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KAKEN_15K09324seika.pdf
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Download
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:108.8 KB
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| Last updated |
:Nov 12, 2018 |
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Total downloads since Nov 12, 2018 : 856
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ケトン体代謝を介したグリア系3細胞の統合的制御による新規脳梗塞治療開発
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ケトンタイ タイシャ オ カイシタ グリアケイ 3サイボウ ノ トウゴウテキ セイギョ ニ ヨル シンキ ノウコウソク チリョウ カイハツ
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Ketontai taisha o kaishita guriakei 3saibō no tōgōteki seigyo ni yoru shinki nōkōsoku chiryō kaihatsu
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Novel therapeutic strategy against ischemic stroke based on glial cell interaction by ketone bodies
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高橋, 慎一
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タカハシ, シンイチ
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Takahashi, Shinichi
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慶應義塾大学・医学部(信濃町)・准教授
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Research team head
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科研費研究者番号 : 20236285
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安部, 貴人
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アベ, タカト
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Abe, Takato
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大阪市立大学大学院医学研究科・講師
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Research team member
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科研費研究者番号 : 30365233
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中原, 仁
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ナカハラ, ジン
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Nakahara, Jin
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慶應義塾大学・医学部(信濃町)・助教
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Research team member
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科研費研究者番号 : 60537950
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2018
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科学研究費補助金研究成果報告書
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2017
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ケトン体の1つβヒドロキシ酪酸(BHB)が脳虚血でアストログリア(AG)から放出されることを明らかにした。ケトン体の脳保護作用と多発性硬化症治療薬フマル酸ジメチル(DMF)の関連が注目されている。Nrf2を介した作用が提唱されてきたが, DMFおよびBHBのHCAR2リガンド作用を介する神経保護的ミクログリア(mg)誘導作用が注目されている。培養細胞でDMFはNrf2活性化を惹起し, qRT-PCRによるHO-1遺伝子転写亢進が確認された。脳梗塞モデルマウスに対するDMF経口投与でも有意に梗塞巣体積を縮小, 運動機能も改善した。Nrf2-KOマウスでも効果が維持され, HCAR2の関与が示唆された。
Astroglia produce and release ketone bodies, especially beta-hydroxybutyrate (BHB) by ischemic insult. BHB plays a neuroprotective role in various neurological disorders. Dimethyl fumarate (DMD), used as a disease modifying drug for multiple sclerosis patients, has been found to be a ligand of HCAR2. BHB also acts as a ligand for HCAR2. We have hypothesized that astroglia-derived BHB reduces infarct volume and improves neurological function after a transient middle cerebral artery occlusion (tMCAO). tMCAO was performed in male C57BL/6 mice and Nrf2-/- mice. Infarct volume and neurological function assessed by hanging wire test was significantly improved by DMF treatment both in C57BL/6 mice and in Nrf2-/- mice, suggestive of a Nrf2-independent mechanism. In cultured central nervous system cells, DMF upregulated the expression HO-1 which is most common downstream gene of Keap1 / Nrf2 system. Importantly, however, both BHB and DMF may play neuroprotective roles through HCAR2.
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研究種目 : 基盤研究(C)(一般)
研究期間 : 2015～2017
課題番号 : 15K09324
研究分野 : 神経内科学, 脳卒中
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