Cannabinoid Receptor 2 Agonism Demonstrates Therapeutic Potential in Experimental Models of Relevance to Diabetic Retinopathy

Evidence of retinal vascular inflammation accompanies diabetic retinopathy (DR) progression, and inflammatory cytokines TNFα and IL-1β 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 non-ocular 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 TNFα- and IL-1β-induced 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 TNFα- and IL-1β-induced leukocyte adhesion to hRMEC monolayers, aligning with their effects on adhesion protein levels. HU-308 and CB65 reduced TNFα- and IL-1β-induced NF-κB 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 STZ-induced diabetes. Therefore, CB2 agonism demonstrates potential for mitigating leukostasis and its pathogenic consequences in DR.