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Kathryn S. Crawford, Laura J. Belen, Allison Rumore, Peter Gaines, George W. Ousler, III, Mark B. Abelson; Murine CAETM Model For Efficient Screening Of Novel Therapeutics For Dry Eye Syndrome. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3781.
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© ARVO (1962-2015); The Authors (2016-present)
To modify an established murine desiccation model of dry eye (Dana, Pflugfelder) to allow for efficient, high-throughput screening of drug candidates and increase predictability of proof-of-concept studies.
Female C57BL/6J mice were exposed to a controlled adverse environment (CAETM) with controlled temperature, low humidity, and high-airflow. Subcutaneous scopolamine was administered 2-4 times daily for 3-10 days during a 7-20 day experimental period. Topical doses of various positive controls or vehicle were administered 2-4 times daily for 7-14 days. Mice were evaluated for corneal fluorescein staining under magnification in 5 distinct corneal regions (modified NEI scale) at multiple timepoints. Tear production was measured using a phenol red thread (Zone-Quick) placed in the lateral canthus. Tears were collected with a PCR Micropipet (Drummond) and placed in low-protein binding microfuge tubes and immediately frozen for subsequent cytokine analysis (Luminex®).
Exposure to CAETM for 7 days resulted in mild to moderate corneal staining in all regions (total staining = 5.3 ± 0.3 vs. baseline; 1.6 ±0.2; 0-15 scale; n=40) with no effect on tear production (5.7 ± 0.3 mm vs. baseline; 6.1 ±0.2 mm). Addition of subcutaneous scopolamine drastically reduced tear production (1.0 ± 0.1 mm), resulting in more severe staining (12.2 ± 0.4). Elevated staining levels were still achieved upon decreasing the number of scopolamine injections from 4 to 3 or 2 times daily. Drug treatment reduced total corneal staining by 3-8 units, depending on the severity of staining and duration/frequency of dosing. A significant elevation in cytokines IFN-γ (4-fold), IL-10 (10-fold), IL-13 (10-fold), and TNFα (4-fold) in response to CAETM and scopolamine injections, and subsequent decrease in response to treatment to baseline levels, was also observed.
This model is an effective and efficient tool for screening drug candidates for the treatment of dry eye. The efficacy profile of known active agents comparable to what has been observed in clinical trials utilizing the human CAETM demonstrates the predictability of this murine CAETM model.
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