Adenosine A2A Receptor in the Choroid Plexus Modulates Ischemia-Reperfusion Injury in the Cortex.

BACKGROUND

Stroke remains a leading cause of death and disability worldwide, but the therapeutic efficacies of the mainstay treatments, mechanical thrombectomy and intravenous thrombolysis, are limited due to constraints such as the narrow treatment window and the issue of reperfusion injury following restoration of blood flow. Ischemia-reperfusion (I/R) injury is characterized by the infiltration of peripheral leukocytes, which are believed to enter the central nervous system through the breakdown of the blood-brain barrier. However, the involvement of the choroid plexus (ChP), a part of the blood-cerebrospinal fluid barrier, in development of I/R injury is often overlooked. The adenosine A2A receptor (A2AR) is recognized as an important regulator of ischemic brain injury, but their action sites remain undefined.

METHODS AND

RESULTS

We investigated ChP A2AR in an I/R model. We showed that I/R induced the upregulated expression of A2ARs in ChP reaching its peak at 24 hours and parallel accumulation of neutrophils in ChP, along with the increased expression of adhesion molecules (ICAM1) and chemokines (CCL2, CXCL10, CXCL1, CXCL2). Importantly, focal knockdown of A2ARs in the ChP protected against I/R injury with reduced neutrophil infiltration and the expression of matrix metalloproteinases 2 and 9 in ChP. Furthermore, ChP-A2AR knockdown exerted a whole-brain protective effect with increased cerebral blood flow. At the cellular level, small interfering RNA knockdown of A2ARs in cultured ChP epithelial cells reduced cell apoptosis under oxidative conditions. Finally, systemic administration of the A2AR antagonist KW6002 during the reperfusion period attenuated the injury with reduced neutrophil infiltration in the ChP.

CONCLUSIONS

Our findings highlight the A2AR in ChP as a pivotal regulator of I/R injury in the cortex, modulating ChP gateway activity and CSF production, providing a promising therapeutic target for stroke management.