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

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.

• Authors: Peng Li, Xiaojun Li, Peng Deng, Dandan Wang, Xuehong Bai, Yujie Li, Chunxia Luo, Karine Belguise, Xiaobo Wang, Xinchuan Wei, Zhengyuan Xia, Bin Yi
• Journal: Aging (Aging (Albany NY)) Vol. 13 Issue 1 Pg. 694-713 (11 30 2020) ISSN: 1945-4589 [Electronic] United States
• PMID: 33253120 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2,3-diethyl-4,5-dipropyl-6-phenylpyridine-3-thiocarboxylate-5-carboxylate
• 4-(benzylamino)-2-((2-(3-chloro-4-hydroxyphenyl)ethyl)amino)pyrimidine-5-carboxamide
• Adenosine A3 Receptor Agonists
• Adenosine A3 Receptor Antagonists
• Cytokines
• Imidazoles
• Pyridines
• Pyrimidines
• Receptor, Adenosine A3
• STAT6 Transcription Factor
• p38 Mitogen-Activated Protein Kinases
• 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole

Topics

• Adenosine A3 Receptor Agonists (pharmacology)
• Adenosine A3 Receptor Antagonists (pharmacology)
• Animals
• Brain (drug effects, immunology)
• Brain Injuries (genetics, immunology)
• Cytokines (immunology)
• Disease Models, Animal
• Gene Knockdown Techniques
• Imidazoles (pharmacology)
• Inflammation (immunology)
• Microglia
• Pyridines (pharmacology)
• Pyrimidines (pharmacology)
• Rats
• Receptor, Adenosine A3 (drug effects, genetics, immunology)
• STAT6 Transcription Factor (antagonists & inhibitors, metabolism)
• Signal Transduction
• Subarachnoid Hemorrhage (immunology)
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)