(+)-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

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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

Keywords

  • Excitotoxicity
  • NMDA
  • Neuroprotection
  • Sigma-1 receptor

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

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