Novel thherapeutic strategy against ischemic stroke based on glial cell interaction by ketone bodies

2017 Fiscal Year Final Research Report

• Project/Area Number: 15K09324
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Keio University
• Principal Investigator: TAKAHASHI Shinichi 慶應義塾大学, 医学部(信濃町), 准教授 (20236285)
• Co-Investigator(Kenkyū-buntansha): 安部 貴人 大阪市立大学, 大学院医学研究科, 准教授 (30365233) ; 中原 仁 慶應義塾大学, 医学部(信濃町), 助教 (60537950)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: ケトン体 / βヒドロキシ酪酸 / アストログリア / ミクログリア / 脳虚血モデル

Outline of Final Research Achievements

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.

Free Research Field

神経内科学、脳卒中