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

Activation of adenosine A3 receptor (A3R) through the P38/STAT6 pathway modulates the phenotypic conversion of microglia and ameliorates early brain injury (EBI) after SAH. (A) During the normal course of SAH, blood components promote the activation of resting microglia, mostly towards the M (LPS) phenotype, with a small proportion towards the M (IL-4) phenotype. The majority of M(LPS) microglia release excessive inflammatory cytokines when eliminating necrotic tissue debris, thus exacerbating neurological damage. Adenosine expression is upregulated in brain injury, which may promote the polarization of microglia towards the M(IL-4) phenotype to play a role in tissue repair. (B) Exogenous A3R agonists may contribute to microglial polarization towards the M(IL-4) phenotype, thereby providing neuroprotection and mitigating EBI. On the one hand, CI-IB-MECA can promote the transcription of M(IL-4) polarization-related genes by successively activating the MAPKs P38 and STAT6; on the other hand, it may also inhibit the PKA/ NF-κB pathway, which is associated with microglial M(LPS) polarization.

Figure 7. Activation of adenosine A3 receptor (A3R) through the P38/STAT6 pathway modulates the phenotypic conversion of microglia and ameliorates early brain injury (EBI) after SAH. (A) During the normal course of SAH, blood components promote the activation of resting microglia, mostly towards the M (LPS) phenotype, with a small proportion towards the M (IL-4) phenotype. The majority of M(LPS) microglia release excessive inflammatory cytokines when eliminating necrotic tissue debris, thus exacerbating neurological damage. Adenosine expression is upregulated in brain injury, which may promote the polarization of microglia towards the M(IL-4) phenotype to play a role in tissue repair. (B) Exogenous A3R agonists may contribute to microglial polarization towards the M(IL-4) phenotype, thereby providing neuroprotection and mitigating EBI. On the one hand, CI-IB-MECA can promote the transcription of M(IL-4) polarization-related genes by successively activating the MAPKs P38 and STAT6; on the other hand, it may also inhibit the PKA/ NF-κB pathway, which is associated with microglial M(LPS) polarization.