BACKGROUND AND PURPOSE:

CB2 R stimulation has immunomodulatory effects. This study investigated the effects of CB2 R modulation 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). Effects of the CB2 R agonist, HU308 (1.5% topical), the CB2 R antagonist, AM630 (2.5 mg kg -1 i.v.), or a combination of agonist and antagonist on leukocyte-endothelial interactions were examined hourly for 6 hrs in rat iridial vasculature using intravital microscopy. The anti-inflammatory actions of HU308 were compared clinical treatments for uveitis: dexamethasone, prednisolone and nepafenac. Transcription factors (NF-κβ, AP-1) and inflammatory mediators (cytokines, chemokines and adhesion molecules) were measured in iris and ciliary body tissue.

KEY RESULTS:

Increased leukocyte-endothelium adherence was seen in iridial microvasculature between 4-6 hrs after LPS. HU308, reduced adherent leukocytes at 4, 5, and 6 hrs after LPS injection (p<0.05) and decreased pro-inflammatory mediators: TNF-α, IL-1β, IL-6, CCL5 and CXCL2 (p<0.05). AM630, blocked the actions of HU-308, and significantly increased leukocyte-endothelium adhesion (p<0.05). HU-308 decreased transcription factors NF-κβ and AP-1 (p<0.001 and p<0.001), while AM630 increased levels of NF- κβ (p<0.05).Topical treatments with dexamethasone, prednisolone, or nepafenac, failed to alter leukocyte adhesion or mitigate LPS-induced increases in inflammatory mediators during the 6 hr EIU time-course (p>0.05).

CONCLUSION AND IMPLICATIONS:

Stimulation of CB2 R is anti-inflammatory in a model of acute EIU by a mechanism involving a reduction in NF-κβ, AP-1 and inflammatory mediators. CB2 R may be a promising drug target for the development of novel ocular anti-inflammatory agents.
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PMID:

 

24308861

 

[PubMed – as supplied by publisher]