Inhibition of ADORA3 Accelerates Hematoma Resolution and Neurological Recovery after ICH

Area of Science:

• Neuroscience
• Immunology
• Cell Biology

Background:

• Intracerebral hemorrhage (ICH) leads to high mortality and disability.
• Microglia-mediated hematoma clearance is crucial for reducing brain damage.
• The role of Adenosine 3 receptor (ADORA3) in microglial phagocytosis and ICH is not well understood.

Purpose of the Study:

• To investigate the role of ADORA3 in the resolution of hematoma after ICH.
• To explore the underlying mechanisms of ADORA3 in microglial function post-ICH.

Main Methods:

• An ICH mouse model was established using autologous blood injection.
• Mice were treated with a microglial depletion agent (PLX3397) and an ADORA3 antagonist (MRS1523).
• Neurobehavioral function, hematoma volume, hemoglobin content, and erythrophagocytosis were assessed. Immunofluorescence, Western blot, Nissl, and TUNEL staining were also performed.

Main Results:

• ADORA3 expression increased post-ICH, primarily in microglia.
• MRS1523 treatment improved neurological function, reduced hematoma, and enhanced microglial erythrophagocytosis.
• ADORA3 inhibition decreased phagocytic receptor expression (AXL, MerTK), reduced neuronal damage/apoptosis, and alleviated neuroinflammation.
• Depleting microglia abrogated the protective effects of MRS1523.

Conclusions:

• Inhibiting ADORA3 accelerates hematoma clearance by promoting microglial phagocytosis of erythrocytes.
• This inhibition reduces neuronal damage and neuroinflammation surrounding the hematoma.
• Targeting ADORA3 with MRS1523 ultimately promotes neurological recovery after ICH.