Ocular hypotensive efficacy of Src-family tyrosine kinase inhibitors via different cellular actions from Rock inhibitors

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• 作者：Tomoko Kirihara ; Atsushi Shimazaki ; Masatsugu Nakamura ; Nobuaki Miyawaki
• 关键词：intraocular pressure ; trabecular meshwork ; Src-family tyrosine kinase ; PP2 ; Rock
• 刊名：Experimental Eye Research
• 出版年：February, 2014
• 年：2014
• 卷：119
• 期：Complete
• 页码：97-105
• 全文大小：1706 K

文摘

We investigated the effects of Src-family tyrosine kinase (SFK) inhibitors on intraocular pressure (IOP) and trabecular meshwork (TM) cells. The SFK inhibitors, PP2, PP1, and damnacanthal, significantly lowered IOP from baseline following intracameral injection in ocular normotensive rabbits, and PP2 decreased trans-epithelial electrical resistance (TEER) of TM cell layers in a dose-dependent manner ranging from 0.1聽渭M to 100聽渭M. The maximal efficacy of PP2 on TEER was a reduction to 71.7% relative to the vehicle-treated group at 100聽渭M. PP2 decreased the adhesion of TM cells to culture surfaces either uncoated with specific ECM proteins dose-dependently or coated with extracellular matrix proteins such as laminin I, fibronectin, collagen type I and basement membrane extraction. Tyrosine phosphorylation of focal adhesion kinase and p130^cas was decreased by PP2. On the other hand, major changes in actin staining of TM cells were not able to be detected after PP2 treatment, although quantitative analysis showed that PP2 induced some morphological changes which were in the different direction to those caused by Y-27632, a Rock inhibitor. Y-27632 at 10聽渭M increased the permeability of TM cell layers, but did not induce changes in the adhesion of TM cells. These results suggest that SFK inhibitors lower IOP, at least partly, by acting on TM cells in a manner that is distinct from Rock inhibitors.