title: Proximal inhibition of p38 MAPK stress signaling prevents distal axonopathy.
abstract: The p38 mitogen-activated protein kinase (MAPK) isoforms are phosphorylated by a variety of stress stimuli in neurodegenerative disease and act as upstream activators of myriad pathogenic processes. Thus, p38 MAPK inhibitors are of growing interest as possible therapeutic interventions. Axonal dysfunction is an early component of most neurodegenerative disorders, including the most prevalent optic neuropathy, glaucoma. Sensitivity to intraocular pressure at an early stage disrupts anterograde transport along retinal ganglion cell (RGC) axons to projection targets in the brain with subsequent degeneration of the axons themselves; RGC body loss is much later. Here we show that elevated ocular pressure in rats increases p38 MAPK activation in retina, especially in RGC bodies. Topical eye-drop application of a potent and selective inhibitor of the p38 MAPK catalytic domain (Ro3206145) prevented both the degradation of anterograde transport to the brain and degeneration of axons in the optic nerve. Ro3206145 reduced in the retina phosphorylation of tau and heat-shock protein 27, both down-stream targets of p38 MAPK activation implicated in glaucoma, as well as expression of two inflammatory responses. We also observed increased p38 MAPK activation in mouse models. Thus, inhibition of p38 MAPK signaling in the retina may represent a therapeutic target for preventing early pathogenesis in optic neuropathies.
authors.affiliation: The Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Electronic address: jasondapper@hotmail.com.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Dapper
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Crish
authors.forename: Iok-Hou
authors.initials: IH
authors.lastname: Pang
authors.forename: David J
authors.initials: DJ
authors.lastname: Calkins
mesh_terms: D051698:Activating Transcription Factor 2 / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000473:pathology*; D018834:Chaperonin 60 / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005786:Gene Expression Regulation / Q000187:drug effects*; D007093:Imidazoles / Q000627:therapeutic use; D066298:In Vitro Techniques; D007429:Intraocular Pressure / Q000502:physiology / Q000528:radiation effects; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009798:Ocular Hypertension / Q000150:complications / Q000188:drug therapy / Q000209:etiology; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D012160:Retina / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D012162:Retinal Degeneration / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: C478623:1-(4-(3-(4-fluorophenyl)-1H-pyrrolo(3,2-b)pyridin-2-yl)pyridin-2-ylamino)propan-2-ol; D051698:Activating Transcription Factor 2; C497106:Atf2 protein, mouse; D018834:Chaperonin 60; D004791:Enzyme Inhibitors; D007093:Imidazoles; D009419:Nerve Tissue Proteins; D011725:Pyridines; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580
keywords: ASK1; ATF2; Axonopathy; CP; CTB; GFAP; Glaucoma; Heat shock protein; Hsp27, Hsp60; IOP; MAPK; Neurodegeneration; RGC; Retinal ganglion cell; Ro3206145 (1-{4-[3-(4-Fluoro-phenyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]-pyridin-2-ylamino}-propan-2-ol), heat-shock protein 27 and 60; SC; TIMP3; activating transcription factor 2; apoptosis signal-regulating kinase 1; ceruloplasmin; cholera toxin subunit β; glial acidic fibrillary protein; intraocular pressure; mitogen-activated protein kinase; p38 MAPK; retinal ganglion cell; superior colliculus; tissue inhibitor of metalloproteinases-3; α-DeTub; α-detyrosinated tubulin