Inhibition of ADORA3 Accelerates Hematoma Resolution and Neurological Recovery after ICH

Intracerebral hemorrhage (ICH) seriously threatens human health with a high mortality and disability rate. Promoting the microglia-mediated endogenous removal of hematoma can effectively reduce brain tissue damage. Adenosine 3 receptor (ADORA3) has been shown to participate in microglial phagocytosis; however, its role in ICH remains unclear. This study was performed to explore the potential role of ADORA3 and related mechanism in endogenous hematoma resolution after ICH.

Autologous blood injection was used to construct ICH model. Mice were administered with the microglial depletion agent (PLX3397) and the specific antagonist of ADORA3, MRS1523. The neurobehavioral function was evaluated through a serious of tests. The residual hematoma volume and hemoglobin content were measured. Erythrophagocytosis was assessed using flow cytometry. Immunofluorescence, Western blot, Nissl and TUNEL staining were also performed.

The expression of ADORA3 increased dynamically, and ADORA3 was mainly located in the microglia after ICH. The ADORA3 inhibitor MRS1523 could improve neurological recovery, reduce the residual hematoma volume and hemoglobin content, and promote erythrophagocytosis of microglia. In addition, the inhibition of ADORA3 reduced the expression of phagocytotic receptors AXL and MerTK, decreased the number of damaged and apoptotic neurons around hematoma on day 3 after ICH, and alleviated the neuroinflammation. In addition, PLX3397, a microglial depletion agent, impaired the protective effect of MRS1523.

The inhibition of ADORA3 by MRS1523 promoted phagocytosis of microglia on erythrocytes, accelerating hematoma clearance after ICH, reducing the damage of neurons and neuroinflammation around the hematoma, and ultimately promoting neurological recovery.