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Robert A Honkanen, Liqun Huang, Gang Xie, Basil Rigas; Treatment of Concanavalin A induced Dry Eye Disease in Rabbits using the novel agent Phosopho-sulindac. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3837.
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© ARVO (1962-2015); The Authors (2016-present)
Phospho-sulindac (PS) is a novel compound with strong anti-inflammatory effects. PS does not inhibit cyclo-oxygenase and is therefore not an NSAID. We tested the hypothesis that PS is efficacious for the treatment of Concanavalin A (ConA) induced Dry Eye Disease (DED) in rabbits.
DED was induced in NZW rabbits by weekly injections of Con A (x3) under ultrasound guidance creating prolonged DED lasting at least three weeks. Efficacy of PS was evaluated with four parameters: tear break up time (TBUT), tear osmolarity (TOsm), Schirmer’s test (STT) and tear lactoferrin levels (TLF). Rabbits were treated topically with PS or vehicle tid for 21 days, starting on day one. Naïve rabbits served as control. In two separate experiments, the effect of PS was compared to cyclosporin or lifitegrast and to diclofenac or ketorolac (tid drop administration for 1 week in both). (n=8-10 eyes/group for all animal experiments) To determine potential mechanisms, NF-κB activation (EMSA), and levels of IL-1β, IL-8, MMP-9 (ELISA) and MMP activity (fluorometric assay) were measured in response to PS in ocular tissues.
Compared to Vehicle, PS restored to normal TBUT, TOsm, and TLF level (Figure 1A).PS improved STT but was significant only for trend.PS demonstrated superior efficacy compared to cyclosporine, lifitegrast (Table 1); ketorolac and diclofenac (Fig 1B).Compared to vehicle, PS suppressed activation of NF-κB in lacrimal gland tissues treated with ConA.Levels of IL-1β and IL-8 in lacrimal glands of rabbits with Con A-induced DED were also significantly lower in eyes treated with PS compared to vehicle after 1 week (Table 1). MMP-9 level in lacrimal glands and MMP activity in cornea was also significantly lowered in DED eyes treated with PS (Figure 1C). PS had no topical or systemic side effects.
Our studies confirm the hypothesis that PS is beneficial for treatment of DED in a rabbit model created with ConA. PS effects may be due in part to its anti-inflammatory properties which inhibit NF-κB. Based on its strong efficacy and safety, PS merits further evaluation for the treatment of DED.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
Figure 1. Effect on clinical and laboratory markers of DED on tears and ocular tissues treated with PS
Table 1. Comparison of PS to Cyclosporine, Lifitegrast and Vehicle in ConA induced DED
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