Bevacizumab eye drops delay corneal epithelial wound healing and increase the stromal response to epithelial injury in rats

Two studies were conducted to check the effects of β-blocker eye drops, 2% carteolol (Mikelan®) and 0.5% timolol (Timoptol®), on regeneration of corneal epithelium in rabbit eyes. For the short-term study, epithelial deficiency was artificially induced in the cornea of albino rabbits. One of the β-blocker eye drops or 0.005% benzalkonium chloride was applied in the right eye and physiological saline solution was applied to the left eye four times a day, and wound healing rate was calculated. Two weeks later, images of the surface epithelium were analyzed by scanning electron microscopy and proliferative capacity was studied, using proliferating cell nuclear antigen as a marker. The long-term study was conducted similarly except that the eye drops were applied twice a day and epithelial deficiency was re-induced every two weeks. In the short-term study, epithelial wound healing rate was slowed in β-blocker groups. Significant differences were detected between the Mikelan® and Timoptol® groups, and the benzalkonium and physiological saline groups. The β-blocker groups had severe epithelial cell desquamation, as well as detachment. In the long-term study, the Mikelan® group had significantly delayed wound healing at first induction, the benzalkonium group showed delay up to the third induction and the Timoptol® group up to the fifth induction. These studies indicate that β-blocker eye drops delay corneal epithelial wound healing and supported the concept that corneal epithelial deficiency occurs clinically after the long-term administration of β-blocker eye drops.

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β-blocker eye drops affect ocular surface through β2 adrenoceptor of corneal limbal stem cells

BMC Ophthalmology ◽

10.1186/s12886-021-02186-w ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Xingyue Yuan ◽

Xiubin Ma ◽

Lingling Yang ◽

Qingjun Zhou ◽

Ya Li

Keyword(s):

Wound Healing ◽

Ocular Surface ◽

Eye Drops ◽

Limbal Stem Cells ◽

Corneal Wound Healing ◽

Corneal Epithelial ◽

Epithelial Wound Healing ◽

Corneal Wound ◽

Specific Antagonist ◽

Β Blocker

Abstract Background Topical application of β-blocker eye drops induces damage to the ocular surface in clinical. However, the mechanism involved remains incompletely understood. The purpose of this study was to investigate the influence and mechanism of β-blocker eye drops on corneal epithelial wound healing. Methods Corneal epithelial wound healing models were constructed by epithelial scraping including in the limbal region and unceasingly received eye drops containing 5 mg/mL β-blocker levobunolol, β1-adrenoceptor (β1AR)-specific antagonist atenolol or β2-adrenoceptor (β2AR)-specific antagonist ICI 118, 551. For the migration assay, the murine corneal epithelial stem/progenitor cells (TKE2) were wounded and subsequently incubated with levobunolol, atenolol, or ICI 118, 551. The proliferation and colony formation abilities of TKE2 cells treated with levobunolol, atenolol, or ICI 118, 551 were investigated by CCK-8 kit and crystal violet staining. The differentiation marker Cytokeratin 3 (CK3), the stem cell markers-Cytokeratin 14 (CK14) and Cytokeratin 19 (CK19), and corneal epithelium regeneration-related signaling including in Ki67 and the phosphorylated epithelial growth factor receptor (pEGFR) and phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) were assessed by immunofluorescence staining. Results Levobunolol and ICI 118, 551 impaired corneal wound healing, decreased the expressions of CK3, CK14, and CK19 after limbal region scraping in vivo and reduced the migration and proliferation of TKE2 in vitro, whereas atenolol had no significant effect. Moreover, levobunolol and ICI 118, 551 inhibited corneal wound healing by mediating the expression of Ki67, and the phosphorylation of EGFR and ERK1/2 in the limbal and regenerated corneal epithelium. Conclusion β-blocker eye drops impaired corneal wound healing by inhibiting the β2AR of limbal stem cells, which decreased corneal epithelial regeneration-related signaling. Therefore, a selective β1AR antagonist might be a good choice for glaucoma treatment to avoid ocular surface damage.

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