P2Y6 receptor inhibition aggravates ischemic brain injury by reducing microglial phagocytosis.

Abstract

INTRODUCTION:

Clearance of damaged cells and debris is beneficial for the functional recovery after ischemic brain injury. However, the specific phagocytic receptor that mediates microglial phagocytosis after ischemic stroke is unknown.

AIM:

To investigate whether P2Y6 receptor-mediated microglial phagocytosis is beneficial for the debris clearance and functional recovery after ischemic stroke.

RESULTS:

The expression of the P2Y6 receptor in microglia increased within 3 days after transient middle cerebral artery occlusion. Inhibition of microglial phagocytosis by the selective inhibitor MRS2578 enlarged the brain atrophy and edema volume after ischemic stroke, subsequently aggravated neurological function as measured by modified neurological severity scores and Grid walking test. MRS2578 treatment had no effect on the expression of IL-1α, IL-1β, IL-6, IL-10, TNF-α, TGF-β, and MPO after ischemic stroke. Finally, we found that the expression of myosin light chain kinase decreased after microglial phagocytosis inhibition in the ischemic mouse brain, which suggested that myosin light chain kinase was involved in P2Y6 receptor-mediated phagocytosis.

CONCLUSION:

Our results indicate that P2Y6 receptor-mediated microglial phagocytosis plays a beneficial role during the acute stage of ischemic stroke, which can be a therapeutic target for ischemic stroke.

• Authors: Ruo-Xue Wen, Hui Shen, Shu-Xian Huang, Li-Ping Wang, Zong-Wei Li, Peng Peng, Muyassar Mamtilahun, Yao-Hui Tang, Fan-Xia Shen, Heng-Li Tian, Guo-Yuan Yang, Zhi-Jun Zhang
• Journal: CNS neuroscience & therapeutics (CNS Neurosci Ther) Vol. 26 Issue 4 Pg. 416-429 (04 2020) ISSN: 1755-5949 [Electronic] England
• PMID: 32154670 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.

Chemical References

• Isothiocyanates
• N,N''-1,4-butanediylbis(N'-(3-isothiocyanatophenyl))thiourea
• Receptors, Purinergic P2
• purinoceptor P2Y6
• Thiourea

Topics

• Animals
• Brain Injuries (metabolism, pathology)
• Brain Ischemia (metabolism, pathology)
• Cells, Cultured
• Coculture Techniques
• Isothiocyanates (pharmacology)
• Male
• Mice
• Mice, Inbred ICR
• Microglia (metabolism, pathology)
• Phagocytosis (drug effects, physiology)
• Receptors, Purinergic P2 (biosynthesis)
• Thiourea (analogs & derivatives, pharmacology)