| First Author | Zhao J | Year | 2016 |
| Journal | Invest Ophthalmol Vis Sci | Volume | 57 |
| Issue | 2 | Pages | 453-61 |
| PubMed ID | 26868747 | Mgi Jnum | J:257643 |
| Mgi Id | MGI:6112365 | Doi | 10.1167/iovs.15-18565 |
| Citation | Zhao J, et al. (2016) (+)-Pentazocine Reduces NMDA-Induced Murine Retinal Ganglion Cell Death Through a sigmaR1-Dependent Mechanism. Invest Ophthalmol Vis Sci 57(2):453-61 |
| abstractText | PURPOSE: To evaluate, in vivo, the effects of the sigma-1 receptor (sigmaR1) 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 sigmaR1-/- (sigmaR1 knockout [KO]) mice. Fellow eyes were injected with phosphate-buffered saline (PBS). An experimental cohort of WT and sigmaR1 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 sigmaR1 showed greater RGC loss ( approximately 80%) than WT animals ( approximately 50%). (+)-Pentazocine treatment promoted neuronal survival, and this effect was prevented by deletion of sigmaR1. (+)-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 sigmaR1 KO mice. CONCLUSIONS: Targeting sigmaR1 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. |
