Ocular Pharmacokinetics And Tert Activation Of Cycloastragenol In Corneal Endothelial And Epithelial Cells

To investigate the safety, telomerase reverse transcriptase (TERT) activity, and ocular pharmacokinetics of cycloastragenol (CAG) in human corneal endothelial and epithelial cells, and to determine its potential to penetrate the cornea as a therapy for telomere-related cellular senescence.

Kirikkale University, Faculty of Veterinary Medicine, Department of Preclinical Sciences, Kirikkale, Turkiye

The cytotoxicity and efficacy of varying CAG concentrations were assessed in corneal endothelial and epithelial cells through IC50 determination, and TERT activity was measured at sub-IC50 concentrations by indirect immunofluorescence with an anti-TERT antibody. Transcorneal passage was evaluated using a 3D organotypic cornea model, while in vivo rabbit studies assessed absorption and tissue distribution after topical application. CAG concentrations in ocular tissues were quantified by LC-MS/MS.

CAG exhibited low cytotoxicity, with IC50 values of 220 µM in corneal endothelial cells and 740 µM in corneal epithelial cells. Sub-IC50 concentrations caused minimal apoptosis or necrosis, with significant TERT activity observed from 2 µM. In 3D organotypic models, transcorneal passage was dose-dependent, ranging from 0.18–0.25% at 24 h to 1.89% at 72 h with repeated dosing. In rabbits, peak CAG levels (Tmax) occurred at 30 min, with Tmax values of 215.56 ng in corneal tissue (mean 162.99 ng), 4 ng in the anterior chamber (mean 2.56 ng), and 14.12 ng in the iris (mean 9.41 ng). Tear levels declined rapidly due to turnover. Overall ocular absorption was 5.39%, with 0.35% reaching the iris.

CAG is safe at therapeutic doses, activates TERT in corneal endothelial and epithelial cells, and efficiently penetrates the cornea to reach intraocular tissues. These findings suggest that CAG may serve as a potential therapeutic approach to reduce age-related decline in corneal endothelial and epithelial cells.