{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T23:25:10Z","timestamp":1791761110718,"version":"4.3.4"},"reference-count":56,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"17","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2025,9,2]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      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\u2013reperfusion (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\u2013brain barrier. However, the involvement of the choroid plexus (ChP), a part of the blood\u2013cerebrospinal fluid barrier, in development of I\/R injury is often overlooked. The adenosine A\n                      <jats:sub>2A<\/jats:sub>\n                      receptor (A\n                      <jats:sub>2A<\/jats:sub>\n                      R) is recognized as an important regulator of ischemic brain injury, but their action sites remain undefined.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods and Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      We investigated ChP A\n                      <jats:sub>2A<\/jats:sub>\n                      R in an I\/R model. We showed that I\/R induced the upregulated expression of A\n                      <jats:sub>2A<\/jats:sub>\n                      Rs in ChP reaching its peak at 24 hours and parallel accumulation of neutrophils in ChP, along with the increased expression of adhesion molecules (\n                      <jats:italic toggle=\"no\">ICAM1<\/jats:italic>\n                      ) and chemokines (\n                      <jats:italic toggle=\"no\">CCL2<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"no\">CXCL10<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"no\">CXCL1<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"no\">CXCL2<\/jats:italic>\n                      ). Importantly, focal knockdown of A\n                      <jats:sub>2A<\/jats:sub>\n                      Rs 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\u2013A\n                      <jats:sub>2A<\/jats:sub>\n                      R knockdown exerted a whole\u2010brain protective effect with increased cerebral blood flow. At the cellular level, small interfering RNA knockdown of A\n                      <jats:sub>2A<\/jats:sub>\n                      Rs in cultured ChP epithelial cells reduced cell apoptosis under oxidative conditions. Finally, systemic administration of the A\n                      <jats:sub>2A<\/jats:sub>\n                      R antagonist KW6002 during the reperfusion period attenuated the injury with reduced neutrophil infiltration in the ChP.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      Our findings highlight the A\n                      <jats:sub>2A<\/jats:sub>\n                      R 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.\n                    <\/jats:p>\n                  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