title: Ocular hypotensive efficacy of Src-family tyrosine kinase inhibitors via different cellular actions from Rock inhibitors.
abstract: 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 μM to 100 μM. The maximal efficacy of PP2 on TEER was a reduction to 71.7% relative to the vehicle-treated group at 100 μM. 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 μM 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.
authors: Ophthalmic Research and Development Center, Santen Pharmaceutical Co., Ltd., 8916-16 Takayama-cho, Ikoma-shi, Nara 630-0101, Japan; Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama-cho, Ikoma-shi, Nara 630-0192, Japan. Electronic address: tomoko.kirihara@santen.co.jp.
authors: Tomoko
authors: T
authors: Kirihara
authors: Ophthalmic Research and Development Center, Santen Pharmaceutical Co., Ltd., 8916-16 Takayama-cho, Ikoma-shi, Nara 630-0101, Japan.
authors: Atsushi
authors: A
authors: Shimazaki
authors: Ophthalmic Research and Development Center, Santen Pharmaceutical Co., Ltd., 8916-16 Takayama-cho, Ikoma-shi, Nara 630-0101, Japan.
authors: Masatsugu
authors: M
authors: Nakamura
authors: Ophthalmic Research and Development Center, Santen Pharmaceutical Co., Ltd., 8916-16 Takayama-cho, Ikoma-shi, Nara 630-0101, Japan.
authors: Nobuaki
authors: N
authors: Miyawaki
mesh_terms: D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005901:Glaucoma / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D006801:Humans; D007429:Intraocular Pressure / Q000187:drug effects*; D018613:Microscopy, Confocal; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011817:Rabbits; D014129:Trabecular Meshwork / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
chemical_list: C108123:4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D019061:src-Family Kinases; D054460:rho-Associated Kinases
keywords: PP2; Rock; Src-family tyrosine kinase; intraocular pressure; trabecular meshwork