Abstract
To investigate the ocular pharmacological profile of hydrocortisone (HC) using in vitro and in vivo models of dry eye disease. Rabbit corneal epithelial cells (SIRCs) were used to assess the effect of HC in two paradigms of corneal damage: hyperosmotic stress and scratch-wound assay. Dry eye was induced in albino rabbits by topical administration of atropine sulfate or by injection of concanavalin A (ConA) into the lacrimal gland. TNFα, TNF-related apoptosis-inducing ligand (TRAIL), IL-1β, and IL-8 were determined by ELISA or western blot in a corneal damage hyperosmotic in vitro model, with or without HC treatment. Inflammatory biomarkers, such as TNFα, IL-8, and MMP-9, were evaluated in tears of rabbit eye injected with ConA and treated with HC. Tear volume and tear film integrity, in both in vivo models, were evaluated by the Schirmer test and tear break-up time (TBUT). Ocular distribution of four formulations containing HC (0.001%, 0.003%, 0.005%, and 0.33%) was performed in the rabbit eye. Aqueous humor samples were collected after 15, 30, 60, and 90 min from instillation and then detected by LC-MS/MS. Hyperosmotic insult significantly activated protein expression of inflammatory biomarkers, which were significantly modulated by HC treatment. HC significantly enhanced the re-epithelialization of scratched SIRCs. Treatment with HC eye drops significantly reduced the tear concentrations of TNF-α, IL-8, and MMP-9 vs. vehicle in the ConA dry eye model. Moreover, HC significantly restored the tear volume and tear film integrity to levels of the control eyes, both in ConA- and atropine-induced dry eye paradigms. Finally, we demonstrated that HC crossed, in a dose-dependent manner, the corneal barrier when the eyes were topically treated with HC formulations (dose range 0.003–0.33%). No trace of HC was detected in the aqueous humor after ocular administration of eye drops containing the lowest dose of the drug (0.001%), indicating that, at this very low concentration, the drug did not pass the corneal barrier avoiding potential side effects such as intraocular pressure rise. Altogether, these data suggest that HC, at very low concentrations, has an important anti-inflammatory effect both in vitro and in vivo dry eye paradigms and a good safety profile.
Highlights
IntroductionCorticosteroids are potent anti-inflammatory drugs that exert their pharmacological effects by binding to the glucocorticoid receptor (GR), leading to the regulation of gene expression by transrepression (i.e., regulating transcriptional regulators such as NF-kB) (Bekhbat et al, 2017)
Corticosteroids are potent anti-inflammatory drugs that exert their pharmacological effects by binding to the glucocorticoid receptor (GR), leading to the regulation of gene expression by transrepression (Bekhbat et al, 2017)
The corneal cells exposed to hyperosmotic insult for 24 h showed a significant (p < 0.05) increase of TNFα, IL-1β, and IL-8 levels that were significantly (p < 0.05) counteracted by HC treatment (Figure 1)
Summary
Corticosteroids are potent anti-inflammatory drugs that exert their pharmacological effects by binding to the glucocorticoid receptor (GR), leading to the regulation of gene expression by transrepression (i.e., regulating transcriptional regulators such as NF-kB) (Bekhbat et al, 2017). The Dry Eye Workshop (DEWS) of the Tear Film Ocular Surface Society (TFOS) described DED as “a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface” (Craig et al, 2017). The canonical approach to treat DED focuses on tear replacement with artificial tears or, alternatively, on preserving the patient’s tears by means of occlusion of the tear drainage system (Ervin et al, 2017) These approaches have been demonstrated to decrease symptoms and signs of dry eye (Pucker et al, 2016), improving the resultant blurred vision and ocular discomfort (Liu and Pflugfelder, 1999). The purpose of the present study was to investigate the ocular pharmacokinetic/pharmacodynamics (PK/ PD) profile of HC using in vitro and in vivo models of dry eye
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