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The role of pericytes in the development of epileptogenesis after traumatic brain injury

Research Project

Project/Area Number 18K06712
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 47040:Pharmacology-related
Research InstitutionFukuoka University

Principal Investigator

TAKATA Fuyuko  福岡大学, 薬学部, 准教授 (70412575)

Co-Investigator(Kenkyū-buntansha) 古賀 允久  福岡大学, 薬学部, 准教授 (60570801)
片岡 泰文  福岡大学, 薬学部, 教授 (70136513)
岩尾 卓朗  福岡大学, 薬学部, 助教 (30846374)
Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Keywordsペリサイト / 頭部外傷 / てんかん / アストロサイト / ミクログリア / 神経易興奮性 / グルタミン酸 / 脳ペリサイト / PDGFRβ / PDGFR
Outline of Final Research Achievements

Traumatic brain injury TBI produces the secondary damages including late-onset epilepsy. To understand how TBI causes an uncoordinated crosstalk in the neurovascular unit (NVU) and neuronal hyperexcitability, we focused on pericyte reactivity in the NVU cell properties in TBI mice. PDGFRβ immunoreactivities in pericytes were significantly increased in the early phase (up to 4 days after TBI). Microglial and astrocyte activations were found during a period from 4 to 28 days after TBI. The severity of seizure induced by pilocarpine gradually increased, becoming significant at 28 days after TBI. Then, treatment of imatinib, an inhibitor of PDGFR signaling, during the early phase lowered seizure susceptibility to pilocarpine, suppressed microglial activation and decreased expression of the astrocytic glutamate transporter. These findings indicate that brain pericytes with rapidly increased PDGFRβ expression may drive TBI-induced dysregulation of NVU function and brain hyperexcitability.

Academic Significance and Societal Importance of the Research Achievements

これまでの頭部外傷後の遅発性てんかん研究では、脳神経活動異常、BBB機能障害、グリア細胞活性化についてそれぞれ個別で議論されてきたため、その発症機構の全貌を捉えることが困難であったと推測される。本研究は、頭部外傷後のペリサイト活性化がneurovascular unitの不調和を牽引することを明らかにし、遅発性てんかんの病態形成過程を段階的かつ複合的に捉えることを可能とした点に学術的意義がある。抗てんかん薬に抵抗性を示す遅発性てんかんの治療法は、未だ確立されていない。ペリサイトを本疾患の新規治療標的として提案することは、新たな治療薬開発の隘路を切り開く可能性があり、社会的意義は大きい。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (9 results)

All 2021 2020 2019 2018

All Journal Article (1 results) (of which Peer Reviewed: 1 results,  Open Access: 1 results) Presentation (8 results) (of which Int'l Joint Research: 5 results,  Invited: 1 results)

  • [Journal Article] Reactive pericytes in early phase are involved in glial activation and late-onset hypersusceptibility to pilocarpine-induced seizures in traumatic brain injury model mice2021

    • Author(s)
      Sakai K, Takata F, Yamanaka G, Yasunaga M, Hashiguchi K, Tominaga K, Itoh K, Kataoka Y, Yamauchi A, Dohgu S.
    • Journal Title

      Journal of Pharmacological Sciences

      Volume: 145 Issue: 1 Pages: 155-165

    • DOI

      10.1016/j.jphs.2020.11.008

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] Brain pericytes increase sodium-dependent glutamate uptake in astrocytes.2021

    • Author(s)
      髙田 芙友子,坂井研太,岩尾 卓朗,松本 純一,片岡 泰文,山内淳史,道具 伸也
    • Organizer
      第94回日本薬理学会年会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Enhanced glutamate uptake in the astrocytes cocultured with brain pericytes.2021

    • Author(s)
      Fuyuko Takata, Kenta Sakai, Takuro Iwao, Atsushi Yamauchi, Yasufumi Kataoka, Shinya Dohgu
    • Organizer
      3rd Mini-symposium on the blood-brain barrier from basic to clinical research
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 6.Activated pericytes in the early stage after traumatic brain injury is a key trigger of the progression of microglial activation and neuronal hyperexcitability in the stage in mice.2020

    • Author(s)
      Fuyuko Takata
    • Organizer
      2nd Mini-symposium on the blood-brain barrier from basic to clinical research
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] 10.Increased PDGFRβ expression of the pericytes in the early stage after traumatic brain injury is a major cause of the subsequent activation of microglia and hypersusceptibility to pilocarpine-induced seizure in mice.2019

    • Author(s)
      Fuyuko Takata, Kenta Sakai, Atsushi Yamauchi, Shinya Dohgu, Yasufumi Kataoka
    • Organizer
      NEURO 2019 (Late Breaking)
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] 12.PDGFRβ signal inhibition in brain pericytes suppresses glial activation and increased seizure susceptibility to pilocarpine in mice with traumatic brain injury.2019

    • Author(s)
      Kenta Sakai, Fuyuko Takata, Yoshie Tanaka, Yume Sezaki, Kazuki Tominaga, Kana Hashiguchi, Miho Yasunaga, Atsushi Yamauchi, Shinya Dohgu, Yasufumi Kataoka.
    • Organizer
      13th International Conference at Cerebral Vascular Biology
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] 頭部外傷後の脳ペリサイトPDGFRβシグナル阻害は、pilocarpineけいれん発作の感受性を減弱させる2019

    • Author(s)
      坂井研太、高田芙友子、冨永一樹、橋口夏奈、安永美保、山内淳史、道具伸也、片岡泰文
    • Organizer
      日本薬学会第139回年会
    • Related Report
      2018 Research-status Report
  • [Presentation] ピロカルピン誘発けいれん感受性テストを用いた頭部外傷後のてんかん原性評価2019

    • Author(s)
      高田芙友子、坂井研太、道具伸也、瀬崎由愛、田中淑恵、山中岳、河島尚志、伊藤康一、山内淳史、片岡泰文
    • Organizer
      第92回日本薬理学会
    • Related Report
      2018 Research-status Report
  • [Presentation] Dysregulation of the CNS supporting vascular and glial cells induces the late posttraumatic epilepsy in mice with mild traumatic brain injury.2018

    • Author(s)
      Kenta Sakai, Fuyuko Takata, Shinya Dohgu, Mitsuhisa Koga, Ikuya Kimura, Atsushi Yamauchi, Yasufumi Kataoka
    • Organizer
      18th World Congress of basic and clinical pharmacology
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research

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Published: 2018-04-23   Modified: 2022-01-27  

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