Sigma-1 receptor stimulation protects retinal ganglion cells from ischemia-like insult through the activation of extracellular-signal-regulated kinases 1/2.

Autor: Mueller BH 2nd; Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, USA; North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX, USA. Electronic address: bmueller@live.unthsc.edu., Park Y; Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, USA; North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX, USA., Ma HY; Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, USA., Dibas A; Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, USA; North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX, USA., Ellis DZ; College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX, USA., Clark AF; Department of Cell Biology and Immunology, University of North Texas Health Science Center, Fort Worth, TX, USA; North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX, USA., Yorio T; Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, USA; North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX, USA. Electronic address: Thomas.Yorio@unthsc.edu.
Jazyk: angličtina
Zdroj: Experimental eye research [Exp Eye Res] 2014 Nov; Vol. 128, pp. 156-69. Date of Electronic Publication: 2014 Oct 08.
DOI: 10.1016/j.exer.2014.10.007
Abstrakt: Sigma-1 receptor (σ-1) activation and mitogen-activated protein kinases (MAPKs) have been shown to protect retinal ganglion cells (RGCs) from cell death. The purpose of this study was to determine if σ-1 receptor stimulation with pentazocine could promote neuroprotection under conditions of an ischemia-like insult (oxygen glucose deprivation (OGD)) through the phosphorylation of extracellular signal regulated kinase (pERK)1/2. Primary RGCs were isolated from P3-P7 Sprague-Dawley rats and purified by sequential immunopanning using Thy1.1 antibodies. RGCs were cultured for 7 days before subjecting the cells to an OGD insult (0.5% oxygen in glucose-free medium) for 6 h. During the OGD, RGCs were treated with pentazocine (σ-1 receptor agonist) with or without BD 1047 (σ-1 receptor antagonist). In other experiments, primary RGCs were treated with pentazocine in the presence or absence of an MEK1/2 inhibitor, PD098059. Cell survival/death was assessed by staining with the calcein-AM/ethidium homodimer reagent. Levels of pERK1/2, total ERK1/2, and beta tubulin expression were determined by immunoblotting and immunofluorescence staining. RGCs subjected to OGD for 6 h induced 50% cell death in primary RGCs (p < 0.001) and inhibited pERK1/2 expression by 65% (p < 0.001). Cell death was attenuated when RGCs were treated with pentazocine under OGD (p < 0.001) and pERK1/2 expression was increased by 1.6 fold (p < 0.05) compared to OGD treated RGCs without pentazocine treatment. The co-treatment of PD098059 (MEK1/2 inhibitor) with pentazocine significantly abolished the protective effects of pentazocine on the RGCs during this OGD insult. Activation of the σ-1 receptor is a neuroprotective target that can protect RGCs from an ischemia-like insult. These results also established a direct relationship between σ-1 receptor stimulation and the neuroprotective effects of the ERK1/2 pathway in purified RGCs subjected to OGD. These findings suggest that activation of the σ-1 receptor may be a therapeutic target for neuroprotection particularly relevant to ocular neurodegenerative diseases that effect RGCs.
(Copyright © 2014 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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