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 language | English (US) |
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Pages (from-to) | 453-461 |
Number of pages | 9 |
Journal | Investigative Ophthalmology and Visual Science |
Volume | 57 |
Issue number | 2 |
DOIs | |
State | Published - Feb 2016 |
Keywords
- Excitotoxicity
- NMDA
- Neuroprotection
- Sigma-1 receptor
ASJC Scopus subject areas
- Ophthalmology
- Sensory Systems
- Cellular and Molecular Neuroscience