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'.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Cannabinoid Receptor Modulators/pharmacology , Receptor, Cannabinoid, CB2/metabolism , Vitreoretinopathy, Proliferative/drug therapy , Vitreoretinopathy, Proliferative/immunology , Animals , 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 , Retina/drug effects , Retina/immunology , Retina/pathology , Vitreoretinopathy, Proliferative/pathologyABSTRACT
The observation that marijuana reduces intraocular pressure was made by Hepler and Frank in the 1970s. Since then, there has been a significant body of work investigating cannabinoids for their potential use as therapeutics. To date, no endocannabinoid system (ECS)-modulating drug has been approved for clinical use in the eye; however, recent advances in our understanding of the ECS, as well as new pharmacological tools, has renewed interest in the development of ocular ECS-based therapeutics. This review summarizes the current state-of-affairs for the use of ECS-modulating drugs for the treatment of glaucoma and ocular inflammatory and ischemic disease.
