{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T22:45:03Z","timestamp":1792622703466,"version":"4.5.0"},"reference-count":84,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,4,24]],"date-time":"2025-04-24T00:00:00Z","timestamp":1745452800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Retinal ischemic disorders present significant threats to vision, characterized by inadequate blood supply oxygen\u2013glucose deprivation (OGD), oxidative stress, and cellular injury, often resulting in irreversible injury. Catalpol, an iridoid glycoside derived from Rehmannia glutinosa, has demonstrated antioxidative and neuroprotective effects. This study aimed at investigating the protective effects and mechanisms of catalpol against oxidative stress or OGD in vitro and retinal ischemia in vivo, focusing on the modulation of key biomarkers of retinal ischemia, including HIF-1\u03b1, vascular endothelial growth factor (VEGF), angiopoietin-2, MCP-1, and the Wnt\/\u03b2-catenin pathway. Cellular viability was assessed using retinal ganglion cell-5 (RGC-5) cells cultured in DMEM; a 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed. H2O2 (1 mM)\/OGD was utilized. Vehicle or different catalpol concentrations were administered 15 min before the ischemic-like insults. The Wistar rat eyes\u2019 intraocular pressure was increased to 120 mmHg for 60 min to induce retinal ischemia. Intravitreous injections of catalpol (0.5 or 0.25 mM), Wnt inhibitor DKK1 (1 \u03bcg\/4 \u03bcL), anti-VEGF Lucentis (40 \u03bcg\/4 \u03bcL), or anti-VEGF Eylea (160 \u03bcg\/4 \u03bcL) were administered to the rats\u2019 eyes 15 min before or after retinal ischemia. Electroretinogram (ERG), fluorogold retrograde labeling RGC, Western blotting, ELISA, RT-PCR, and TUNEL were utilized. In vitro, both H2O2 and OGD models significantly (p &lt; 0.001\/p &lt; 0.001; H2O2 and OGD) induced oxidative stress\/ischemic-like insults, decreasing RGC-5 cell viability (from 100% to 55.14 \u00b1 2.19%\/60.84 \u00b1 4.57%). These injuries were insignificantly (53.85 \u00b1 1.28% at 0.25 mM)\/(63.46 \u00b1 3.30% at 0.25 mM) and significantly (p = 0.003\/p = 0.012; 64.15 \u00b1 2.41%\/77.63 \u00b1 8.59% at 0.5 mM) altered by the pre-administration of catalpol, indicating a possible antioxidative and anti-ischemic effect of 0.5 mM catalpol. In vivo, catalpol had less effect at 0.25 mM for ERG amplitude ratio (median [Q1, Q3] 14.75% [12.64%, 20.48%]) and RGC viability (mean \u00b1 SE 63.74 \u00b1 5.13%), whereas (p &lt; 0.05 and p &lt; 0.05) at 0.5 mM ERG\u2019s ratio (35.43% [24.35%, 43.08%]) and RGC\u2019s density (74.34 \u00b1 5.10%) blunted the ischemia-associated significant (p &lt; 0.05 and p &lt; 0.01) reduction in ERG b-wave amplitude (6.89% [4.24%, 10.40%]) and RGC cell viability (45.64 \u00b1 3.02%). Catalpol 0.5 mM also significantly protected against retinal ischemia supported by the increased amplitude ratio of ERG a-wave and oscillatory potential, along with recovering a delayed a-\/b-wave response time ratio. When contrasted with DKK1 or Lucentis, catalpol exhibited similar protective effects against retinal ischemia via significantly (p &lt; 0.05) blunting the ischemia-induced overexpression of \u03b2-catenin, VEGF, or angiopoietin-2. Moreover, ischemia-associated significant increases in apoptotic cells in the inner retina, inflammatory biomarker MCP-1, and ischemic indicator HIF-1\u03b1 were significantly nullified by catalpol. Catalpol demonstrated antiapoptotic, anti-inflammatory, anti-ischemic (in vivo retinal ischemia or in vitro OGD), and antioxidative (in vitro) properties, counteracting retinal ischemia via suppressing upstream Wnt\/\u03b2-catenin and inhibiting downstream HIF-1\u03b1, VEGF, and angiopoietin-2, together with its decreasing TUNEL apoptotic cell number and inflammatory MCP-1 concentration.<\/jats:p>","DOI":"10.3390\/ijms26094019","type":"journal-article","created":{"date-parts":[[2025,4,24]],"date-time":"2025-04-24T09:26:58Z","timestamp":1745486818000},"page":"4019","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Catalpol Protects Against Retinal Ischemia Through Antioxidation, Anti-Ischemia, Downregulation of \u03b2-Catenin, VEGF, and Angiopoietin-2: In Vitro and In Vivo Studies"],"prefix":"10.3390","volume":"26","author":[{"given":"Howard Wen-Haur","family":"Chao","sequence":"first","affiliation":[{"name":"Department of Medicine, School of Medicine, Aston University, Birmingham B4 7ET, UK"},{"name":"Department of Medical Education, Leeds University, Leeds LS2 9JT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Windsor Wen-Jin","family":"Chao","sequence":"additional","affiliation":[{"name":"Department of Medicine, School of Medicine, Aston University, Birmingham B4 7ET, UK"},{"name":"Department of Science, University of British Columbia, Vancouver, BC V6T 1Z4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1545-9936","authenticated-orcid":false,"given":"Hsiao-Ming","family":"Chao","sequence":"additional","affiliation":[{"name":"Department of Chinese Medicine, School of Chinese Medicine, China Medical University, Taichung 404, Taiwan"},{"name":"Institute of Pharmacology, Department of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan"},{"name":"Department of Ophthalmology, Shin Kong Hospital, Taipei 105, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Chao, W.H., Lai, M.Y., Pan, H.T., Shiu, H.W., Chen, M.M., and Chao, H.M. 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