Abstract
The intraocular pressure lowering property of a new rho kinase inhibitor, SB772077B (SB77) has been previously demonstrated in perfused human cadaveric eyes. In this study, the efficacy of SB77 in alleviating the aqueous outflow resistance mediated by cyclic mechanical stress in perfused human cadaveric eyes was investigated. A human anterior segment perfusion culture model was used to investigate the effect of cyclic intraocular pressure (IOP) on aqueous outflow facility in presence or absence of SB77. The status of RhoA activation and the downstream effector molecule myosin-light chain phosphorylation (p-MLC) was investigated by Western blot. Cyclic mechanical stress resulted in decrease in aqueous outflow facility (–19.79 ± 4.93%; p = 0.019) in perfused human eyes and treatment with SB77 (50 µM) significantly enhanced outflow facility by 15% (p = 0.05). The increase in outflow facility by SB77 was confirmed with the inactivation of RhoA/ROCK signaling and decreased expression of extracellular matrix markers. SB77 effectively reduced the outflow resistance mediated by cyclic IOP and thus may be a potential clinical candidate for the management of glaucoma.
Highlights
Several studies support the concept that aqueous outflow is pulsatile in nature and corresponds to transient oscillatory or cyclic intraocular pressure (IOP) fluctuations such as those that occur with the ocular pulse, blinking and eye movements[5,6]
Human anterior segments showed an average decrease in percentage outflow facility (−19.79 ± 4.93%) (p = 0.019) in response to IOP oscillations as compared to control eyes under steady state perfusion (Experiment 1)
Rho-associated coiled-coil forming protein kinase (ROCK) inhibitors are in clinical practice for the management of glaucoma, their efficacy in modulating cyclic mechanical stress condition is not well studied
Summary
Several studies support the concept that aqueous outflow is pulsatile in nature and corresponds to transient oscillatory or cyclic IOP fluctuations such as those that occur with the ocular pulse, blinking and eye movements[5,6]. Laboratory studies are expected to provide a meaningful insight into how the cellular responses are regulated in response to cyclic mechanical stress Modulation of such responses may pave the way for restoring the IOP homeostasis in glaucoma. Primary molecules that transmit RhoA/ROCK signaling (e.g.: myosin light chain phosphatase, LIM kinase, cofilin) are expressed in human TM with mediators for this signaling pathway present in the aqueous humour[15,16,17]. Inhibition of this pathway is an attractive strategy to increase outflow facility in the TM and reduce IOP in the management of glaucoma. SB77 may be a potential clinical candidate for the management of glaucoma
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