Therapeutic Potential of Topical Fenofibrate Eyedrops in Diabetic Retinopathy and AMD Rat Models

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.

Therapeutic Effects of Fenofibrate Nano-Emulsion Eye Drops on Retinal Vascular Leakage and Neovascularization

“…The optimized mass spectrometric parameters, MRM transitions for fenofibrate, and fenofibric acid were m/z 361.0 to 121 in positive ESI mode and m/z 319.0 to 232.9 in negative ESI mode, respectively. The ion source parameters were Curtain Gas (CUR) 20, Turbo Gas 1 (GS1) 30, Turbo Gas 2 (GS2) 60, Temperature (TEM) 400 °C, Entrance Potential (EP) 10, and Cell Exit Potential (CXP) 6 for maximum sensitivity [ 24 ].…”

Evolution of a 4-Benzyloxy-benzylamino Chemotype to Provide Efficacious, Potent, and Isoform Selective PPARα Agonists as Leads for Retinal Disorders

“…Because the report of these results and mechanistic and genetic studies have determined that the protective effects of Feno are unrelated to its lipid-lowering activity, but rather result from agonism of PPARα by the Feno metabolite fenofibric acid (FenoFA). , Feno/FenoFA, however, suffers from low ocular distribution, low affinity and selectivity for PPARα, and dose-limiting toxicities, all of which will likely limit its use as a DR therapy. Proof-of-concept, however, for targeting retinal PPARα with systemically available small molecules has been established with Feno and revealed that small molecule agonists with improved PK/PD profiles have high promise to become first-in-class noninvasive treatment options for DR and related ocular conditions (e.g., age-related macular degeneration and retinopathy of prematurity). , …”