Optimization and validation of an existing, surgical and robust dry eye rat model for the evaluation of therapeutic compounds

Abstract

The aim of this research was to optimize and validate an animal model for dry eye, adopting clinically relevant evaluation parameters. Dry eye was induced in female Wistar rats by surgical removal of the exorbital lacrimal gland. The clinical manifestations of dry eye were evaluated by tear volume measurements, corneal fluorescein staining, cytokine measurements in tear fluid, MMP-9 mRNA expression and CD3(+) cell infiltration in the conjunctiva. The animal model was validated by treatment with Restasis(®) (4 weeks) and commercial dexamethasone eye drops (2 weeks). Removal of the exorbital lacrimal gland resulted in 50% decrease in tear volume and a gradual increase in corneal fluorescein staining. Elevated levels of TNF-α and IL-1α have been registered in tear fluid together with an increase in CD3(+) cells in the palpebral conjunctiva when compared to control animals. Additionally, an increase in MMP-9 mRNA expression was recorded in conjunctival tissue. Reference treatment with Restasis(®) and dexamethasone eye drops had a positive effect on all evaluation parameters, except on tear volume. This rat dry eye model was validated extensively and judged appropriate for the evaluation of novel compounds and therapeutic preparations for dry eye disease.

TRPV1 and TRPM8 Channels and Nocifensive Behavior in a Rat Model for Dry Eye

“…Although factors known to excite corneal nociceptors are elevated in tears of DE patients, 11 – 13 the relationship between nociceptor activity and ocular pain is limited due to a lack of reliable measures of adverse behavior in animals. The present study uses a model for tear deficient DE 14 – 16 and recording of muscle activity via orbicularis oculi muscle electromyography (OOemg), 17 to assess the roles of transient receptor potential vanilloid 1 (TRPV1) and melastatin 8 (TRPM8) ion channels on hypertonic saline (HS)–evoked ocular behavior. HS is well correlated with disease severity and is a risk factor for ocular irritation in DE.…”

A novel serine protease inhibitor as potential treatment for dry eye syndrome and ocular inflammation

“…Induction of dry eye. DES was induced by removal of the exorbital lacrimal gland, as described previously 43 .…”

“…At the end of the experiment, animals were euthanized by gradual CO 2 overdose. Immediately after death, the cornea and palpebral and bulbar conjunctiva were removed and stored in the appropriate manner 43 . For qRT-PCR, tissue was placed in RNA-later (Sigma-Aldrich, Seelze, Germany) and stored at − 80 °C until RNA-extraction and subsequent RT-PCR-analysis.…”

“…As these processes feature prominently in the disease progression of DES, we hypothesized that this multi-target inhibitor could become a potential treatment. As the compound did not show any signs of cytotoxicity, it was evaluated after local application in a tear drop formulation in a DES animal model 43 . The tear drop formulation was specifically developed to preserve the chemical and physical stability of the serine protease inhibitor to safeguard its longer shelf-life.…”

Cluster Analysis of Dry Eye Disease Models Based on Immune Cell Parameters – New Insight Into Therapeutic Perspective

“…Another study used 1% atropine sulfate to instill into the eyes three times a day for 3 days ( 54 ). For Wister rats, Joossen et al, and Park et al, induced dry eye by removing the lacrimal gland ( 55 , 56 ). Ru et al, induced dry eye by injecting scopolamine hydrobromide ( 57 ).…”