May 2008
Volume 49, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2008
Inhibition of Rho-Kinase (ROCK) Reduces Reactive Gliosis and Promotes Cell Survival in the Retina
Author Affiliations & Notes
  • A. Tura
    University Eye Hospital of the Center of Ophthalmology at the Eberhard-Karls University of Tübingen, Tuebingen, Germany
  • P. P. Monnier
    Toronto Western Research Institute, Toronto, Ontario, Canada
  • K. U. Bartz-Schmidt
    University Eye Hospital of the Center of Ophthalmology at the Eberhard-Karls University of Tübingen, Tuebingen, Germany
  • S. Henke-Fahle
    University Eye Hospital of the Center of Ophthalmology at the Eberhard-Karls University of Tübingen, Tuebingen, Germany
  • Footnotes
    Commercial Relationships  A. Tura, None; P.P. Monnier, None; K.U. Bartz-Schmidt, None; S. Henke-Fahle, None.
  • Footnotes
    Support  Herbert Funke-Stiftung, Germany; Dr. Wolfbauer-Stiftung, Germany
Investigative Ophthalmology & Visual Science May 2008, Vol.49, 2064. doi:https://doi.org/
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      A. Tura, P. P. Monnier, K. U. Bartz-Schmidt, S. Henke-Fahle; Inhibition of Rho-Kinase (ROCK) Reduces Reactive Gliosis and Promotes Cell Survival in the Retina. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2064. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : The extent of glial cell reactivity is recognized as a critical factor influencing neuronal survival following a primary damage. The Rho-kinase/ROCK signalling pathway regulates essential cellular events including actin dynamics, motility, proliferation, gene expression, growth cone retraction, and apoptosis. Here, we analyzed the role of ROCK in the response of the retinal glia to adverse conditions and the impact of this process on retinal cell survival.

Methods: : Mouse retinal whole mounts were incubated with or without the specific ROCK inhibitor H-1152P for 24 hours under serum deprivation. Cell damage was determined by ethidium homodimer-1 uptake and caspase-3 cleavage. Immunohistochemistry and Western blot was performed to detect glial cell reactivity and to confirm the specificity of H-1152P for ROCK. A cytokine array was used for analyzing the cytokine profile of the culture medium.

Results: : The extent of cell damage was significantly reduced in response to 1 µM H-1152P particularly in the ganglion cell layer (P<0.001). This was associated with a decrease in the levels of GFAP isoforms as well as the number of reactive astrocytes, Müller cells, and microglia. A similar reduction was also observed in the release of proinflammatory cytokines such as tumor necrosis factor-alpha, interferon-gamma, and IL-6. These changes in the cytokine profile likely contributed to the significantly lower toxicity of the conditioned media collected from retinae incubated with H-1152P. Western blot analysis using phospho-specific antibodies demonstrated that the incubation with 1 µM H-1152P suppressed the ROCK-dependent phosphorylation of adducin without a considerable interference with the protein kinase A/C mediated phosphorylation events, indicating the specificity of the inhibitor for ROCK.

Conclusions: : These results provide evidence for the neuroprotective potential of H-1152P-mediated ROCK inhibition on retinal cells, which may rely partly on the attenuation of glial cell reactivity and the associated decline in secondary damage.

Keywords: astrocyte • Muller cells • cytokines/chemokines 
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