The Adenosine A2A Receptor Antagonist KW6002 Mitigates Aldosterone-induced Central Serous Chorioretinopathy in Mice

Purpose Central serous chorioretinopathy (CSC), a prevalent disease characterized by choroidal vascular abnormalities, has extremely limited treatment options. This study investigates the effects of the selective adenosine A _2A receptor (A _2A R) antagonist KW6002 on choroidal vascular hyperpermeability and the blood-retinal barrier (BRB), and explores its therapeutic potential in experimental CSC. Methods We examined the expression of A _2A R in the retinal pigment epithelium (RPE)-choroid-sclera complex using quantitative real-time PCR (qPCR) and Western blotting (WB) in mice with an established aldosterone-induced acute CSC model. Before modeling, mice were administered 5 mg/kg KW6002 or a vehicle control via intraperitoneal injection. The retinal and choroidal thickness was assessed by optical coherence tomography (OCT) and hematoxylin-eosin(H&E) staining. We observed Müller cells activation, retinal microglia infiltration, and proinflammatory cytokine expression via immunofluorescence and qPCR. Next, we employed the effects of the A _2A R antagonist KW6002 and genetic A _2A R knockout on BRB integrity using immunofluorescence and WB. Finally, to clarify how A _2A R knockout confers therapeutic benefits in CSC, we assessed activation of the TNF-α/NF-κB-MMP2/9 signaling pathway. Results We found that A _2A R signaling was significantly upregulated in the RPE-choroid-sclera complex in CSC models, and both A _2A R antagonist KW6002 and A _2A R knockout significantly inhibited the aldosterone-induced central retinal and choroidal pathologic thickening. Moreover, KW6002 treatment decreased the activation of Müller cells and the proliferation of microglia, inhibited the secretion of proinflammatory cytokines (TNF-α, IL-6, and IL-1β), and ameliorated the retinal damage caused by aldosterone; in contrast, A _2A R knockout resulted in significant upregulation of key tight junction proteins (ZO-1, Claudin-1, and Claudin-5). In summary, these results suggest that the protective effects are likely due to A _2A R inhibiting TNF-α/NF-κB–MMP2/9 signaling axis. Conclusions Our findings show that the A _2A R antagonist KW6002, or A _2A R knockout, offers a protective effect in experimental CSC, reduces inflammation and maintains the integrity of the BRB, and mediates such protection through inhibiting TNF-α/NF-κB pathway. These findings present a new method for treating CSC, which will guide our future clinical strategy development.