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Published on: July 23, 2016
Effect of Rho Kinase Inhibitor RKI-1447 on Dexamethasone-Induced Ocular Hypertension and Its Molecular Mechanisms in
Junhui Wu1,2, Yalong Dang2,3,4, Fang Lei4
1Department of Ophthalmology, the First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, People's Republic of China.
Purpose:
To evaluate the ocular hypotensive effect of the Rho-associated kinase (ROCK) inhibitor RKI-1447 in normotensive and dexamethasone (DEX)-induced ocular hypertension rats, while elucidating its molecular mechanisms involving cytoskeletal remodeling and extracellular matrix (ECM) metabolism via the RhoA/ROCK pathway in trabecular meshwork (TM) cells.
Methods:
In vivo: Intraocular pressure (IOP) dynamics were monitored in normotensive and DEX-induced ocular hypertension rats following topical RKI-1447 administration. Conjunctival hyperemia, systemic safety (body weight), and IOP recovery post-withdrawal were assessed. In vitro: Primary human trabecular meshwork (HTM) cells were used to observe the effects of RKI-1447 on morphology and migration. Immunofluorescence assessed cross-linked actin networks (CLANs), ECM proteins, and alpha smooth muscle actin (α-SMA) expression. RhoA activity and the phosphorylation of myosin light chain (MLC) and myosin phosphatase target subunit-1 (MYPT-1) were detected via Pull-down assays and Western blot.
Results:
Topical RKI-1447 was associated with a dose-dependent trend in IOP reduction in both normotensive and DEX-induced ocular hypertension rats, with a peak effect observed at approximately 2 hours and only mild, transient hyperemia. In HTM cells, RKI-1447 treatment was observed to induce reversible morphological changes and mitigate cell migration. Furthermore, descriptive assessments suggested that RKI-1447 appeared to disassemble DEX-induced cytoskeletal assemblies and attenuate the upregulation of collage type IV (COL IV), fibronectin (FN), laminin (LN), and α-SMA. Additionally, RKI-1447 appeared to modulate DEX-associated RhoA activation and demonstrated a trend toward downregulating MLC and MYPT-1 phosphorylation.
Conclusion:
Our data suggest that RKI-1447 is associated with reduced aqueous outflow resistance, potentially through its inhibitory effect on the RhoA/ROCK pathway and the subsequent mitigation of steroid-induced cytoskeletal and fibrotic alterations. These preliminary observations suggest that RKI-1447 may serve as a viable pharmacological approach for treating steroid-induced glaucoma, although further long-term safety and efficacy evaluations are warranted.
