Abstract
Dry eye disease is one of the most common diseases, with increasing prevalence in many countries, but treatment options are limited. Cystic fibrosis transmembrane conductance regulator (CFTR) is a major ion channel that facilitates fluid secretion in ocular surface epithelium and is a potential target of therapeutic agent for the treatment of dry eye disease. In this study, we performed a cell-based, high-throughput screening for the identification of novel natural products that activate CFTR and restore the aqueous deficiency in dry eye. Screening of 1000 natural products revealed isorhamnetin, a flavonol aglycone, as a novel CFTR activator. Electrophysiological studies showed that isorhamnetin significantly increased CFTR chloride current, both wild type and ∆F508-CFTR. Isorhamnetin did not alter intracellular cAMP levels and the activity of other ion channels, including ANO1, ENaC, and hERG. Notably, application of isorhamnetin on mouse ocular surface induced CFTR activation and increased tear volume. In addition, isorhamnetin significantly reduced ocular surface damage and expression of interleukin (IL)-1β, IL-8, and tumor necrosis factor (TNF)-α in an experimental mouse model of dry eye. These data suggest that isorhamnetin may be used to treat dry eye disease.
Highlights
Recent studies on dry eye disease have shown that inflammation of the lacrimal gland, meibomian gland, cornea, and conjunctiva plays an important role in its pathogenesis, with a marked increase in tear inflammatory cytokines and immune cell infiltration [5]
Mutations in CFTR, which impair its expression and function, cause cystic fibrosis (CF), the most common lethal genetic disease, and CF patients showed that they exhibit ocular surface abnormality of low tear film stability [12]
Apical membrane currents were measured to verify the effect of isorhamnetin on CFTR chloride channel activity in WT-CFTR expressing Fisher rat thyroid (FRT) cells
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Available treatments for the dry eye disease include artificial eye drops, which can moisten the eyes for a short period of time upon treatment before it evaporates, and cyclosporine, which is used to subdue inflammation [6,7]. P2Y2 receptor agonists, such as diquafosol, which could restore the tear film stability by transiently increasing water secretion from calcium-activated chloride channels expressed on the conjunctival epithelium, have been suggested as a possible treatment for the disease [8]. Mutations in CFTR, which impair its expression and function, cause cystic fibrosis (CF), the most common lethal genetic disease, and CF patients showed that they exhibit ocular surface abnormality of low tear film stability [12]. We identified a novel CFTR activator, isorhamnetin, and investigated the effectiveness of isorhamnetin in an experimental mouse model of dry eye
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