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Ruiyi Ren, Anne A. Humphrey, Casey Kopczynski, Haiyan Gong; Rho Kinase Inhibitor AR-12286 Reverses Steroid-induced Changes in Mouse Eyes. Invest. Ophthalmol. Vis. Sci. 2020;61(7):2720.
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This study investigated the mechanisms of Rho kinase inhibitor AR-12286 on reduction of intraocular pressure (IOP) in steroid-induced ocular hypertension (SIOH).
C57BL/6 mice (N=56) were randomly divided into 4 groups: Saline, Dexamethasone (DEX), DEX+AR-12286, and DEX-discontinuation (DEX-DC). The detailed experimental design with daily treatment for each mouse is shown in Table 1. The dosage of each treatment was 10μl of saline, 0.1% DEX, or 0.25% AR-12286 to both eyes, respectively. IOP was measured weekly. For Saline, DEX, and DEX+AR-12286 groups, week 5 was the last week of the experiment, and IOP was measured on days 0, 1, 3, 5, and 7. Mice in DEX-DC group were observed without any treatment until IOP returned to a similar level as the Saline group (at week 9). After the completion of dosing, fluorescent tracer was injected into the anterior chamber of one eye of each mouse to visualize the outflow pattern in the trabecular meshwork (TM). Percent effective filtration length of the TM (PEFL= tracer-labeled TM length/total TM length X 100%) was determined for each eye. Radial sections from both high- and low-tracer regions of 5-6 randomly selected eyes from each group were processed for electron microscopy.
AR-12286 treatment significantly reduced IOP in SIOH mouse eyes in one day (p<0.01) and kept it lower than the DEX group for the rest of week 5. At the end of week 5, mean IOP in DEX+AR-12286 group was ~4mmHg lower than DEX group (p<0.001) and ~2mmHg lower than DEX-DC group (p<0.05). DEX-induced reduction of PEFL was rescued after 1-week AR-12286 treatment (DEX+AR-12286 vs. DEX: 70% vs 48%, p<0.05) or 5-weeks following DC of DEX (DEX-DC vs. DEX: 76% vs 48%, p<0.01). There was a significant negative correlation between PEFL and IOP (N=35, R2=0.36, p<0.001). DEX-induced morphological changes, including compacted juxtacanalicular connective tissue and increased deposition of extracellular matrix in the TM, were partially reversed by 1-week AR-12286 treatment or 5-weeks following DC of DEX.
AR-12286 reversed steroid-induced morphological changes in the TM, reversed the reduced PEFL, and this correlated with reduced IOP in SIOH mouse eyes. AR-12286 reduced IOP elevation in SIOH eyes more efficiently than discontinuing DEX treatment even when it was accompanied by continuous DEX treatment. Therefore, Rho kinase inhibitors may lower SIOH in patients who rely on steroid treatment.
This is a 2020 ARVO Annual Meeting abstract.
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