Anti-inflammatory effects of cannabinoid CB₂ receptor activation in endotoxin-induced uveitis

Background and Purpose Cannabinoid CB₂ receptors mediate immunomodulation. Here, we investigated the effects of CB₂ receptor ligands on leukocyte-endothelial adhesion and inflammatory mediator release in experimental endotoxin-induced uveitis (EIU). Experimental Approach EIU was induced by intraocular injection of lipopolysaccharide (LPS, 20 ng·μL^-1). Effects of the CB₂ receptor agonist, HU308 (1.5% topical), the CB₂ receptor antagonist, AM630 (2.5 mg·kg^-1 i.v.), or a combination of both compounds on leukocyte-endothelial interactions were measured hourly for 6 h in rat iridial vasculature using intravital microscopy. Anti-inflammatory actions of HU308 were compared with those of clinical treatments for uveitis - dexamethasone, prednisolone and nepafenac. Transcription factors (NF-κB, AP-1) and inflammatory mediators (cytokines, chemokines and adhesion molecules) were measured in iris and ciliary body tissue. Key Results Leukocyte-endothelium adherence was increased in iridial microvasculature between 4-6 h after LPS. HU308 reduced this effect after LPS injection and decreased pro-inflammatory mediators: TNF-α, IL-1β, IL-6, CCL5 and CXCL2. AM630 blocked the actions of HU-308, and increased leukocyte-endothelium adhesion. HU-308 decreased levels of the transcription factors NF-κB and AP-1, while AM630 increased levels of NF-κB. Topical treatments with dexamethasone, prednisolone or nepafenac, failed to alter leukocyte adhesion or mitigate LPS-induced increases in inflammatory mediators during the 6 h of EIU. Conclusion and Implications Activation of CB₂ receptors was anti-inflammatory in a model of acute EIU and involved a reduction in NF-κB, AP-1 and inflammatory mediators. CB₂ receptors may be promising drug targets for the development of novel ocular anti-inflammatory agents. Linked Articles This article is part of a themed section on Cannabinoids 2013. To view the other articles in this section visit http://dx.doi.org/10. 1111/bph.2014.171.