title: Cannabinoid 2 receptor is a novel anti-inflammatory target in experimental proliferative vitreoretinopathy.
abstract: Proliferative vitreoretinopathy (PVR) can develop after ocular trauma or inflammation and is a common complication of surgery to correct retinal detachment. Currently, there are no pharmacological treatments for PVR. Cannabinoids acting at cannabinoid 2 receptor (CB2R) can decrease inflammation and fibrosis. The objective of this study was to examine the anti-inflammatory actions of CB2R as a candidate novel therapeutic target in experimental PVR. PVR was induced by intravitreal injection of dispase in wild-type (WT) and CB2R genetic knockout (CB2R-/-) mice. Ocular pathology was studied at 24 h or one week after dispase injection. CB2R modulation was examined in WT mice, using the CB2R agonist, HU308, and the CB2R antagonist, AM630. Histopathological scoring and quantification of microglia was used to evaluate tissue pathology. Quantitative PCR and multiplex assays were used to assess changes in proinflammatory cytokines. Intravital microscopy (IVM) was used to visualize and quantify leukocyte-endothelial adhesion to the iridial microcirculation. Activation of CB2R with HU308 in WT mice with PVR decreased mean histopathological scores, the number of microglia, and leukocyte adhesion compared to vehicle-treated animals. Conversely, an increase in histopathological scores and activated microglia was observed in PVR animals after treatment with AM630. CB2R-/-mice with PVR exhibited exacerbated ocular histopathology, increased microglia numbers, and elevated protein levels of cytokines as compared to WT mice. In conclusion, our results indicate that intervention at early stage PVR with CB2R agonists reduces ocular inflammation and disease severity. CB2R may represent a therapeutic target to prevent PVR progression and vision loss. This article is part of the Special Issue entitled 'Lipid Sensing G Protein-Coupled Receptors in the CNS'.
authors: Departments of Pharmacology, Dalhousie University, Halifax, NS, Canada. Electronic address: anna.maria.szczesniak@dal.ca.
authors: Anna-Maria
authors: AM
authors: Szczesniak
authors: Departments of Pharmacology, Dalhousie University, Halifax, NS, Canada.
authors: Richard F
authors: RF
authors: Porter
authors: Departments of Pharmacology, Dalhousie University, Halifax, NS, Canada.
authors: James T
authors: JT
authors: Toguri
authors: Departments of Pharmacology, Dalhousie University, Halifax, NS, Canada.
authors: Joanna
authors: J
authors: Borowska-Fielding
authors: Departments of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada.
authors: Simon
authors: S
authors: Gebremeskel
authors: Departments of Anesthesia, Dalhousie University, Halifax, NS, Canada; Departments of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada.
authors: Anuja
authors: A
authors: Siwakoti
authors: Departments of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada.
authors: Brent
authors: B
authors: Johnston
authors: Departments of Pharmacology, Dalhousie University, Halifax, NS, Canada; Departments of Anesthesia, Dalhousie University, Halifax, NS, Canada; Departments of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada; Departments of Physiology and Biophysics, Dalhousie University, Halifax, NS, Canada.
authors: Christian
authors: C
authors: Lehmann
authors: Departments of Pharmacology, Dalhousie University, Halifax, NS, Canada; Departments of Anesthesia, Dalhousie University, Halifax, NS, Canada; Departments of Ophthalmology and Vision Sciences, Dalhousie University, Halifax, NS, Canada.
authors: Melanie E M
authors: ME
authors: Kelly
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology*; D002186:Cannabinoids / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D010450:Endopeptidases; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D007211:Indoles / Q000494:pharmacology; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008070:Lipopolysaccharides; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012160:Retina / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D018630:Vitreoretinopathy, Proliferative / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D007211:Indoles; D008070:Lipopolysaccharides; D043885:Receptor, Cannabinoid, CB2; C402416:HU 308; D010450:Endopeptidases; C023139:dispase; C094023:iodopravadoline
keywords: Anti-inflammatory agents; Cannabinoid 2 receptor; Endocannabinoid system; Inflammation; Proliferative vitreoretinopathy