{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T04:55:52Z","timestamp":1781758552042,"version":"3.54.5"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:00:00Z","timestamp":1781740800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Excessive neuroinflammation mediates blood\u2013brain barrier (BBB) disruption and poor outcomes after acute ischemic stroke (AIS). Cyclophilin A (CypA), when released into the extracellular space (designated as eCypA), may participate in inflammatory reactions and vascular dysfunction. However, its role in regulating neuroinflammation and BBB injury in AIS, as well as the therapeutic potential of targeting eCypA remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      ELISA was used to detect eCypA release in serum from 22 AIS patients (17 mild, 5 severe; 13 males, 9 females; mild: age 65.41\u202f\u00b1\u202f10.20\u202fyears, NIHSS 2.88\u202f\u00b1\u202f1.45; severe: age 64.00\u202f\u00b1\u202f5.04\u202fyears, NIHSS 9.40\u202f\u00b1\u202f3.29; blood sampled within 48\u202fh of onset), in serum\/cerebrospinal fluid (CSF) from transient middle cerebral artery occlusion (tMCAO) rats, and in supernatants from BV2 (microglia) or bEnd.3 (brain microvascular endothelial cells) exposed to oxygen\u2013glucose deprivation\/reoxygenation (OGD\/R) or lipopolysaccharide (LPS). Nine-week-old male Sprague\u2013Dawley rats (\n                      <jats:italic>n<\/jats:italic>\n                      =\u202f5 per group) underwent 1.5\u202fh of tMCAO via the intraluminal suture method followed by 24\u202fh of reperfusion before sampling. These rats received intracerebroventricular injection of cyclophilin A-binding heptameric peptide (C46) before tMCAO establishment. Cerebral infarct volume was measured via TTC staining. BBB permeability was assessed by Evans blue extravasation. Western blot was employed to determine protein levels of tight junction (TJ) proteins, matrix metalloproteinases (MMPs) and proinflammatory mediators. Microglial activation was evaluated by immunofluorescence.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      eCypA levels were significantly elevated in AIS patient serum (1.74\u202f\u00b1\u202f0.23\u202fng\/mL in mild, 2.39\u202f\u00b1\u202f0.09\u202fng\/mL in severe vs. 1.30\u202f\u00b1\u202f0.19\u202fng\/mL in healthy controls,\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt;\u202f0.001), in tMCAO rat serum (2.57\u202f\u00b1\u202f0.14 vs. 1.62\u202f\u00b1\u202f0.07\u202fng\/mL,\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt;\u202f0.001) and CSF (2.14\u202f\u00b1\u202f0.23 vs. 1.47\u202f\u00b1\u202f0.19\u202fng\/mL,\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt;\u202f0.001), as well as in the supernatants of OGD\/R-challenged BV2 (0.92\u202f\u00b1\u202f0.01 vs. 0.55\u202f\u00b1\u202f0.03\u202fng\/mL,\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt;\u202f0.001) and bEnd.3 cells (1.10\u202f\u00b1\u202f0.05 vs. 0.52\u202f\u00b1\u202f0.03\u202fng\/mL,\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt;\u202f0.001) and LPS-induced BV2 cells (1.12\u202f\u00b1\u202f0.08 vs. 0.56\u202f\u00b1\u202f0.13\u202fng\/mL,\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt;\u202f0.001) compared with their respective control groups. The eCypA inhibitory peptide C46 effectively improved neurological function, reduced cerebral infarct volume and edema in tMCAO rats. Moreover, C46 mitigated BBB permeability, preserved the expression levels of TJ proteins, and suppressed the activation of MMPs in tMCAO rats and OGD\/R-treated bEnd.3 cells. Meanwhile, C46 administration inhibited microglial activation and downregulated the expression of proinflammatory mediators both\n                      <jats:italic>in vivo<\/jats:italic>\n                      (tMCAO rats) and\n                      <jats:italic>in vitro<\/jats:italic>\n                      (OGD\/R- or LPS-induced BV2 microglia).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>eCypA, released by microglia and brain microvascular endothelial cells under ischemic\u2013hypoxic and inflammatory conditions, serves as a critical pathogenic mediator that drives neuroinflammation and BBB disruption in AIS. Targeting eCypA with C46 peptide effectively abrogates these pathological cascades, thereby supporting eCypA as a novel therapeutic target for AIS.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fneur.2026.1791750","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T04:41:36Z","timestamp":1781757696000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Brain cell-released Cyclophilin A induces neuroinflammation and exacerbates blood\u2013brain barrier injury in acute ischemic stroke"],"prefix":"10.3389","volume":"17","author":[{"given":"Enyue","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Neurology, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University","place":["Haikou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qihui","family":"Wu","sequence":"additional","affiliation":[{"name":"Clinical Research Center, Affiliated Chinese Medicine, Hainan Medical University","place":["Haikou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunwen","family":"Xue","sequence":"additional","affiliation":[{"name":"Clinical Research Center, Affiliated Chinese Medicine, Hainan Medical University","place":["Haikou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shixiong","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University","place":["Haikou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Gu","sequence":"additional","affiliation":[{"name":"Clinical Research Center, Affiliated Chinese Medicine, Hainan Medical University","place":["Haikou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,18]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1286","DOI":"10.4103\/1673-5374.358609","article-title":"Overexpression of vascular endothelial growth factor enhances the neuroprotective effects of bone marrow mesenchymal stem cell transplantation in ischemic stroke","volume":"18","author":"Liu","year":"2023","journal-title":"Neural Regen Res"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1007\/s11910-023-01282-2","article-title":"Neuroinflammation in acute ischemic and hemorrhagic stroke","volume":"23","author":"Alsbrook","year":"2023","journal-title":"Curr Neurol Neurosci Rep"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"1491952","DOI":"10.3389\/fncel.2024.1491952","article-title":"Neurovascular unit, neuroinflammation and neurodegeneration markers in brain 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