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Springer Nature [academic journals on nature.com], Cell Death & Differentiation, 2(20), p. 270-280, 2012

DOI: 10.1038/cdd.2012.122

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Inhibition of ASK1-p38 pathway prevents neural cell death following optic nerve injury

This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

Optic nerve injury (ONI) induces retinal ganglion cell (RGC) death and optic nerve atrophy that lead to visual loss. Apoptosis signal-regulating kinase 1 (ASK1) is an evolutionarily conserved mitogen-activated protein kinase (MAPK) kinase kinase and has an important role in stress-induced RGC apoptosis. In this study, we found that ONI-induced p38 activation and RGC loss were suppressed in ASK1-deficient mice. Sequential in vivo retinal imaging revealed that post-ONI treatment with a p38 inhibitor into the eyeball was effective for RGC protection. ONI-induced monocyte chemotactic protein-1 production in RGCs and microglial accumulation around RGCs were suppressed in ASK1-deficient mice. In addition, the productions of tumor necrosis factor and inducible nitric oxide synthase in microglia were decreased when the ASK1-p38 pathway was blocked. These results suggest that ASK1 activation in both neural and glial cells is involved in neural cell death, and that pharmacological interruption of ASK1-p38 pathways could be beneficial in the treatment of ONI.Cell Death and Differentiation advance online publication, 14 September 2012; doi:10.1038/cdd.2012.122.