AMA0428, A Potent Rock Inhibitor, Attenuates Early and Late Experimental Diabetic Retinopathy

Hollanders, Karolien; Hove, Inge Van; Sergeys, Jurgen; Bergen, Tine Van; Lefevere, Evy; Kindt, Nele; Castermans, Karolien; Vandewalle, Evelien; Pelt, Jos van; Moons, Lieve; Stalmans, Ingeborg

doi:10.1080/02713683.2016.1183030

Cited by 27 publications

(17 citation statements)

References 88 publications

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“…In addition, further cell-type specific analysis of diabetesinduced retinal neurodegeneration within the inner retina showed a significant reduction in RGC density starting in the early diabetic phase, further diminishing over time, all in line with earlier findings described in the mouse STZ 21,72,73 and the Ins2 Akita model. 74 Notably, some contradictory results have been reported in literature, in which neurodegeneration was found to be most prominent in the STZ-induced diabetic mice at later time points (e.g., 10-14 weeks) after diabetes onset, 30 or RGC death was not detected up to 6 months after diabetes induction.…”

Section: Discussionsupporting

confidence: 89%

Longitudinal In Vivo Characterization of the Streptozotocin-Induced Diabetic Mouse Model: Focus on Early Inner Retinal Responses

Sergeys

Étienne

Hove

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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The goal of this study was to perform an extensive temporal characterization of the early pathologic processes in the streptozotocin (STZ)-induced diabetic retinopathy (DR) mouse model, beyond the vascular phenotype, and to investigate the potential of clinically relevant compounds in attenuating these processes. METHODS. Visual acuity and contrast sensitivity (CS) were studied in the mouse STZ model until 24 weeks postdiabetes onset. ERG, spectral domain optical coherence tomography (SD-OCT), leukostasis, and immunohistochemistry were applied to investigate neurodegeneration, inflammation, and gliosis during early-, mid-and late-phase diabetes. Aflibercept or triamcinolone acetonide (TAAC) was administered to investigate their efficacy on the aforementioned processes. RESULTS. Visual acuity and CS loss started at 4 and 18 weeks postdiabetes onset, respectively, and progressively declined over time. ERG amplitudes were diminished and OP latencies increased after 6 weeks, whereas SD-OCT revealed retinal thinning from 4 weeks postdiabetes. Immunohistochemical analyses linked these findings to retinal ganglion and cholinergic amacrine cell loss at 4 and 8 weeks postdiabetes onset, respectively, which was further decreased after aflibercept administration. The number of adherent leukocytes was augmented after 2 weeks, whereas increased micro-and macroglia reactivity was present from 4 weeks postdiabetes. Aflibercept or TAAC showed improved efficacy on inflammation and gliosis. CONCLUSIONS. STZ-induced diabetic mice developed early pathologic DR hallmarks, from which inflammation seemed the initial trigger, leading to further development of functional and morphologic retinal changes. These findings indicate that the mouse STZ model is suitable to study novel integrative non-vascular therapies to treat early DR.

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Section: Discussionsupporting

confidence: 89%

Longitudinal In Vivo Characterization of the Streptozotocin-Induced Diabetic Mouse Model: Focus on Early Inner Retinal Responses

Sergeys

Étienne

Hove

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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“…The results of the present study are consistent with a previous report that involved intravitreal injection and reduced inflammation in the retina, and that showed another ROCK inhibitor, AMA0428, significantly reduced retinal leukocyte adhesion in the streptozotocin-induced murine diabetic model. 44 However, the present study administered the ROCK inhibitor systemically and did not investigate the topical administration of ripasudil, which is one of the limitations that should be further investigated in future studies. Because it has been previously reported that radiolabelled ripasudil reached the retina and choroid following the administration of eye drops in rabbits, 15,24 there are enough possibilities that topical administration of ripasudil could attenuate ocular inflammation both in the anterior and posterior segments of the eye.…”

Section: Discussionmentioning

confidence: 99%

The Anti-Inflammatory Effect of Ripasudil (K-115), a Rho Kinase (ROCK) Inhibitor, on Endotoxin-Induced Uveitis in Rats

Uchida

Honjo

Yamagishi

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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Citation: Uchida T, Honjo M, Yamagishi R, Aihara M. The anti-inflammatory effect of ripasudil (K-115), a Rho kinase (ROCK) inhibitor, on endotoxin-induced uveitis in rats. Invest Ophthalmol Vis Sci. 2017;58:5584-5593. DOI:10.1167/iovs.17-22679 PURPOSE. To investigate the anti-inflammatory properties of ripasudil, a Rho kinase (ROCK) inhibitor, using endotoxin-induced uveitis (EIU) in rats.METHODS. Endotoxin-induced uveitis was induced by footpad injection of lipopolysaccharide (LPS). Ripasudil was administered intraperitoneally 1 hour before and after LPS injection. The aqueous humor was collected 24 hours after injection, and the infiltrating cells, protein concentration, and levels of monocyte chemotactic protein-1 (MCP-1) were determined. Infiltrating cells in the iris ciliary body (ICB) and adherent leukocytes in retinal vessels were evaluated. The mRNA levels of IL-1b, IL-6, TNF-a, and MCP-1 in the retina and ICB were determined. A mouse macrophage cell line, RAW264.7, was stimulated with LPS in the presence or absence of ripasudil, and the expression of MCP-1 and nuclear translocation of nuclear factor (NF)-jB was analyzed.RESULTS. Ripasudil significantly reduced infiltrating cells and protein exudation in the aqueous humor, as well as the number of infiltrating cells in the ICB and adherent leukocytes in retinal vessels in EIU. Additionally, the protein level of MCP-1 in the aqueous humor and mRNA levels of IL-1b, IL-6, TNF-a, MCP-1, and intercellular adhesion molecule-1 in the ICB and retina were suppressed by ripasudil. The production of MCP-1 and nuclear translocation of NF-jB in RAW264.7 cells were also suppressed by ripasudil.CONCLUSIONS. The Rho/ROCK pathway plays a role in adhesion molecule expression and inflammatory cell infiltration in EIU, and ripasudil is a potent anti-inflammatory agent against ocular inflammatory diseases, including acute uveitis and possibly uveitic glaucoma.

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“…Previous studies have suggested that the expression of Rho-kinase can be selectively blocked by its competitive inhibitors. Treatment with ROCK inhibitors improved type 2 diabetes in animal models [24]. The up-regulated Rho-kinase pathway was also reported in diabetic db/db mice, and the ROCK inhibitor was suggested to improve the diabetic complications [25].…”

Section: Discussionmentioning

confidence: 99%

Alkannin Inhibited Hepatic Inflammation in Diabetic Db/Db Mice

Xue¹,

Fan

et al. 2018

Cell Physiol Biochem

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Background/Aims: The current study was designed to investigate the protective role of alkannin (ALK) on liver injury in diabetic C57BL/KsJ-db/db mice and explore its potential mechanisms. Methods: An oral glucose tolerance test (OGTT) was performed. The levels of insulin, alanine aminotransferase (ALT), aspartate aminotransaminase (AST), total cholesterol (TC) and triglyceride (TG) were determined by commercial kits. The pro-inflammatory cytokines interleukin (IL)-1β, IL-6 and tumour necrosis factor (TNF)-α were determined by ELISA. The levels of the ROCK/NF-κB pathway were determined by Western blotting. Results: The contents of pro-inflammatory cytokines interleukin (IL)-1β, IL-6 and tumour necrosis factor (TNF)-α were inhibited by ALK, metformin or fasudil in diabetic db/db mice. Further, Western blotting analysis showed that the expression of Rho, ROCK1, ROCK2, p-NF-κBp65, and p-IκBα was significantly reversed by ALK treatment. In human hepatic HepG2 cells, the hepatoprotective effects of ALK were further characterized. With response to palmitic acid-challenge, increased amounts of insulin, ALT, AST, TG, and TC were observed, whereas ALK pretreatment significantly inhibited their leakage in HepG2 cells without appreciable cytotoxic effects. The inflammation condition was recovered with ALK treatment as shown by changes of IL-1β, IL-6 and TNF-α. Further, Western blotting analysis also suggested that ALK improves hepatic inflammation in a Rho-kinase pathway. Conclusion: The present study successfully investigated the role of Rho-kinase signalling in diabetic liver injury. ALK exhibited hepatoprotective effects in diabetic db/db mice, and it might act through improving hepatic inflammation through the Rho-kinase pathway.

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AMA0428, A Potent Rock Inhibitor, Attenuates Early and Late Experimental Diabetic Retinopathy

Cited by 27 publications

References 88 publications

Longitudinal In Vivo Characterization of the Streptozotocin-Induced Diabetic Mouse Model: Focus on Early Inner Retinal Responses

Longitudinal In Vivo Characterization of the Streptozotocin-Induced Diabetic Mouse Model: Focus on Early Inner Retinal Responses

The Anti-Inflammatory Effect of Ripasudil (K-115), a Rho Kinase (ROCK) Inhibitor, on Endotoxin-Induced Uveitis in Rats

Alkannin Inhibited Hepatic Inflammation in Diabetic Db/Db Mice

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