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Tsutomu Fujihara, Tadahiro Murakami, Hiromi Fujita, Masatsugu Nakamura, Katsuhiko Nakata; Improvement of Corneal Barrier Function by the P2Y2 Agonist INS365 in a Rat Dry Eye Model. Invest. Ophthalmol. Vis. Sci. 2001;42(1):96-100.
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purpose. Because purinoceptor P2Y2 receptor agonists elicit
increases in net Cl, fluid transport, and glycoprotein release onto the
ocular surface, they are candidates for treatment of dry eye syndrome.
Accordingly, the effects of such an agonist INS365 on these parameters
were characterized in a rat dry eye model.
methods. An SD rat dry eye model was used in which exorbital lacrimal gland
extirpation decreased the Schirmer test score by at least 50%. After 8
weeks, when significant increases occurred in corneal epithelial
permeability, INS365-containing eye drops were applied six times daily
for the next 4 weeks at concentrations from 0.03% to 3.0%. Corneal
barrier function was evaluated based on measurements with a modified
anterior fluorometer of fluorescein penetrance at 1, 2, and 4 weeks
after initial application. After INS365 application, the periodic
acid–Schiff reagent (PAS)–stained area was evaluated in histologic
sections of the tarsal and bulbar conjunctiva.
results. Ten minutes after INS365 eye drop application at doses of either 3.0%
or 8.5%, a 1.5-fold transient increase in tear fluid secretion
occurred in both the control and dry eye model animals. These transient
increases nearly returned to baseline after 60 minutes. Furthermore,
after 5 minutes, 1.0% INS365 was sufficient to cause a maximal
transient decrease in the PAS-stained area of more than 30%, which
thereafter recovered toward the initial level. Beginning at 2 weeks and
continuing for an additional 2 weeks, maximal declines in dye
penetrance of approximately 50% occurred with doses of INS365 as low
as 1%. Such improvement in corneal epithelial resistance was
accompanied by complete restoration of the PAS-stained area to the
level seen in the control animal.
conclusions. In a rat dry eye model, the P2Y2 agonist INS365 was found
to improve surface health, based on increases in tear fluid secretion,
corneal epithelial resistance, and release of glycoprotein-containing
moieties from goblet cells. These effects suggest that INS365 is a
potential therapeutic agent for use in the treatment of dry eye
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