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

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K10734
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurosurgery
• Research Institution: Yokohama City University
• Principal Investigator: Suenaga Jun 横浜市立大学, 医学部, 講師 (30610365)
• Research Collaborator: Chen Jun
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: Microglia / Melatonin / Interleukin-4 / Focal cerebral ischemia / Reperfusion

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.

Free Research Field

脳虚血、神経保護、ミクログリア

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。