1243-OR: Novel Montelukast Derivatives for Treating Diabetic Retinopathy

Introduction and Objective: Early-stage diabetic retinopathy (DR) is characterized by vascular endothelial cell damage and breakdown of the blood-retinal barrier. We and others previously shown that CysLTR1 antagonist Montelukast (MON) is a promising treatment for diabetes-related eye issues. This study aims to develop and assess the effectiveness of new MON derivatives in alleviating endothelial dysfunction and subsequent neurodegeneration in diabetic mice. Methods: Two analogs (MA-01 & MA-02) were synthesized. In silico docking with CysLTR1 was performed. Solubility and cytotoxicity were evaluated. Human retinal microvascular endothelial cells (HREC) treated with 20 ng/mL TNF-α and 30 mM D-glucose (30 mM L-glucose as control) were analyzed for inflammation, autophagy and vascular leakage, with and without analog treatment. Owing to the superior efficacy of MA-01, further in-vivo studies were performed for visual function in 8-week-old streptozotocin induced diabetic mouse model over three months. Results: In silico, analogs exhibited higher CysLTR1 receptor binding affinity than MON and showed good solubility in DMSO/water. Cell viability assays indicated MA-01 and MON are tolerable up to 5 µM, while MA-02 is tolerable up to 10 µM. HREC cells exposed to D-glucose+TNF-α and pre-treated with MA-01 or MA-02 (5 µM) showed significant reductions in IL1β, CXCL10, VCAM1, and CCL2 levels. MA-01 and MA-02 improved transendothelial resistance versus D-glucose+TNF-α and inhibited leukocyte transmigration, reducing endothelial permeability. In diabetic mice, MA-01 provided sustained neuroprotection over three months. Conclusion: The novel derivatives of MON effectively reduce inflammation-driven effects in HREC. In-vivo studies confirmed that MA-01 protects against diabetes-induced visual impairments. Our preliminary research has established a strong foundation for MON analogs as promising treatments for DR-associated endothelial dysfunction. Future studies will compare systemic versus local intravitreal delivery and potential neurobehavioral complications.