Development of novel therapeutic approaches in ischemic stroke targeting regulation of inflammation through RANKL/RANK signal

2015 Fiscal Year Final Research Report

• Project/Area Number: 25462214
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurosurgery
• Research Institution: Osaka University
• Principal Investigator: Munehisa Shimamura 大阪大学, 医学(系)研究科(研究院), 寄附講座准教授 (60422317)
• Co-Investigator(Kenkyū-buntansha): KURINAMI HITOMI 大阪大学, 大学医学部附属病院, 助教 (10638555)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: 脳梗塞 / マクロファージ / ミクログリア / 炎症 / RANKL / RANK / OPG

Outline of Final Research Achievements

In the present study, we examined the possibilities of a novel therapy using recombinant RANKL (rRANKL) in ischemic stroke model in mice. The optimal dose of rRANKL for preventing exacerbation of stroke size and inflammation was 5 ng i.c.v. or 1 μg s.c. with repetitive injections, whose therapeutic window was 6 hrs after the insult.Expression of inflammatory cytokines was also inhbitted in rRANKL-treated mice. However, we found that another group showed repetitive systemic injections of rRANKL caused osteoporotic changes in bone in mice. To avoid the side effects, we tried intranasal injection of rRANKL to achieve direct delivery of rRANKL in brain. rRANKL was successfully delivered to brain, but the therapeutic effects were not shown probably due to insufficient amount of delivered rRANKL. Thus, therapeutic application of rRANKL has been shown to be possible in intracerebroventricular injection or systemic injection with some modifications, which do not activate osteoclast.

Free Research Field

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