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R. S. Ver hoeven, N. Kuney, C. Robinson, W. M. Peterson, J. L. Vittitow; Topical Administration of Cytoskeletal Disrupting Agents Modulates Central Corneal Thickness, Pupil Diameter and Pupillary Light Response in the New Zealand White Rabbit. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2102.
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Cytoskeletal drugs modulate cellular contractility and are being tested in the clinic as potential IOP-lowering therapies. Here we determine the effects of actin and microtubule disrupting agents, rho kinase inhibitors and current IOP-lowering therapies on central corneal thickness (CCT), static pupillary diameter (PD) and kinetic pupillary light response (PLR) following topical administration.
Measures of CCT, PD, and PLR are noninvasive methods to quantify and characterize the ocular pharmacodynamic and potential toxicokinetic profile of molecules. Select cytoskeletal agents reported to lower IOP by directly or indirectly targeting actin stress fibers or microtubules were tested alongside marketed IOP-lowering therapies in male New Zealand white (NZW) rabbits. CCT was determined using ultrasonic pachymeter, and PD and PLR were measured with an infrared pupillometer. All measurements were taken prior to and at 1, 2 and 4 hr following a single 30 ul topical administration.
Administration of select kinase inhibitors caused a transient dose-dependant decrease in CCT from a mean baseline of ~360 µm. The potent rho kinase inhibitor Y-39983 [8 mM] resulted in a 10.4±0.5% central thinning while the less potent Y-27632 [12 mM] decreased CCT by 6.4±1.1%. The non-selective kinase inhibitor H-7 [150 mM] led to a 5.3±0.4% thinning. Inhibitors of microtubule formation also caused a transient, dose-dependant decrease in CCT. Colchicine [10 mM] and vinblastine [2 mM] led to 4.2±0.6% and 6.8±1.5% thinning, respectively. Inhibitors of actin stress fiber formation/polymerization, cytochalasin D [1.5 mM] and phalloidin [0.5 mM] resulted in thinning of 2.74±0.6% and 2.5±0.5%, respectively. Xalatan decreased CCT by 2.46±0.8%. Trusopt had no effect. Instillation of Y-39983 [3 mM] and Y-27632 [6 mM] led to a transient increase in resting PD (mydriasis) of 8.2±1.8% and 3.1±1.2%, respectively from an average baseline of ~7.5mm. Timolol and Xalatan decreased PD by 1.8±1.9% and 2.7±2.5% respectively. There were no changes in the kinetics of the PLR of any molecules studied.
In NZW rabbits, cytoskeletal agents cause mild changes in resting PD and CCT but do not affect the kinetics of PLR. Changes in CCT and PD may be related to the known ability of these molecules to disrupt the actin microfilament and microtubule network, altering cell contractility and tight junctions. The physiological/clinical relevance of such mild, transient changes is unknown.
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