June 2013
Volume 54, Issue 15
Free
ARVO Annual Meeting Abstract  |   June 2013
Sigma-1 Receptor Stimulation Protects Purified RGCs from Ischemic Insult through the Phosphorylation of Extracellular Signal Regulated Kinase 1/2
Author Affiliations & Notes
  • Brett Mueller
    Pharmacology & Neuroscience, Univ of North Texas Hlth Sci Ctr, Fort Worth, TX
    North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX
  • Yong Park
    Pharmacology & Neuroscience, Univ of North Texas Hlth Sci Ctr, Fort Worth, TX
    North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX
  • Hai-Ying Ma
    Pharmacology & Neuroscience, Univ of North Texas Hlth Sci Ctr, Fort Worth, TX
    North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX
  • Thomas Yorio
    Pharmacology & Neuroscience, Univ of North Texas Hlth Sci Ctr, Fort Worth, TX
    North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX
  • Footnotes
    Commercial Relationships Brett Mueller, None; Yong Park, None; Hai-Ying Ma, None; Thomas Yorio, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2013, Vol.54, 3699. doi:https://doi.org/
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      Brett Mueller, Yong Park, Hai-Ying Ma, Thomas Yorio; Sigma-1 Receptor Stimulation Protects Purified RGCs from Ischemic Insult through the Phosphorylation of Extracellular Signal Regulated Kinase 1/2. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3699. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: Sigma-1 receptor activation and mitogen-activated protein kinases (MAPKs) have been shown to have neuroprotective roles in protecting retinal ganglion cells (RGCs) from cell death. The purpose of this study was to determine if sigma-1 receptor stimulation with pentazocine could promote neuroprotection under conditions of ischemia through the phosphorylation of extracellular signal regulated kinase (pERK)1/2.

Methods: Primary RGCs were isolated from P3-P7 Sprague-Dawley rats and purified by sequential immunopanning using a Thy 1.1 antibody. RGCs were cultured for 7 days before subjecting the cells to an ischemic insult (0.5% oxygen in glucose-free medium) for 6 hours. During the ischemic insult, RGCs were treated with pentazocine (sigma-1 receptor agonist) with or without BD1047 (sigma-1 receptor antagonist). In other experiments primary RGCs were treated with pentazocine, in the presence or absence of PD98059 (MEK1 inhibitor). 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 with immunoblotting and immunofluorescence.

Results: RGCs subjected to an ischemic insult demonstrated more than a 40% increase in cell death, compared to untreated controls. RGCs maintained under ischemia also showed a 50% decrease in expression of pERK1/2 (p<0.05). Cell death was attenuated when RGCs were treated with pentazocine under ischemic conditions and levels of pERK1/2 were increased more than 60% (p<0.05), compared to untreated RGCs subjected to ischemia. Treatment with BD1047 abrogated the pentazocine neuroprotection effects, and also attenuated the increase in levels of pERK1/2 (p<0.05). Finally, treatment with PD98059 also reversed the pentazocine mediated neuroprotective effects on RGCs, and abolished the expression of pERK1/2 (p<0.05).

Conclusions: These results establish a direct relationship between sigma-1 receptor stimulation and neuroprotective effects under ischemia through the involvement of the MAPK/Erk1/2 pathway in purified RGCs. These findings support a role for sigma receptor agonists as potential neuroprotective agents.

Keywords: 615 neuroprotection • 531 ganglion cells • 548 hypoxia  
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