(+)-pentazocine reduces NMDA-induced murine retinal ganglion cell death through a σr1-dependent mechanism

Jing Zhao, Barbara A. Mysona, Azam Qureshi, Lily Kim, Taylor Fields, Graydon B. Gonsalvez, Sylvia B. Smith, Kathryn E. Bollinger

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Abstract

PURPOSE. To evaluate, in vivo, the effects of the sigma-1 receptor (σR1) agonist, (+)- pentazocine, on N-methyl-D-aspartate (NMDA)-mediated retinal excitotoxicity. METHODS. Intravitreal NMDA injections were performed in C57BL/6J mice (wild type [WT]) and σR1-/- (σR1 knockout [KO]) mice. Fellow eyes were injected with phosphate-buffered saline (PBS). An experimental cohort of WT and σR1 KO mice was administered (+)- pentazocine by intraperitoneal injection, and untreated animals served as controls. Retinas derived from mice were flat-mounted and labeled for retinal ganglion cells (RGCs). The number of RGCs was compared between NMDA and PBS-injected eyes for all groups. Apoptosis was assessed using TUNEL assay. Levels of extracellular-signal–regulated kinases (ERK1/2) were analyzed by Western blot. RESULTS. N-methyl-D-aspartate induced a significant increase in TUNEL-positive nuclei and a dose-dependent loss of RGCs. Mice deficient in σR1 showed greater RGC loss (≈80%) than WT animals (≈50%). (+)-Pentazocine treatment promoted neuronal survival, and this effect was prevented by deletion of σR1. (+)-Pentazocine treatment resulted in enhanced activation of ERK at the 6-hour time point following NMDA injection. The (+)-pentazocine–induced ERK activation was diminished in σR1 KO mice. CONCLUSIONS. Targeting σR1 activation prevented RGC death while enhancing activation of the mitogen-activated protein kinase (MAPK), ERK1/2. Sigma-1 receptor is a promising therapeutic target for retinal neurodegenerative diseases.

Original languageEnglish (US)
Pages (from-to)453-461
Number of pages9
JournalInvestigative Ophthalmology and Visual Science
Volume57
Issue number2
DOIs
StatePublished - Feb 2016

Fingerprint

Pentazocine
Retinal Ganglion Cells
N-Methylaspartate
Cell Death
Knockout Mice
In Situ Nick-End Labeling
Phosphates
Retinal Diseases
Injections
Wild Animals
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Intraperitoneal Injections
Inbred C57BL Mouse
Neurodegenerative Diseases
Retina
Therapeutics
Western Blotting
Apoptosis

Keywords

  • Excitotoxicity
  • NMDA
  • Neuroprotection
  • Sigma-1 receptor

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

@article{144aaef371c641b0a4929ef9a66dbeeb,
title = "(+)-pentazocine reduces NMDA-induced murine retinal ganglion cell death through a σr1-dependent mechanism",
abstract = "PURPOSE. To evaluate, in vivo, the effects of the sigma-1 receptor (σR1) agonist, (+)- pentazocine, on N-methyl-D-aspartate (NMDA)-mediated retinal excitotoxicity. METHODS. Intravitreal NMDA injections were performed in C57BL/6J mice (wild type [WT]) and σR1-/- (σR1 knockout [KO]) mice. Fellow eyes were injected with phosphate-buffered saline (PBS). An experimental cohort of WT and σR1 KO mice was administered (+)- pentazocine by intraperitoneal injection, and untreated animals served as controls. Retinas derived from mice were flat-mounted and labeled for retinal ganglion cells (RGCs). The number of RGCs was compared between NMDA and PBS-injected eyes for all groups. Apoptosis was assessed using TUNEL assay. Levels of extracellular-signal–regulated kinases (ERK1/2) were analyzed by Western blot. RESULTS. N-methyl-D-aspartate induced a significant increase in TUNEL-positive nuclei and a dose-dependent loss of RGCs. Mice deficient in σR1 showed greater RGC loss (≈80{\%}) than WT animals (≈50{\%}). (+)-Pentazocine treatment promoted neuronal survival, and this effect was prevented by deletion of σR1. (+)-Pentazocine treatment resulted in enhanced activation of ERK at the 6-hour time point following NMDA injection. The (+)-pentazocine–induced ERK activation was diminished in σR1 KO mice. CONCLUSIONS. Targeting σR1 activation prevented RGC death while enhancing activation of the mitogen-activated protein kinase (MAPK), ERK1/2. Sigma-1 receptor is a promising therapeutic target for retinal neurodegenerative diseases.",
keywords = "Excitotoxicity, NMDA, Neuroprotection, Sigma-1 receptor",
author = "Jing Zhao and Mysona, {Barbara A.} and Azam Qureshi and Lily Kim and Taylor Fields and Gonsalvez, {Graydon B.} and Smith, {Sylvia B.} and Bollinger, {Kathryn E.}",
year = "2016",
month = "2",
doi = "10.1167/iovs.15-18565",
language = "English (US)",
volume = "57",
pages = "453--461",
journal = "Investigative Ophthalmology and Visual Science",
issn = "0146-0404",
publisher = "Association for Research in Vision and Ophthalmology Inc.",
number = "2",

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TY - JOUR

T1 - (+)-pentazocine reduces NMDA-induced murine retinal ganglion cell death through a σr1-dependent mechanism

AU - Zhao, Jing

AU - Mysona, Barbara A.

AU - Qureshi, Azam

AU - Kim, Lily

AU - Fields, Taylor

AU - Gonsalvez, Graydon B.

AU - Smith, Sylvia B.

AU - Bollinger, Kathryn E.

PY - 2016/2

Y1 - 2016/2

N2 - PURPOSE. To evaluate, in vivo, the effects of the sigma-1 receptor (σR1) agonist, (+)- pentazocine, on N-methyl-D-aspartate (NMDA)-mediated retinal excitotoxicity. METHODS. Intravitreal NMDA injections were performed in C57BL/6J mice (wild type [WT]) and σR1-/- (σR1 knockout [KO]) mice. Fellow eyes were injected with phosphate-buffered saline (PBS). An experimental cohort of WT and σR1 KO mice was administered (+)- pentazocine by intraperitoneal injection, and untreated animals served as controls. Retinas derived from mice were flat-mounted and labeled for retinal ganglion cells (RGCs). The number of RGCs was compared between NMDA and PBS-injected eyes for all groups. Apoptosis was assessed using TUNEL assay. Levels of extracellular-signal–regulated kinases (ERK1/2) were analyzed by Western blot. RESULTS. N-methyl-D-aspartate induced a significant increase in TUNEL-positive nuclei and a dose-dependent loss of RGCs. Mice deficient in σR1 showed greater RGC loss (≈80%) than WT animals (≈50%). (+)-Pentazocine treatment promoted neuronal survival, and this effect was prevented by deletion of σR1. (+)-Pentazocine treatment resulted in enhanced activation of ERK at the 6-hour time point following NMDA injection. The (+)-pentazocine–induced ERK activation was diminished in σR1 KO mice. CONCLUSIONS. Targeting σR1 activation prevented RGC death while enhancing activation of the mitogen-activated protein kinase (MAPK), ERK1/2. Sigma-1 receptor is a promising therapeutic target for retinal neurodegenerative diseases.

AB - PURPOSE. To evaluate, in vivo, the effects of the sigma-1 receptor (σR1) agonist, (+)- pentazocine, on N-methyl-D-aspartate (NMDA)-mediated retinal excitotoxicity. METHODS. Intravitreal NMDA injections were performed in C57BL/6J mice (wild type [WT]) and σR1-/- (σR1 knockout [KO]) mice. Fellow eyes were injected with phosphate-buffered saline (PBS). An experimental cohort of WT and σR1 KO mice was administered (+)- pentazocine by intraperitoneal injection, and untreated animals served as controls. Retinas derived from mice were flat-mounted and labeled for retinal ganglion cells (RGCs). The number of RGCs was compared between NMDA and PBS-injected eyes for all groups. Apoptosis was assessed using TUNEL assay. Levels of extracellular-signal–regulated kinases (ERK1/2) were analyzed by Western blot. RESULTS. N-methyl-D-aspartate induced a significant increase in TUNEL-positive nuclei and a dose-dependent loss of RGCs. Mice deficient in σR1 showed greater RGC loss (≈80%) than WT animals (≈50%). (+)-Pentazocine treatment promoted neuronal survival, and this effect was prevented by deletion of σR1. (+)-Pentazocine treatment resulted in enhanced activation of ERK at the 6-hour time point following NMDA injection. The (+)-pentazocine–induced ERK activation was diminished in σR1 KO mice. CONCLUSIONS. Targeting σR1 activation prevented RGC death while enhancing activation of the mitogen-activated protein kinase (MAPK), ERK1/2. Sigma-1 receptor is a promising therapeutic target for retinal neurodegenerative diseases.

KW - Excitotoxicity

KW - NMDA

KW - Neuroprotection

KW - Sigma-1 receptor

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U2 - 10.1167/iovs.15-18565

DO - 10.1167/iovs.15-18565

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VL - 57

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JO - Investigative Ophthalmology and Visual Science

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SN - 0146-0404

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