title: Anti-inflammatory effects of cannabinoid CB(2) receptor activation in endotoxin-induced uveitis.
abstract: OBJECTIVE
  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).
  
  
  METHODS
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  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.
authors.affiliation: Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.
authors.forename: J T
authors.initials: JT
authors.lastname: Toguri
authors.forename: C
authors.initials: C
authors.lastname: Lehmann
authors.forename: R B
authors.initials: RB
authors.lastname: Laprairie
authors.forename: A M
authors.initials: AM
authors.lastname: Szczesniak
authors.forename: J
authors.initials: J
authors.lastname: Zhou
authors.forename: E M
authors.initials: EM
authors.lastname: Denovan-Wright
authors.forename: M E M
authors.initials: ME
authors.lastname: Kelly
mesh_terms: D000818:Animals; D002186:Cannabinoids / Q000494:pharmacology / Q000627:therapeutic use*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D016328:NF-kappa B / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011917:Rats, Inbred Lew; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018808:Transcription Factor AP-1 / Q000235:genetics; D014605:Uveitis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*
chemical_list: D002186:Cannabinoids; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012333:RNA, Messenger; D043885:Receptor, Cannabinoid, CB2; D018808:Transcription Factor AP-1; C402416:HU 308
keywords: cannabinoid; cannabinoid 2 receptor; endotoxin-induced uveitis; uveitis