心的外傷後ストレス症候群(PTSD)の神経機序と治療戦略  [in Japanese] Neurological mechanism and therapeutic strategy for posttraumatic stress disorders  [in Japanese]

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Author(s)

    • 福永 浩司 Fukunaga Kohji
    • 東北大学大学院 薬学研究科 薬理学分野 Department of Pharmacology, Tohoku University Graduate School of Pharmaceutical Sciences
    • 矢吹 悌 Yabuki Yasushi
    • 東北大学大学院 薬学研究科 薬理学分野 Department of Pharmacology, Tohoku University Graduate School of Pharmaceutical Sciences
    • 高畑 伊吹 Takahata Ibuki
    • 東北大学大学院 薬学研究科 薬理学分野 Department of Pharmacology, Tohoku University Graduate School of Pharmaceutical Sciences
    • 松尾 和哉 Matsuo Kazuya
    • 東北大学大学院 薬学研究科 薬理学分野 Department of Pharmacology, Tohoku University Graduate School of Pharmaceutical Sciences

Abstract

<p>心的外傷後ストレス症候群(PTSD:post traumatic stress disorders)は戦争体験,交通事故,自然災害,性被害など深刻なイベントにより引き起こされる.わが国の生涯有病率は1.3%と報告されている.PTSDでは文脈記憶への過剰反応,恐怖記憶消去系の障害に加えて,軽度の認知機能,注意力,学習障害が見られる.ヒトや動物実験では扁桃体,前頭前野,海馬を含む情動・恐怖の神経回路の感受性亢進が関わる.しかし,PTSDのメカニズムは不明であり,根本治療薬もない.最近,オメガ3(ω3)多価不飽和脂肪酸の摂取が自動車事故や東北大震災後のPTSD症状を軽減することが報告されている.脳型脂肪酸結合タンパク質(FABP7)の遺伝子欠損マウスではPTSD様の不安行動と恐怖記憶の固定が亢進される.私達はFABP3欠損マウスにおいて恐怖記憶消去系が障害されること,多動と認知機能障害がみられPTSD様症状を呈すること見出した.さらに,睡眠障害治療薬でメラトニン受容体作用薬であるラメルテオンの経口投与がFABP3欠損マウスのPTSD様行動を改善することを見出した.FABP3欠損マウスでは前帯状回皮質(ACC)のCa<sup>2+</sup>/カルモデュリン依存性プロテインキナーゼII(CaMKII)の活性が低下していた.逆に扁桃体基底外側部(BLA)のCaMKII活性は上昇した.CaMKII活性化と相関して扁桃体基底外側部での恐怖条件に伴うc-Fosタンパク質の発現は著しく亢進した.これらの反応もラメルテオンの慢性投与で改善された.これらの知見から,ACCの機能低下による扁桃体の過剰興奮がPTSDの発現に関わること,睡眠障害治療薬ラメルテオンはPTSD症状の治療薬としての臨床応用が期待できる.</p>

<p>Posttraumatic stress disorder (PTSD) is most often induced by traumatic events and serious public health problems. PTSD is characterized by excessive response to contextual memory and impaired fear extinction and also associated with mild cognitive impairment, attention and learning deficits. Clinical and animal studies suggest that increased susceptibility of emotion- and fear-related neuronal circuits, including those in the amygdala, prefrontal cortex and hippocampus, contributes to development and retention of PTSD symptoms. However, mechanisms underlying this susceptibility to fear are not known and the useful therapeutic approaches are limited. Recently, there have been reports that ω3 LCPUFA supplementation can prevent development of PTSD and significantly ameliorate symptoms in patients with PTSD after accidental injury such as motor vehicle accidents and natural calamities. Importantly, <i>Fabp7</i> null mice exhibit enhancement of fear memory consolidation and anxiety-related behaviors that resemble PTSD-like behaviors in humans. In this review, we focused behavioral phenotype of PTSD in <i>Fabp3</i> null mice. The <i>Fabp3</i> null mice exhibit cognitive deficits, hyperlocomotion and impaired fear extinction, and thus show PTSD-like behaviors. Chronic administration of ramelteon, a melatonin receptor agonist, improved all PTSD-like behaviors tested in <i>Fabp3</i><sup>-/-</sup> mice. Relevant to mechanisms underlying impaired fear extinction, we observed that Ca<sup>2+</sup>/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation increases in the basolateral amygdala (BLA) but remained unchanges in the hippocampus of <i>Fabp3</i><sup>-/-</sup> mice. Likewise, the number of c-Fos positive neurons in BLA significantly increased after exposure to contextual fear conditions. Finally, chronic ramelteon administration restored abnormal c-Fos expression and CaMKII autophosphorylation in the BLA of <i>Fabp3</i><sup>-/-</sup> mice. Taken together, <i>Fabp3</i><sup>-/-</sup> mice show PTSD-like behaviors, and ramelteon is an attractive candidate for PTSD therapeutics in human.</p>

Journal

  • Folia Pharmacologica Japonica

    Folia Pharmacologica Japonica 152(4), 194-201, 2018

    The Japanese Pharmacological Society

Codes

  • NII Article ID (NAID)
    130007495997
  • NII NACSIS-CAT ID (NCID)
    AN00198335
  • Text Lang
    JPN
  • ISSN
    0015-5691
  • NDL Article ID
    029295284
  • NDL Call No.
    Z19-247
  • Data Source
    NDL  J-STAGE 
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