title: (+)-Pentazocine Reduces NMDA-Induced Murine Retinal Ganglion Cell Death Through a σR1-Dependent Mechanism.
abstract: OBJECTIVE
  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.
authors: James and Jean Culver Vision Discovery Institute Augusta, Georgia, United States 2Department of Ophthalmology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States 3Department of Cellular Biology and Anatomy, Medical Col.
authors: Jing
authors: J
authors: Zhao
authors: James and Jean Culver Vision Discovery Institute Augusta, Georgia, United States 2Department of Ophthalmology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States 3Department of Cellular Biology and Anatomy, Medical Col.
authors: Barbara A
authors: BA
authors: Mysona
authors: James and Jean Culver Vision Discovery Institute Augusta, Georgia, United States 2Department of Ophthalmology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States.
authors: Azam
authors: A
authors: Qureshi
authors: James and Jean Culver Vision Discovery Institute Augusta, Georgia, United States 2Department of Ophthalmology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States.
authors: Lily
authors: L
authors: Kim
authors: James and Jean Culver Vision Discovery Institute Augusta, Georgia, United States 2Department of Ophthalmology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States.
authors: Taylor
authors: T
authors: Fields
authors: Department of Cellular Biology and Anatomy, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States.
authors: Graydon B
authors: GB
authors: Gonsalvez
authors: James and Jean Culver Vision Discovery Institute Augusta, Georgia, United States 2Department of Ophthalmology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States 3Department of Cellular Biology and Anatomy, Medical Col.
authors: Sylvia B
authors: SB
authors: Smith
authors: James and Jean Culver Vision Discovery Institute Augusta, Georgia, United States 2Department of Ophthalmology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States 3Department of Cellular Biology and Anatomy, Medical Col.
authors: Kathryn E
authors: KE
authors: Bollinger
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002452:Cell Count; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D020287:In Situ Nick-End Labeling; D007274:Injections, Intraperitoneal; D058449:Intravitreal Injections; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016202:N-Methylaspartate / Q000633:toxicity*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D010423:Pentazocine / Q000494:pharmacology*; D017480:Receptors, sigma / Q000378:metabolism*; D012162:Retinal Degeneration / Q000378:metabolism / Q000517:prevention & control*; D012165:Retinal Ganglion Cells / Q000378:metabolism / Q000473:pathology*; D000097605:Sigma-1 Receptor
chemical_list: D018690:Excitatory Amino Acid Agonists; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D016202:N-Methylaspartate; D009292:Narcotic Antagonists; D010423:Pentazocine; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor