th World Congress of Basic and Clinical Pharmacology
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Astrogliosis by status epilepticus is dependent on IP3 receptor type22018

    • Author(s)
      佐野史和
    • Organizer
      第52回日本てんかん学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Enhanced astrocytic Ca2+ signals via IP3R2 contribute to epileptogenesis after status epilepticus2017

    • Author(s)
      佐野史和
    • Organizer
      14th Asian Oceanian Congress of Child Neurology
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Microglial VNUT contribute to epileptogenesis including astrogliosis after status epilepticus2017

    • Author(s)
      佐野史和
    • Organizer
      第59回日本小児神経学会学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] Acute microglial activation phenotype after status epilepticus: role of microglial vesicular nucleotide transporter in epileptogenesis2017

    • Author(s)
      佐野史和
    • Organizer
      第51回日本てんかん学会学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] Contributions of reactive astrocytes triggered by microglia to epileptogenesis following status epilepticus.2016

    • Author(s)
      Fumikazu Sano, Eiji Shigetomi, Schuichi Koizumi, Hideaki Kanemura, Kanji Sugita, Masao Aihara
    • Organizer
      第50回日本てんかん学会学術集会
    • Place of Presentation
      グランシップ静岡(静岡県静岡市)
    • Year and Date
      2016-10-07
    • Related Report
      2016 Research-status Report
  • [Presentation] Activated microglia as a potential therapeutic target for epileptogenesis after status epilepticus2016

    • Author(s)
      Fumikazu Sano, Eiji Shigetomi, Schuichi Koizumi, Hideaki Kanemura, Kanji Sugita, Masao Aihara.
    • Organizer
      第58回日本小児神経学会学術集会
    • Place of Presentation
      京王プラザホテル新宿(東京都新宿区西新宿)
    • Year and Date
      2016-06-03
    • Related Report
      2016 Research-status Report
  • [Remarks] 薬理学講座 - 山梨大学医学部

    • URL

      https://www.med.yamanashi.ac.jp/clinical_basic/pharmaco/1-Japanese/home.html

    • Related Report
      2018 Annual Research Report

URL: 

Published: 2016-04-21   Modified: 2020-03-30  

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