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Abstract
Purpose: To determine the effects of misakinolide (MISA) A, which leads to the disassembly of actin filaments, on the actin cytoskeleton of cultured human trabecular meshwork (HTM) cells and on intraocular pressure (IOP) in living rats and monkeys. Methods: Cultured HTM cells were treated with MISA A, and the changes in the actin cytoskeleton were determined by immunofluorescence microscopy. Elevated IOP was induced in cynomolgus monkeys by unilateral laser photocoagulation of the trabecular meshwork (TM). The IOP response after topical administration of MISA A was determined in normotensive rats (Tonopen) and glaucomatous monkeys (pneumotonometer and Tonopen) at 0.5, 1, 2, 3, 4, 5, and 6 hr. Results: MISA A caused dose- and time-dependent disruption of actin stress fibers in cultured HTM cells. Actin microfilaments and vinculin containing focal contacts deteriorated after 2 hr, 30 and 10 min of incubation with 5 nM, 10 nM, and 25 nM MISA A, respectively. Recovery was also dose- and time-dependent. The actin-disrupting effects were not reversible when the cells were incubated with MISA A at a low dose (10 nM) for 24 hr or a high dose (25 nM) for 30 min. Topical administration of MISA A significantly decreased IOP in rats by 5.8 ± 0.5 (mean ± SEM) (p < 0.05) Tonopen rat units. In monkeys, IOP was decreased by 3.8 ± 0.5 mmHg (p < 0.001) in the normotensive eye and by 9.2 ± 1.2 mmHg (p < 0.001) in the glaucomatous eye. Conclusions: MISA A greatly altered the actin cytoskeleton and cellular adhesions and reduced IOP, suggesting that MISA A may be a useful antiglaucoma strategy.