Proximal inhibition of p38 MAPK stress signaling prevents distal axonopathy

Title

Proximal inhibition of p38 MAPK stress signaling prevents distal axonopathy

Creator

Dapper J D; Crish S D; Pang I H; Calkins D J

Publisher

Neurobiology of Disease

Date

2013
2013-11

Description

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 IVIAPK 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. (C) 2013 Elsevier Inc. All rights reserved.

Subject

Glaucoma; Neurodegeneration; Neurosciences & Neurology; death; amyotrophic-lateral-sclerosis; mouse model; ocular hypertension; activated protein-kinase; up-regulation; alzheimers-disease brain; Axonopathy; experimental glaucoma; ganglion-cell neurons; Heat shock protein; p38 MAPK; rat retina; Retinal ganglion cell

Format

Journal Article or Conference Abstract Publication

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Rights

Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).

Pages

26-37

Volume

59

Citation

Dapper J D; Crish S D; Pang I H; Calkins D J, “Proximal inhibition of p38 MAPK stress signaling prevents distal axonopathy,” NEOMED Bibliography Database, accessed October 27, 2021, https://neomed.omeka.net/items/show/9000.

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