The role of ERK1/2 activation in sarpogrelate-mediated neuroprotection

Cristy A. Ku, Renee C. Ryals, Dan Jiang, Aaron S. Coyner, Kyle K. Weller, Wrik Sinha, Bryan M. Robb, Paul Yang, Mark Pennesi

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

PURPOSE. To characterize the mediators of 5-HT2A serotonin receptor-driven retinal neuroprotection. METHODS. Albino mice were treated intraperitoneally with saline or sarpogrelate, a 5-HT2A antagonist, immediately before light exposure (LE). Following LE, retinas were harvested for a high-throughput phosphorylation microarray to quantify activated phosphorylated proteins in G protein-coupled receptor (GPCR) signaling. To confirm microarray results and define temporal changes, Western blots of select GPCR signaling proteins were performed. Since both methodologies implicated MAPK/ERK activation, the functional significance of sarpogrelate-mediated ERK1/2 activation was examined by inhibition of ERK1/2 phosphorylation via pretreatment with the MEK inhibitor (MEKi) PD0325901. The degree of neuroprotection was evaluated with spectral-domain optical coherence tomography (SDOCT) and electroretinography (ERG). To determine the effects of sarpogrelate on gene expression, a qPCR array measuring the expression of 84 genes involved in oxidative stress and cell death was performed 48 hours post LE. RESULTS. Sarpogrelate led to an activation of the MAPK/ERK pathway. Temporal analysis further demonstrated a transient activation of ERK1/2, starting with an early inhibition 20 minutes into LE, a maximum activation at 3 hours post LE, and a return to baseline at 7 hours post LE. Inhibition of ERK1/2 with MEKi pretreatment led to attenuation of sarpogrelatemediated neuroprotection. LE caused significant changes in the expression of genes involved in iron metabolism, oxidative stress, and apoptosis. These changes were prevented by sarpogrelate treatment. CONCLUSIONS. Sarpogrelate-mediated retinal protection involves a transient activation of the MAPK/ERK pathway, although this pathway alone does not account for the full effect of neuroprotection.

Original languageEnglish (US)
Pages (from-to)462-471
Number of pages10
JournalInvestigative Ophthalmology and Visual Science
Volume59
Issue number1
DOIs
StatePublished - Jan 1 2018

Keywords

  • 5-HT2A
  • Light damage
  • MAPK/ERK
  • Retinal degeneration
  • Sarpogrelate

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

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