British journal of pharmacology · 2014
Anti-inflammatory effects of cannabinoid CB(2) receptor activation in endotoxin-induced uveitis.
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Toguri J T, Lehmann C, Laprairie R B, Szczesniak A M, Zhou J, Denovan-Wright E M, Kelly M E M
Аннотация
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.issue-6.
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.issue-6.