Aquaporin‐4 activation facilitates glymphatic system function and hematoma clearance post‐intracerebral hemorrhage

Abstract Efficient clearance of hematomas is crucial for improving clinical outcomes in patients with intracerebral hemorrhage (ICH). The glymphatic system, facilitated by aquaporin‐4 (AQP4), plays a crucial role in cerebrospinal fluid (CSF) entry and metabolic waste clearance. This study examined the role of the glymphatic system in ICH pathology, with a focus on AQP4. Collagenase‐induced ICH models were established, with AQP4 expression regulated through mifepristone as an agonist, TGN‐020 as an inhibitor, and Aqp4 gene knockout. Fluorescence tracing and multimodal magnetic resonance imaging (MRI) were employed to observe glymphatic system functionality, hematoma, and edema volumes. Neurological deficit scoring was performed using the modified Garcia Scale. AQP4 expression was quantified using RT‐qPCR and Western blotting, and cellular localization was explored using immunofluorescence. The brain tissue sections were examined for neuronal morphology, degenerative changes, and iron deposition. Three days post‐ICH, the AQP4 agonist group showed increased AQP4 protein expression and perivascular polarization, decreased hemoglobin levels, and reduced iron deposition. Conversely, the inhibition group exhibited contrasting trends. AQP4 activation improved glymphatic system function, leading to a wider distribution, improved neurological function, and reduced hematoma. Pharmacological inhibition and genetic knockout of AQP4 have opposing effects. The glymphatic system, facilitated by AQP4, plays a crucial role in hematoma clearance following cerebral hemorrhage. Upregulation of AQP4 improves glymphatic system function, facilitates hematoma clearance, and promotes brain tissue recovery.