Ppar Alpha-Dependent Effects Of Palmitoylethanolamide Against Retinal Neovascularization And Fibrosis

PURPOSE. Pathological neovascularization and fibrosis are common pathological changes of many retinal diseases, such as proliferative retinopathy (PR) and age-related macular degeneration (AMD). Treatment modalities for these pathological changes are limited. The purpose of the present study was to test the effects of palmitoylethanolamide (PEA), an endocannabinoid mimetic amide, on retinal neovascularization and fibrosis and to determine its molecular mechanism of action.METHODS. A rat Muller cell line (rMC-1), a mouse model of oxygen-induced retinopathy (OIR), and the very-low-density lipoprotein receptor (VLDLR) knockout mouse model were used. PEA was intraperitoneally injected or orally administrated in animal models. Inflammation and profibrotic changes were evaluated by western blot analysis. Glial fibrillary acidic protein (GFAP) and peroxisome proliferator-activated receptor alpha (PPAR alpha) were measured by RT-PCR and western blot analysis.RESULTS. Profibrotic changes were present in OIR and Vldlr(-/-) retinas. PEA significantly alleviated inflammation and inhibited neovascularization in OIR and Vldlr(-/-) retinas and suppressed profibrotic changes in OIR and Vldlr(-/-) retinas. Moreover, PEA potently suppressed Muller gliosis in these retinas. In rMC-1 cells, PEA suppressed Muller gliosis, reduced inflammatory cytokines, and attenuated profibrotic changes. Further, both mRNA and protein levels of PPAR alpha were elevated in the retina under PEA treatment, and the effects of PEA were abolished in Ppara(-/-) OIR mice.CONCLUSIONS. PEA reduced retinal neovascularization and fibrotic changes and suppressed Muller gliosis in experimental PR and neovascular AMD by activating PPAR alpha. PEA may be a potential treatment for retinopathies with pathological neovascularization and fibrosis.