A rabbit model of age‐dependant ocular hypertensive response to topical corticosteroids

Abstract

ABSTRACT.Objective: To investigate the ocular hypertensive response to topical dexamethasone (DEX), rimexolone (RIM), loteprednol etabonate (LOT) and fluorometholone (FML) in rabbits of different ages. Methods: Seventy-five rabbits of three age groups (7 weeks, 6 months and 1-year old) received topical administration of 0.1% DEX, 1% RIM, 0.5% LOT, 0.1% FML or balanced salt solution four times daily for 1 month. Intraocular pressure (IOP) was monitored at regular time intervals. After a month, eyes were harvested for histological study with haematoxylin and eosin (H&E), periodic acid Schiff and Masson trichrome staining. Trabecular meshwork changes were graded by masked ocular pathologists. Results: Topical DEX caused the greatest increase in IOP, followed by RIM and FML. LOT caused the least IOP increase. Similar pattern of IOP response to the four corticosteroids was observed in the three studied age groups. Young rabbits (7 week) were the most responsive to corticosteroids among the age groups. Extracellular matrix thickening in the trabecular meshwork region and loss of trabecular meshwork cells were observed after DEX, FML or RIM treatments. Conclusion: Young rabbits are more susceptible to steroid induced increase in IOP, even for milder steroids such as fluorometholone and rimexolone.

Model systems for the study of steroid-induced IOP elevation

“…Notably such IOP elevation cannot often be sustained for long periods of time. In addition IOP elevation was shown to occur only when treatment began during the developmental period (8-10 weeks of age), while even relatively young, mature rabbits (3 years of age) were shown to be refractory to this effect even when dexamethasone was applied every 6 hours for 4 weeks (Knepper et al, 1978; Qin et al, 2012). Thus despite the fact that glucocorticoid receptor concentration is high in ocular tissues of rabbits and intravenously administered steroid has been found to bind specifically to the nuclei of cells in the outflow channels (Knepper et al, 1985), rabbits have fallen out of favor as a model for steroid-induced IOP elevation.…”

Experimental Models of Glaucoma: A Powerful Translational Tool for the Future Development of New Therapies for Glaucoma in Humans—A Review of the Literature

“…The age-dependent ocular hypertensive response to topical steroids has been observed in experimental model rabbits with good resemblance to clinical observations in humans. Topical application of dexamethasone resulted in an increase of intraocular pressure of young rabbits (5 mmHg or more IOP rise in 76%) but had no effect on the intraocular pressure of old rabbits [17,18]. In young rabbits, it is possible to observe alterations in the outflow of aqueous humor due to the immaturity of the iridocorneal angle, these particularities are also observed in young patients.…”

Animal models of glucocorticoid-induced glaucoma

“…IOPs returned to normal when topical dosing was discontinued. Topical ocular dosing with potent GCs for 3-5 weeks caused thickening of trabecular beams, loss of TM cells, and increased deposition of extracellular matrix material in the outflow pathway, including at the aqueous plexus (Ticho et al, 1979; François et al, 1984; Knepper et al, 1985; Qin et al, 2010). However, not everyone has been successful in generating ocular hypertension in rabbits by topical ocular administration of potent GCs (Hester et al, 1987; personal communication).…”