scholarly journals Thrombospondin‐1 mediates Rho‐kinase inhibitor‐induced increase in outflow‐facility

2021 ◽  
Author(s):  
Sze‐Wan Shan ◽  
Chi‐Wai Do ◽  
Thomas Chuen Lam ◽  
Hoi‐Lam Li ◽  
W. Daniel Stamer ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Rho Kinase ◽  
Outflow Facility ◽  
Rho Kinase Inhibitor ◽  
Thrombospondin 1

scholarly journals SB772077B, A New Rho Kinase Inhibitor Enhances Aqueous Humour Outflow Facility in Human Eyes

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Soundararajan Ashwinbalaji ◽  
Srinivasan Senthilkumari ◽  
Chidambaranathan Gowripriya ◽  
Subbaiah Krishnadas ◽  
B’ Ann T. Gabelt ◽  
...  
Keyword(s):  
Aqueous Humour ◽  
Kinase Inhibitor ◽  
Rho Kinase ◽  
Outflow Facility ◽  
Rho Kinase Inhibitor ◽  
Human Eyes

scholarly journals Ocular Hypotension, Actin Stress Fiber Disruption and Phagocytosis Increase by RKI-1447, a Rho-Kinase Inhibitor

2018 ◽  
Author(s):  
Yalong Dang ◽  
Chao Wang ◽  
Priyal Shah ◽  
Susannah Waxman ◽  
Ralitsa T. Loewen ◽  
...  
Keyword(s):  
Rho Gtpase ◽  
Kinase Inhibitor ◽  
Rho Kinase ◽  
Vehicle Control ◽  
Pigmentary Glaucoma ◽  
Actin Stress Fiber ◽  
Normal Medium ◽  
Macroscopic Appearance ◽  
Outflow Facility ◽  
Rho Kinase Inhibitor

Objective: The Rho GTPase/Rho kinase pathway is an important target in glaucoma treatment. This study investigated the hypotensive effect of RKI-1447, a Rho kinase inhibitor developed for cancer treatment, in a porcine ex vivo pigmentary glaucoma model. Materials and Methods: Twenty-eight fresh porcine anterior chambers were perfused with pigment medium (1.67 × 107 pigment particles/mL) for 48 hours before being subjected to the RKI-1447 (n = 16) or the vehicle control (n = 12). Another twelve eyes with normal medium perfusion served as the control. The intraocular pressure (IOP) was recorded at two-minute intervals and the outflow facility was calculated. To investigate the intracellular mechanism of the IOP reduction, primary trabecular meshwork cells were exposed to RKI-1447 or the vehicle control and then analyzed for changes in cytoskeleton, motility, and phagocytosis. Results: Compared to the baseline, the perfusion of pigment caused a significant increase in IOP in the RKI-1447 group (P = 0.003) at 48 hours. Subsequent treatment with RKI-1447 significantly reduced IOP from 20.14 ± 2.59 mmHg to 13.38 ± 0.91 mmHg (P = 0.02). Pigment perfusion reduced the outflow facility from 0.27 ± 0.03 at baseline to 0.18 ± 0.02 at 48 hours (P < 0.001). This was partially reversed with RKI-1447. RKI-1447 exhibited no apparent changes in the micro- or macroscopic appearance, including histology. Primary TM cells exposed to RKI-1447 showed a significant disruption of the actin cytoskeleton both in the presence and absence of pigment exposure (P < 0.001) but no effect on TM migration was observed. Pigment-treated TM cells exhibited a reduction in TM phagocytosis, which RKI reversed. Conclusions: RKI-1447 is a novel ROCK inhibitor that significantly reduces IOP by disrupting TM stress fibers and increasing TM phagocytosis. These features may make it especially useful for the treatment of secondary glaucomas with an increased phagocytosis load but also for other open angle glaucomas.

scholarly journals RKI-1447, a Rho-Kinase Inhibitor Causes Ocular Hypotension, Actin Stress Fiber Disruption and Increased Phagocytosis

2018 ◽  
Author(s):  
Yalong Dang ◽  
Chao Wang ◽  
Priyal Shah ◽  
Susannah Waxman ◽  
Ralitsa T. Loewen ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Ex Vivo ◽  
Rho Kinase ◽  
Hypotensive Effect ◽  
Vehicle Control ◽  
Subsequent Treatment ◽  
Pigmentary Glaucoma ◽  
Actin Stress Fiber ◽  
Outflow Facility ◽  
Rho Kinase Inhibitor

Purpose: This study investigated the hypotensive effect of RKI-1447, a Rho kinase inhibitor, in a porcine ex vivo pigmentary glaucoma model. Methods: Twenty-eight porcine anterior chambers were perfused with medium supplemented with 1.67 × 107 pigment particles/mL for 48 hours before treatment with RKI-1447 (n = 16) or vehicle control (n = 12). Intraocular pressure (IOP) was recorded and outflow facility was calculated. Primary trabecular meshwork cells were exposed to RKI-1447 or vehicle control; effects on the cytoskeleton, motility, and phagocytosis were evaluated. Result: Compared to baseline, the perfusion of pigment caused a significant increase in IOP in the RKI-1447 group (P = 0.003) at 48 hours. Subsequent treatment with RKI-1447 significantly reduced IOP from 20.14 ± 2.59 mmHg to 13.38 ± 0.91 mmHg (P = 0.02). Pigment perfusion reduced the outflow facility from 0.27 ± 0.03 at baseline to 0.18 ± 0.02 at 48 hours (P < 0.001). This was partially reversed with RKI-1447. RKI-1447 caused no apparent histological changes in the micro- or macroscopic TM appearance. RKI-1447-treated primary TM cells showed significant disruption of the actin cytoskeleton both in the presence and absence of pigment (P < 0.001) but no effect on TM migration was observed. Pigment-treated TM cells exhibited a reduction in TM phagocytosis, which RKI-1447 reversed. Conclusion: RKI-1447 significantly reduces IOP by disrupting TM stress fibers and increasing TM phagocytosis. These features may make it useful for the treatment of secondary glaucomas with an increased phagocytic load.

scholarly journals Rho-kinase inhibitor hydroxyfasudil protects against HIV-1 Tat-induced dysfunction of tight junction and neprilysin/Aβ transfer receptor expression in mouse brain microvessels

2021 ◽  
Vol 476 (5) ◽  
pp. 2159-2170
Author(s):  
Qiangtang Chen ◽  
Yu Wu ◽  
Yachun Yu ◽  
Junxiang Wei ◽  
Wen Huang
Keyword(s):  
Tight Junction ◽  
Signaling Pathway ◽  
Mouse Brain ◽  
Kinase Inhibitor ◽  
Rho Kinase ◽  
Receptor Expression ◽  
Mrna Levels ◽  
Brain Microvessels ◽  
Rho Kinase Inhibitor ◽  
Hiv 1

AbstractHIV-1 transactivator protein (Tat) induces tight junction (TJ) dysfunction and amyloid-beta (Aβ) clearance dysfunction, contributing to the development and progression of HIV-1-associated neurocognitive disorder (HAND). The Rho/ROCK signaling pathway has protective effects on neurodegenerative disease. However, the underlying mechanisms of whether Rho/ROCK protects against HIV-1 Tat-caused dysfunction of TJ and neprilysin (NEP)/Aβ transfer receptor expression have not been elucidated. C57BL/6 mice were administered sterile saline (i.p., 100 μL) or Rho-kinase inhibitor hydroxyfasudil (HF) (i.p., 10 mg/kg) or HIV-1 Tat (i.v., 100 μg/kg) or HF 30 min before being exposed to HIV-1 Tat once a day for seven consecutive days. Evans Blue (EB) leakage was detected via spectrophotometer and brain slides in mouse brains. The protein and mRNA levels of zonula occludens-1 (ZO-1), occludin, NEP, receptor for advanced glycation end products (RAGE), and low-density lipoprotein receptor-related protein 1 (LRP1) in mouse brain microvessels were, respectively, analyzed by Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) analyses. Exposure of the mice to HIV-1 Tat increased the amount of EB leakage, EB fluorescence intensity, blood–brain barrier (BBB) permeability, as well as the RAGE protein and mRNA levels, and decreased the protein and mRNA levels of ZO-1, occludin, NEP, and LRP1 in mouse brain microvessels. However, these effects were weakened by Rho-kinase inhibitor HF. Taken together, these results provide information that the Rho/ROCK signaling pathway is involved in HIV-1 Tat-induced dysfunction of TJ and NEP/Aβ transfer receptor expression in the C57BL/6 mouse brain. These findings shed some light on potentiality of inhibiting Rho/Rock signaling pathway in handling HAND.

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