{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T18:46:34Z","timestamp":1792608394279,"version":"4.5.0"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T00:00:00Z","timestamp":1767744000000},"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. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Cerebral ischemia\/reperfusion (I\/R) injury remains a leading cause of neurological disability and is characterized by oxidative stress, calcium overload, inflammation, and endoplasmic reticulum (ER) stress following reperfusion. Hypericin, a bioactive naphthodianthrone derived from Hypericum perforatum, exhibits antioxidant and anti-apoptotic properties. This study investigated the neuroprotective effects and underlying mechanisms of hypericin in experimental cerebral I\/R injury.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Male Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) and treated intraperitoneally with hypericin (5, 10, or 20 mg\/kg) 30 minutes before reperfusion or nimodipine (10 mg\/kg) as a positive control. Neurological severity scores (mNSS), grip strength, rotarod performance, infarct volume, and brain water content were evaluated 24 hours after reperfusion.\n                      <jats:italic>In vitro<\/jats:italic>\n                      , murine hippocampal HT22 cells underwent oxygen-glucose deprivation\/reoxygenation (OGD\/R) and were treated with hypericin (6.25-25 \u03bcg\/mL). Cell viability (MTT assay), apoptosis (Annexin V\/PI flow cytometry), and ER stress-related markers were assessed using qRT-PCR and Western blotting. In silico pharmacokinetic analysis was performed to evaluate blood -brain barrier permeability.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Hypericin significantly reduced cerebral infarct volume by approximately 40%, alleviated brain edema, and improved neurological and motor function compared with untreated I\/R animals (p &amp;lt; 0.05). Histopathological and immunohistochemical analyses demonstrated preserved hippocampal structure and reduced caspase-3 activation. In OGD\/R-injured HT22 cells, hypericin increased cell viability, reduced apoptotic rates from 30.3% to 10.3%, suppressed ER stress-associated markers (CHOP, GRP78, caspase-12), and normalized the Bax\/Bcl-2 ratio. Pharmacokinetic predictions suggested moderate lipophilicity and physicochemical properties compatible with partial blood-brain barrier penetration, particularly under ischemia-induced barrier disruption.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These findings demonstrate that hypericin confers significant neuroprotection against cerebral I\/R injury by attenuating ER stress-mediated apoptosis and preserving neuronal integrity. Hypericin may represent a promising therapeutic candidate for ischemic stroke.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2025.1723495","type":"journal-article","created":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T05:14:39Z","timestamp":1767762879000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Hypericin alleviates cerebral ischemia\/reperfusion injury by modulating endoplasmic reticulum stress"],"prefix":"10.3389","volume":"16","author":[{"given":"Tingting","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"277","DOI":"10.38058\/ijsl.1121636","article-title":"Neuroprotective effect of Hypericum perforatum extract against aluminum-maltolate induced toxicity in SH-SY5Y cells","volume":"4","author":"Akku\u015f","year":"2022","journal-title":"Int. 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