Anti-inflammatory effects of cannabinoid CB(2) receptor activation in endotoxin-induced uveitis

Br J Pharmacol. 2014 Mar;171(6):1448-61. doi: 10.1111/bph.12545.

Abstract

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.

Keywords: cannabinoid; cannabinoid 2 receptor; endotoxin-induced uveitis; uveitis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cannabinoids / pharmacology
  • Cannabinoids / therapeutic use*
  • Lipopolysaccharides / toxicity*
  • Male
  • NF-kappa B / genetics
  • RNA, Messenger / genetics
  • Rats
  • Rats, Inbred Lew
  • Receptor, Cannabinoid, CB2 / agonists*
  • Receptor, Cannabinoid, CB2 / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription Factor AP-1 / genetics
  • Uveitis / chemically induced
  • Uveitis / drug therapy
  • Uveitis / metabolism*

Substances

  • Cannabinoids
  • Lipopolysaccharides
  • NF-kappa B
  • RNA, Messenger
  • Receptor, Cannabinoid, CB2
  • Transcription Factor AP-1
  • HU 308