Cannabinoid 2 receptor is a novel anti-inflammatory target in experimental proliferative vitreoretinopathy

Anna-Maria Szczesniak; Richard F Porter; James T Toguri; Joanna Borowska-Fielding; Simon Gebremeskel; Anuja Siwakoti; Brent Johnston; Christian Lehmann; Melanie E M Kelly

doi:10.1016/j.neuropharm.2016.08.030

Cannabinoid 2 receptor is a novel anti-inflammatory target in experimental proliferative vitreoretinopathy

Neuropharmacology. 2017 Feb;113(Pt B):627-638. doi: 10.1016/j.neuropharm.2016.08.030. Epub 2016 Aug 25.

Authors

Anna-Maria Szczesniak¹, Richard F Porter², James T Toguri², Joanna Borowska-Fielding², Simon Gebremeskel³, Anuja Siwakoti⁴, Brent Johnston³, Christian Lehmann⁵, Melanie E M Kelly⁶

Affiliations

¹ Departments of Pharmacology, Dalhousie University, Halifax, NS, Canada. Electronic address: anna.maria.szczesniak@dal.ca.
² Departments of Pharmacology, Dalhousie University, Halifax, NS, Canada.
³ Departments of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada.
⁴ Departments of Anesthesia, Dalhousie University, Halifax, NS, Canada; Departments of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada.
⁵ 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.
⁶ 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.

PMID: 27569993
DOI: 10.1016/j.neuropharm.2016.08.030

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'.

Keywords: Anti-inflammatory agents; Cannabinoid 2 receptor; Endocannabinoid system; Inflammation; Proliferative vitreoretinopathy.

MeSH terms

Animals
Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
Cannabinoid Receptor Modulators / pharmacology*
Cannabinoids / pharmacology
Disease Models, Animal
Dose-Response Relationship, Drug
Endopeptidases
Endothelial Cells / drug effects
Endothelial Cells / immunology
Endothelial Cells / pathology
Indoles / pharmacology
Leukocytes / drug effects
Leukocytes / immunology
Leukocytes / pathology
Lipopolysaccharides
Macrophages / drug effects
Macrophages / immunology
Macrophages / pathology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Microglia / drug effects
Microglia / immunology
Microglia / pathology
Receptor, Cannabinoid, CB2 / agonists
Receptor, Cannabinoid, CB2 / antagonists & inhibitors
Receptor, Cannabinoid, CB2 / genetics
Receptor, Cannabinoid, CB2 / metabolism*
Retina / drug effects
Retina / immunology
Retina / pathology
Vitreoretinopathy, Proliferative / drug therapy*
Vitreoretinopathy, Proliferative / immunology*
Vitreoretinopathy, Proliferative / pathology

Substances

Anti-Inflammatory Agents, Non-Steroidal
Cannabinoid Receptor Modulators
Cannabinoids
Indoles
Lipopolysaccharides
Receptor, Cannabinoid, CB2
HU 308
Endopeptidases
dispase
iodopravadoline