title: Inhibition of ASK1-p38 pathway prevents neural cell death following optic nerve injury.
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.
authors.affiliation: Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Katome
authors.forename: K
authors.initials: K
authors.lastname: Namekata
authors.forename: X
authors.initials: X
authors.lastname: Guo
authors.forename: K
authors.initials: K
authors.lastname: Semba
authors.forename: D
authors.initials: D
authors.lastname: Kittaka
authors.forename: K
authors.initials: K
authors.lastname: Kawamura
authors.forename: A
authors.initials: A
authors.lastname: Kimura
authors.forename: C
authors.initials: C
authors.lastname: Harada
authors.forename: H
authors.initials: H
authors.lastname: Ichijo
authors.forename: Y
authors.initials: Y
authors.lastname: Mitamura
authors.forename: T
authors.initials: T
authors.lastname: Harada
mesh_terms: D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D007093:Imidazoles / Q000494:pharmacology; D048848:MAP Kinase Kinase Kinase 5 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000201:enzymology*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D020221:Optic Nerve Injuries / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D007093:Imidazoles; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D052247:Nitric Oxide Synthase Type II; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C093642:SB 203580