Post-stroke administration of melatonin improves long-term outcomes after focal cerebral ischemia/reperfusion (FI/R) via interleukin-4 (IL-4) dependent M2 microglial polarization
Project/Area Number |
16K10734
|
Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Research Field |
Neurosurgery
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Research Institution | Yokohama City University |
Principal Investigator |
Suenaga Jun 横浜市立大学, 医学部, 講師 (30610365)
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Research Collaborator |
Chen Jun
|
Project Period (FY) |
2016-04-01 – 2019-03-31
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Project Status |
Completed (Fiscal Year 2018)
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Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥260,000 (Direct Cost: ¥200,000、Indirect Cost: ¥60,000)
Fiscal Year 2017: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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Keywords | Microglia / Melatonin / Interleukin-4 / Focal cerebral ischemia / Reperfusion / Ischemia / Primary culture / Interleukin 4 / 脳虚血 |
Outline of Final Research Achievements |
Microglia represent rational but difficult therapeutic targets for stroke due to their diverse phenotypes that play dual-faced protective (M2 phenotype) and toxic (M1 phenotype) effects. Melatonin injection increased the level of Interleukin-4(IL-4), the best known M2 inducing cytokine. Melatonin significantly reduced infarct volume and attenuated sensorimotor deficits. IL-4 deficiency, abolished melatonin-afforded long term protection. Melatonin-treated mice showed significantly reduced expression of inflammatory cytokine and chemokines, with significantly increased expression of M2 markers and decreased expression of M1 markers. Melatonin inhibited LPS (a M1 inducer)-induced production of NO and TNFα, confirming that melatonin has direct anti-inflammatory effect on microglia. Melatonin may represent an innovative therapeutic strategy that shifts microglia polarization toward a protective M2 phenotype in an IL-4-dependent manner and thus enhance long-term recovery after stroke.
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Academic Significance and Societal Importance of the Research Achievements |
ミクログリアの極性を、有用なM2にシフトさせるメカニズムや作用を調べることは、脳虚血での新たな治療ターゲットを開発する上で非常に価値がある。今回は、IL-4を介する経路を明らかにすることで、今後の急性期脳卒中、血栓回収時の脳・神経保護の新たなターゲットとする可能性が生まれた。メラトニンは現在ロゼレムとして内服薬があり、これを使った臨床研究などにもつなげていきたい。
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Report
(4 results)
Research Products
(2 results)
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[Presentation] Experience and evaluation of Dual-Table Autoradiography(DTARG)123I-IMP SPECT: safe, time shortening, and effective modality to predict cerebral infarction in chronic ischemic patients2017
Author(s)
Jun Suenaga, Masao Kishimoto, Ryu Ueno, Ryo Matsuzawa, Shunsuke Seki, Takahiro Hayashi, Ryohei Miyazaki, Taishi Nakamura, Mitsuru Sato, Kensuke Tateishi, Nobuyuki Shimizu, and Hidetoshi Murata
Organizer
Brain PET 2017(28th Symposium on Cerebral Blood Flow, Metabolism and Function, 13th Conference on Quantification of Brain Function with PET)
Place of Presentation
Berlin, Germany
Year and Date
2017-04-01
Related Report
Int'l Joint Research