3164 - The Protective Effect of Targeting AQP4 on Acute Radiation-Induced Brain Injury in Rats: Reducing Brain Edema, Inflammation, Apoptosis and Maintaining the Integrity of Blood-Brain Barrier

05:00pm - 06:00pm PT

Hall F

Screen: 17

Presenter(s)

Yaozu Xiong, PhD - Department of Radiotherapy for Oncology, The First Affiliated Hospital of 8 Soochow University, Suzhou,

Y. Xiong¹, Y. Wang², C. Yu³, Y. Tong³, and X. Xu⁴; ¹Department of Radiotherapy for Oncology, The First Affiliated Hospital of 8 Soochow University, Suzhou, China, ²Department of Pathology, Children's Hospital of Soochow University, Suzhou, China, ³Department of Tumor Radiotherapy, Huai'an First Hospital, Nanjing Medical University, Huai'an, China, ⁴Department of Radiation Oncology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China

Purpose/Objective(s):

The current understanding of AQP4 expression changes in radiation-induced brain injury (RIBI) and its potential role in the pathological development of RIBI remains limited. This study aimed to elucidate the function of AQP4 in RIBI pathogenesis by establishing an animal model through whole-brain irradiation in Sprague-Dawley (SD) rats. Subsequently, we investigated the effects of inhibiting AQP4 expression using the specific inhibitor AER-271 on radiation-induced brain edema, blood-brain barrier disruption, neuroinflammatory responses, and cell apoptosis.

Materials/Methods:

SD rats were randomly assigned to Sham and Irradiation (IR) groups. Pathological damage was assessed via hematoxylin and eosin (H&E) staining, protein expression levels were evaluated by Western blotting, brain edema was quantified by measuring brain water content, and blood-brain barrier integrity was examined using Evans blue permeability assays. Immunofluorescence staining was employed to investigate AQP4 distribution and function in RIBI. In a subsequent experiment, SD rats were divided into four groups: Sham, AER-271, IR, and IR+AER-271. Various molecular biological techniques were utilized to explore the neuroprotective effects of targeting AQP4 in RIBI.

Results:

In the acute phase of the RIBI model, radiation induced brain edema, upregulated AQP4 expression in brain tissue, and caused neuronal damage in the hippocampal region. The expression level of AQP4 correlated with the severity of radiation-induced brain edema. 2. Radiation reduced the aggregate morphology of AQP4 in astrocytic endfeet while increasing its punctate distribution in the plasma membrane, disrupting its polarized state. 3. Targeting AQP4 alleviated radiation-induced brain edema, astrocyte activation, and hippocampal neuronal damage. 4. Targeted inhibition of AQP4 reduced the expression and release of inflammatory factors (IL-6 and TNF-a) and mitigated radiation-induced neuroinflammation by inhibiting Jak2/Stat3 signaling pathway activation. 5. Radiation disrupted blood-brain barrier integrity by downregulating tight junction proteins between vascular endothelial cells; however, AQP4 inhibition preserved these proteins (ZO-1, Occludin, Claudin-5), maintaining barrier integrity and reducing permeability. 6. Radiation-induced apoptosis in brain tissue via PI3K/AKT/mTOR pathway activation was attenuated by AQP4 inhibition, which suppressed phosphorylation of this pathway.

Conclusion:

This study highlights the critical role of AQP4 in the acute phase of RIBI. AQP4 mediates brain edema formation and influences subsequent inflammatory responses, blood-brain barrier damage, and neuronal apoptosis. These findings provide new insights into RIBI pathogenesis. Targeting AQP4 offers neuroprotection by alleviating brain edema, neuronal damage, neuroinflammation, blood-brain barrier disruption, and apoptosis.