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H. Wang, X. Liu, B. Wang, B.T. Gabelt, P.Y. Lee, S.M. Podos, N. Wang, P.L. Kaufman; MISA A Effects on Actin of Cultured HTM Cells, and on Structure of Rat TM and IOP of Rats and Monkeys . Invest. Ophthalmol. Vis. Sci. 2006;47(13):414.
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© ARVO (1962-2015); The Authors (2016-present)
To determine the effects of misakinolide (MISA) A on (1) the actin cytoskeleton of cultured human trabecular meshwork (HTM) cells; (2) intraocular pressure (IOP) in rats and normotensive and glaucomatous monkeys, and (3) the structure of TM in rat eyes.
Cultured HTM cells were treated with MISA A, and the changes in the actin cytoskeleton were determined by immunofluorescence microscopy. The IOP response after topical administration of MISA A was determined by Tonopen (rat) or pneumotonometer (monkey) in rat and normotensive and hypertensive (by lasering TM) monkey eyes at 0.5, 1, 2, 3, 4, 5 and 6 h. The changes in TM morphology of rats were studied by light and transmission electron microscopy.
MISA A caused dose– and time–dependent disruption of actin stress fibers in cultured HTM cells. Actin and vinculin–containing focal contacts deteriorated after 2hr, 30 and 10 min of incubation with 5, 10, and 25nM MISA A, respectively. Recovery was also dose– and time–dependent. Topical MISA A significantly decreased IOP in rats by 5.8 ± 1.2 tonopen rat units (from 20.6 ± 0.8) and in monkeys by 4.1 ± 0.6 mmHg in normotensive eyes (from 21 ± 0.6) and by 9.2 ± 2.9 mmHg in glaucomatous eyes (from 31.3 ± 2.3). No obvious differences in light microscopic morphology between the treated and control rat eyes were observed. Electron microscopy showed that MISA A induced (1) expansion of the intercellular spaces in the juxtacanalicular meshwork; (2) removal of extracellular material; (3) TM cell rounding, and (4) loss or weakness of junctions of TM and Schlemm’s canal inner wall cells.
MISA A significantly inhibited actin and cellular adhesions in cultured HTM cells, and reduced IOP in rats and monkeys. These results, together with the morphological changes in rat TM, indicate that pharmacologic disorganization of actin and relaxation in TM by MISA A may be a useful antiglaucoma strategy.
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