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Hiroyoshi Hidaka, Hitomi Tanimoto, Koichi Takahashi, Kei Hasegawa, Ryohei Nakamura, Yoshihiro Inoue; Hsp90-binding Compound, H-1129, Produces IOP Lowering And Fibronectin Reduction. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5094.
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© ARVO (1962-2015); The Authors (2016-present)
We synthesized a novel isoquinolinesulfonamide, H-1129, which was found (ARVO2012 abstract Yoshida et al.) to bind to a heat shock protein Hsp90. We investigated the effect of H-1129 on intraocular pressure (IOP) of normotensive and hypertensive rabbits and normotensive monkeys. To elucidate the mechanism of lowering IOP through Hsp90 by H-1129, we measured fibronectin level in cultured trabecular meshwork cells.
The IOP was monitored in rabbits and monkeys with topical administration of H-1129, in single administration. Effects on the expression level of fibronectin of cultured human trabecular meshwork cell (HTMC) were assessed by ELISA method.
Topical administration of H-1129 resulted in a significant decrease in IOP in a dose-dependent manner in normal monkeys and rabbits. The maximum 5.0 mmHg reduction was observed at 2 hours in rabbits after administration of 1.0% H-1129. Reduction of IOP with 1.0% H-1129 returned to normal at 8 hours after H-1129 treatment. Treatment of the cells with H-1129 for 24 hours produced dose dependent decrease in fibronectin level. These dose dependent decreases were observed by addition of 10 μM to 30 μM H-1129. Maximum reduction of fibronectin was found to be 40% from control level.
H-1129 is effective in lowering IOP topically in both rabbits and monkeys. Our results demonstrate that treatment with H-1129 reduces expression level of fibronectin in HTMC, and increases aqueous humor outflow through trabecular meshwork. It is reported that deposition of fibronectin is induced by activation of glucocorticoid receptor (GR) signaling, which is observed in steroid-induced glaucoma. Hsp90 is known as a key regulator of nuclear translocation of GR, which indicates that H-1129 interferes binding of Hsp90 to GR. We provide evidence that H-1129 is a first reported anti-glaucoma agent binding to Hsp90α.
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