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Research Paper|Volume 13, Issue 1|pp 694—713

Activation of adenosine A3 receptor reduces early brain injury by alleviating neuroinflammation after subarachnoid hemorrhage in elderly rats

Peng Li1,2, Xiaojun Li1, Peng Deng1, Dandan Wang1, Xuehong Bai1, Yujie Li1, Chunxia Luo3, Karine Belguise4, Xiaobo Wang4, Xinchuan Wei2, Zhengyuan Xia5,6, Bin Yi1
  • 1Department of Anesthesia, Southwest Hospital, Third Military Medical University, Chongqing, China
  • 2Department of Anesthesia, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, China
  • 3Department of Neurology, Southwest Hospital, The Third Military Medical University, Chongqing, China
  • 4Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération (LBCMCP), University P. Sabatier, Toulouse Cedex 9, France
  • 5Department of Anesthesiology, University of Hong Kong, Hong Kong SAR, China
  • 6Department of Cerebrovascular Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
* Equal contribution
Received: January 27, 2020Accepted: October 5, 2020Published: November 30, 2020
https://doi.org/10.18632/aging.202178

Copyright: © 2020 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

The incidence of subarachnoid hemorrhage (SAH) and hazard ratio of death increase with age. Overactivation of microglia contributes to brain damage. This study aimed to investigate the effects of A3 adenosine receptors (A3R) activation on neurofunction and microglial phenotype polarization in the context of SAH in aged rats. The A3R agonist (CI-IB-MECA) and antagonist (MRS1523) were used in the SAH model. Microglia were cultured to mimic SAH in the presence or absence of CI-IB-MECA and/or siRNA for A3R. The neurofunction and status of the microglial phenotype were evaluated. The P38 inhibitor SB202190 and the STAT6 inhibitor AS1517499 were used to explore the signaling pathway. The results showed that SAH induced microglia to polarize to the M(LPS) phenotype both in vivo and in vitro. CI-IB-MECA distinctly skewed microglia towards the M(IL-4) phenotype and ameliorated neurological dysfunction, along with the downregulation of inflammatory cytokines. Knockdown of A3R or inhibition of P38 and/or STAT6 weakened the effects of CI-IB-MECA on microglial phenotypic shifting. Collectively, our findings suggest that activation of A3R exerted anti-inflammatory and neuroprotective effects by regulating microglial phenotype polarization through P38/STAT6 pathway and indicated that A3R agonists may be a promising therapeutic options for the treatment of brain injury after SAH.