{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T06:16:51Z","timestamp":1778566611307,"version":"3.51.4"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T00:00:00Z","timestamp":1778544000000},"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. Behav. Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Blood-brain barrier (BBB) disruption is a critical pathological feature of ischemic stroke, yet effective therapies targeting BBB repair remain limited. Gardenoside, an iridoid glycoside from\n                      <jats:italic>Gardenia jasminoides<\/jats:italic>\n                      Ellis, has shown neuroprotective properties, but its role in post-stroke BBB restoration is unclear. This study investigated whether Gardenoside preserves BBB integrity after ischemic stroke via AMPK-dependent regulation of the tight junction protein ZO-1.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Male and female C57BL\/6 mice (8\u201310 weeks) underwent transient middle cerebral artery occlusion (MCAO; 60 min ischemia, 24 h reperfusion). Gardenoside (20 mg\/kg\/day, i.p.) was administered for 21 days pre-MCAO and continued post-reperfusion. Neurological deficits, BBB permeability (sodium fluorescein, Evans blue), infarct volume (TTC), endothelial activation markers (ICAM-1, VCAM-1), ZO-1 expression (qPCR, western blot, immunofluorescence), and AMPK phosphorylation were assessed. In parallel, human brain microvascular endothelial cells (HBMVECs) were subjected to oxygen-glucose deprivation\/reperfusion (OGD\/R; 6 h OGD, 24 h reoxygenation) with Gardenoside (5\u201310 \u03bcM) \u00b1 the AMPK inhibitor compound C. Outcomes included cell viability (CCK-8), LDH release, permeability (FITC-dextran, TEER), and ZO-1\/AMPK signaling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In MCAO mice, Gardenoside significantly reduced neurological deficit scores (by ~50%), BBB permeability (28\u201332% reduction), and infarct volume (45% reduction) compared to vehicle-treated controls. It suppressed ICAM-1 and VCAM-1 expression (mRNA: 43\u201352%; protein: 30\u201334%) and restored ZO-1 levels to near-sham values. Gardenoside increased AMPK phosphorylation (p-AMPK\/AMPK ratio: 2.1-fold). Co-administration of compound C (10 mg\/kg) abolished these protective effects, reversing infarct volume, BBB leakage, neurological scores, and ZO-1 restoration.\n                      <jats:italic>In vitro<\/jats:italic>\n                      , Gardenoside (5\u201310 \u03bcM) dose-dependently improved HBMVEC viability (from 42% to 68\u201388% of control), reduced LDH release (27\u201347%), decreased permeability (25\u201340%), and restored TEER (40\u201366%) and ZO-1 expression (50\u201398%) following OGD\/R. These effects were associated with enhanced AMPK phosphorylation and were completely reversed by compound C (10 \u03bcM). Comparable efficacy was observed in female mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Gardenoside preserves BBB integrity and improves neurological outcomes after ischemic stroke through AMPK-dependent restoration of ZO-1. These findings identify AMPK-mediated tight junction preservation as a previously unrecognized mechanism of Gardenoside, supporting its potential as a vascular-targeted therapy for ischemic stroke.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnbeh.2026.1768582","type":"journal-article","created":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T05:43:49Z","timestamp":1778564629000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Gardenoside restores blood\u2013brain barrier integrity following ischemic stroke via AMPK-dependent ZO-1 preservation"],"prefix":"10.3389","volume":"20","author":[{"given":"Rongze","family":"Jia","sequence":"first","affiliation":[{"name":"Changchun University of Chinese Medicine","place":["Changchun, Jilin, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,12]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.nbd.2009.07.030","article-title":"Structure and function of the blood-brain barrier","volume":"37","author":"Abbott","year":"2010","journal-title":"Neurobiol. 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