Abstract
Purpose :
Purpose Patients with the rare eye disease aniridia suffer from a PAX6 mutation and are thus susceptible to vision loss from a progressive limbal stem cell deficiency (LSCD) as part of an aniridia-associated keratopathy (AAK). Recently, it has been shown that Duloxetine, a serotonin and norepinephrine reuptake inhibitor used orally against severe depression, is able to enhance endogenous PAX6 expression and target genes in vitro. To establish new potential therapeutic options for AAK, it is essential to investigate the potential toxicity of duloxetine in vivo in the cornea and examine its effect on PAX6 and the limbal stem cell niche.
Methods :
Method Wild type (C57BL/6) male mice aged 4-6 weeks were treated with 1µM or 10µM duloxetine topically 4 times a day for 7 days. On day 7, inflammation status was evaluated using in vivo confocal microscopy (IVCM). Subsequently, immunostaining was performed on corneas for PAX6 and stem cell markers including GPHA2, ABCG2, and P63. Quantitative evaluation was also performed for PAX6 by Western blot (WB). A novel aniridia mouse model (129S Sey/+) was also employed to determine the localization of limbal stem cell markers by immunostaining.
Results :
IVCM images indicated that two concentrations of duloxetine (1µM and 10µM) had no observable toxic effect on corneas as no inflammatory cell infiltration was observed. Immunostaining and WB showed that duloxetine increased PAX6 expression in the healthy wild-type corneas (*p=0.047) which confirmed previous in vitro studies. Duloxetine did not induce any prominent changes in the immunostaining of stem cell markers in the treated corneas.
Conclusions :
Topically administered duloxetine during a short course of treatment may be a safe and potential therapeutic compound for further investigation and does not appear to be detrimental to the limbal stem cell niche.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.