The Role of ERK1/2 Activation in Sarpogrelate-Mediated Neuroprotection.
Invest Ophthalmol Vis Sci
; 59(1): 462-471, 2018 01 01.
Article
em En
| MEDLINE
| ID: mdl-29368005
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 (SD-OCT) 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 sarpogrelate-mediated 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.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Lesões Experimentais por Radiação
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Retina
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Degeneração Retiniana
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Antagonistas da Serotonina
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Succinatos
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Sistema de Sinalização das MAP Quinases
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Neuroproteção
Limite:
Animals
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article