[Inhibition of stress-responsive signaling pathway prevents neural cell death following optic nerve injury].

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 kinase kinase (MAPKKK) and plays an important role in stress-induced RGC apoptosis. In this study, we found that ONI-induced p38 MAPK activation and RGC loss were suppressed in ASK1-deficient mice. Sequential in vivo retinal imaging revealed that post-ONI treatment with a p38 MAPK inhibitor into the eyeball was effective for RGC protection. ONI-induced monocyte chemotactic protein-1 (MCP-1) production in RGCs and microglial accumulation around RGCs were suppressed in ASK1-deficient mice. In addition, the productions of tumor necrosis factor (TNF) and inducible nitric oxide synthase (iNOS) in microglia were decreased when the ASK1-p38 MAPK pathway was blocked by inhibitor of ASK1 or p38 MAPK. ONI-induced expression of TNF and iNOS in the retina were absent in ASK1-deficient mice. 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 MAPK pathways could be beneficial in the treatment of ONI.