Abstract
Objective: Diabetic retinopathy (DR) combined with age-related macular degeneration (AMD) is the leading cause of blindness in the US. Here, we report the efficacy of topical application of fenofibrate, an anti-lipid drug, in the treatment of retinal inflammation and neovascularization in rat models of DR and wet AMD, and in order to propose its use as a revolutionary therapy for ocular microvascular diseases.Research design and methods: Fenofibrate was topically administered to rats. Following administration, the bioavailability of fenofibrate and its activated metabolite, fenofibric acid, in the retina, liver, and serum was determined using mass spectrometry. The effects of topical fenofibrate on retinal vascular leakage and inflammation were assessed using vascular permeability and leukostasis assays in streptozotocin (STZ)-induced diabetic rats. The anti-angiogenic effect of topical fenofibrate was evaluated in oxygen-induced retinopathy (OIR) rats and choroidal neovascularization (CNV) rats induced by laser photocoagulation.Results: Treatment with topical fenofibrate caused no apparent corneal irritation or significant alterations in retinal histology in eyes. Fenofibrate rapidly distributed to the retina when applied topically, and the peak level of fenofibric acid in the retina occurred at 6 hours after administration. The terminal half-life of fenofibric acid in the retina was nearly 12 hours. Fenofibrate or fenofibric acid was not detected in the serum or liver by topical application, whereas oral administration of fenofibrate showed that the concentration of fenofibric acid in liver or serum was over 100-fold of that in the retina. Topical application of fenofibrate reduced the over-expression of soluble intercellular adhesion molecule-1 (sICAM-1) and vascular endothelial growth factor (VEGF), attenuated retinal vascular leakage, and ameliorated inflammation in the experimental diabetic models and prevented retinal neovascularization in the OIR and CNV models.Conclusion: Topical application of fenofibrate has therapeutic potential in preventing retinal and choroidal NV formation, amelioration retinal inflammation, and reduction of retinal NV leakage.
Highlights
Diabetic retinopathy (DR), an ocular complication of diabetes, and wet age-related macular degeneration (AMD) are the leading causes of blindness in the US [1,2,3]
The majority of the fenofibrate was converted into fenofibric acid at 4 h and reached a maximal concentration at 6 h, which was sustained until 24 h (Figure 1C-1E)
These results demonstrate that topical ocular fenofibrate application penetrates well into the ocular tissues and does not exhibit systemic adverse effects on the serum or liver
Summary
Diabetic retinopathy (DR), an ocular complication of diabetes, and wet age-related macular degeneration (AMD) are the leading causes of blindness in the US [1,2,3] Both the pathologic features of DR and wet AMD include oxidative stress-associated inflammation, breakdown of the blood-retina barrier (BRB), vascular leakage, and neovascularization (NV) [4,5,6]. In addition to its anti-lipid effects, fenofibrate reduces VEGF receptor 2 (VEGFR2) and plateletderived growth factor (PDGF) levels, inhibits EC proliferation and migration [12,13], reduces ROS accumulation, induces superoxide dismutase and glutathione peroxide, prevents oxidative stress– associated neuronal death [14,15,16,17], reduces intercellular adhesion molecule-1 (ICAM-1) levels, and inhibits tumor necrosis factor-alpha (TNF-α)/ nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling [2,13]. This study was designed to investigate the potential of fenofibrate eyedrops as a novel treatment for ocular microvascular diseases, including DR and AMD
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