Corneal Alterations Induced by Topical Application of Commercial Latanoprost, Travoprost and Bimatoprost in Rabbit

Abstract

Prostaglandin (PG) analogs, including latanoprost, travoprost, and bimatoprost, are currently the most commonly used topical ocular hypotensive medications. The purpose of this study was to investigate the corneal alterations in rabbits following exposure to commercial solution of latanoprost, travoprost and bimatoprost. A total of 64 New Zealand albino rabbits were used and four groups of treatments were constituted. Commercial latanoprost, travoprost, bimatoprost or 0.02% benzalkonium chloride (BAK) was applied once daily to one eye each of rabbits for 30 days. The contralateral untreated eyes used as controls. Schirmer test, tear break-up time (BUT), rose Bengal and fluorescein staining were performed on days 5, 10, 20, and 30. Central corneal changes were analyzed by in vivo confocal microscopy, and the corneal barrier function was evaluated by measurement of corneal transepithelial electrical resistance on day 5. Whole mount corneas were analyzed by using fluorescence confocal microscopy for the presence of tight-junction (ZO-1, occludin) and adherens-junction (E-cadherin, β-catenin) proteins, actin cytoskeleton, proliferative marker Ki67 and cell apoptosis in the epithelium. Topical application of commercial PG analogs resulted in significant corneal epithelial and stromal defects while no significant changes in aqueous tear production, BUT, rose bengal and fluorescein staining scores on day 5. Commercial PG analogs induced dislocation of ZO-1 and occludin from their normal locus, disorganization of cortical actin cytoskeleton at the superficial layer, and disruption of epithelial barrier function. The eyes treated with 0.02% BAK and latanoprost exhibited significantly reduced Schirmer scores, BUT, and increased fluorescein staining scores on days 10 and 30, respectively. Topical application of commercial PG analogs can quickly impair the corneal epithelium and stroma without tear deficiency. Commercial PG analogs break down the barrier integrity of corneal epithelium, concomitant with the disruption of cell junction and actin cytoskeleton between superficial cells in the corneal epithelium in vivo.

Effects of sustained daily latanoprost application on anterior chamber anatomy and physiology in mice

“…Anatomically, the cornea and iris of treated mice were relatively unaffected by sustained latanoprost treatment. Consistent with findings from other studies 54 , long-term treatment with the preservative present in commercial latanoprost, BAK, leads to corneal thinning. In comparing our findings to those from clinical studies conducted in humans, we noted both similarities and differences, all of which are relevant to ongoing studies of ophthalmic drug development and glaucoma.…”

Reduction in Ocular Hypotensive Eyedrops by Ab Interno Trabeculotomy Improves Not Only Ocular Surface Condition But Also Quality of Vision

“…Since the tear meniscus height and TBUT did not show any significant change, the role of superficial punctate keratitis, or SPK, improvement might not be due to an increase in tear volume but to alleviation of drug-induced cytotoxicity and/or tear film formation. Chen et al reported that commercial latanoprost, travoprost, and bimatoprost damaged the corneal epithelium by breaking down the barrier integrity, cell junction, and cytoskeleton but did not affect aqueous tear production or the TBUT [ 18 ], which is consistent with the current results. Lee et al also reported no significant difference in the TBUT and Schirmer's test between chronically medicated patients and patients who underwent trabeculectomy [ 17 ].…”

0.005% Preservative-Free Latanoprost Induces Dry Eye-Like Ocular Surface Damage via Promotion of Inflammation in Mice

“…ZO-1 and occludin-1, as markers of corneal epithelial tight junction, are expressed in the superficial cell layer of the corneal epithelium. 5 In this study, immunofluorescent staining showed topical latanoprost eye drops treatment resulted in loss of ZO-1 in the superficial corneal epithelial cellular border (Fig. 2C), and qRT-PCR showed that topical latanoprost eye drops treatment significantly decreased the mRNA levels of ZO-1 and occludin-1 in corneal epithelium at day 7 (Figs.…”

“…A growing body of clinical and experimental studies revealed that long-term use of latanoprost eye drops may lead to tear film instability; epithelial apoptosis; corneal epithelial barrier disruption; conjunctival inflammation; and ocular discomfort including burning, stinging, pain, and foreign body sensation. [4][5][6][7] Latanoprost eye drops usually contain a preservative, which is generally considered to be the major factor responsible for ocular surface side effects. Preservatives used in latanoprost eye drops, such as benzalkonium chloride (BAC), may cause or aggravate dry eye disease through various mechanisms such as its toxic and proinflammatory effects as well as detergent properties, which have been well demonstrated in numerous experimental and clinical investigations.…”