{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T20:37:07Z","timestamp":1789763827638,"version":"4.0.1"},"reference-count":59,"publisher":"American Diabetes Association","issue":"9","license":[{"start":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T00:00:00Z","timestamp":1749686400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/journals\/pages\/license"}],"funder":[{"name":"Mildred Almen Reeves Foundation"},{"name":"NIH","award":["R01 EY007533"],"award-info":[{"award-number":["R01 EY007533"]}]},{"name":"NIH","award":["R01 EY023397"],"award-info":[{"award-number":["R01 EY023397"]}]},{"name":"NIH","award":["T32 EY007135"],"award-info":[{"award-number":["T32 EY007135"]}]},{"name":"NIH","award":["T32 EY021453"],"award-info":[{"award-number":["T32 EY021453"]}]},{"DOI":"10.13039\/100001818","name":"Research to Prevent Blindness, Inc","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100001818","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100001209","name":"Knights Templar Eye Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001209","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,9,1]]},"abstract":"<jats:p>Evidence of retinal vascular inflammation accompanies diabetic retinopathy (DR) progression, and inflammatory cytokines tumor necrosis factor-\u03b1 (TNF\u03b1) and interleukin-1\u03b2 (IL-1\u03b2) are experimentally linked to several hallmark DR features, including retinal leukostasis. Cannabinoid receptor 2 (CB2) agonism has been shown to decrease inflammatory cytokine production and leukocyte recruitment and adhesion in nonocular inflammation models, suggesting CB2 agonism could have therapeutic potential in DR. We tested the efficacy of two CB2-selective agonists, HU-308 and CB65, to attenuate leukocyte adhesion to human retinal microvascular endothelial cells (hRMEC) in response to diabetes-relevant inflammatory stimuli and to the walls of retinal capillaries in murine models of DR. In vitro, HU-308 and CB65 significantly reduced TNF\u03b1-induced and IL-1\u03b2\u2013induced gene expression of the adhesion molecules ICAM1, VCAM1, and SELE and protein expression of ICAM-1 and VCAM-1 in hRMEC. Additionally, HU-308 and CB65 inhibited TNF\u03b1-induced and IL-1\u03b2\u2013induced leukocyte adhesion to hRMEC monolayers, aligning with their effects on adhesion protein levels. HU-308 and CB65 reduced TNF\u03b1-induced and IL-1\u03b2\u2013induced nuclear factor \u03baB translocation and activation, suggesting downstream mechanisms of CB2 receptor activation. In vivo, both intraocular and systemic HU-308 administration significantly decreased retinal leukostasis in cytokine-induced inflammation and streptozotocin-induced diabetes. Therefore, CB2 agonism demonstrates potential for mitigating leukostasis and its pathogenic consequences in DR.<\/jats:p>\n                  <jats:sec>\n                    <jats:title>ARTICLE HIGHLIGHTS<\/jats:title>\n                    <jats:p>An effective treatment strategy for early-stage diabetic retinopathy (DR) could delay or prevent disease progression and limit or eliminate irreparable retinal damage and vision loss associated with progression to later stages of DR. Cannabinoid receptor 2 (CB2) activation strategies may provide a promising therapeutic approach to address the chronic retinal inflammation that encourages DR progression. CB2 activation therapeutically addresses leukocyte binding in human retinal microvascular endothelial cells and retinal leukostasis in diabetic mice, presumably by inhibiting nuclear factor \u03baB\u2013dependent transcription of adhesion molecules VCAM-1 and ICAM-1. CB2 agonism constitutes a rational therapeutic approach for clinical application to patients with early-stage DR.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2337\/db24-0805","type":"journal-article","created":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T14:34:23Z","timestamp":1749738863000},"page":"1675-1686","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":3,"title":["Cannabinoid Receptor 2 Agonism Demonstrates Therapeutic Potential in Experimental Models of Relevance to Diabetic Retinopathy"],"prefix":"10.2337","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6771-6108","authenticated-orcid":false,"given":"Cayla D.","family":"Ontko","sequence":"first","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine 1 , Nashville, TN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taylor 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