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

Cell Death Differ. 2013 Feb;20(2):270-80. doi: 10.1038/cdd.2012.122. Epub 2012 Sep 14.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Cells, Cultured
  • Imidazoles / pharmacology
  • MAP Kinase Kinase Kinase 5 / antagonists & inhibitors
  • MAP Kinase Kinase Kinase 5 / genetics
  • MAP Kinase Kinase Kinase 5 / metabolism*
  • Mice
  • Mice, Knockout
  • Neurons / enzymology*
  • Nitric Oxide Synthase Type II / metabolism
  • Optic Nerve Injuries / metabolism*
  • Optic Nerve Injuries / pathology
  • Phosphorylation / drug effects
  • Pyridines / pharmacology
  • Retinal Ganglion Cells / cytology
  • Retinal Ganglion Cells / drug effects
  • Retinal Ganglion Cells / metabolism
  • Signal Transduction / drug effects
  • Tumor Necrosis Factor-alpha / metabolism
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Imidazoles
  • Pyridines
  • Tumor Necrosis Factor-alpha
  • Nitric Oxide Synthase Type II
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 5
  • SB 203580