title: Light-induced photoreceptor and RPE degeneration involve zinc toxicity and are attenuated by pyruvate, nicotinamide, or cyclic light.
abstract: OBJECTIVE
  Light-induced damage can be a problem after surgery or sun exposure. Short-duration, intense light causes preferential photoreceptor death in the superior central retina of albino mice and rats and serves as a model of oxidation-induced neurodegeneration. Previous work on retinal ischemia-induced neuronal death suggests the involvement of zinc (Zn(2+)) toxicity in the death and collapse of many retinal cell layers and demonstrates the protective efficacy of pyruvate. Retinal pigment epithelial (RPE) cells were shown to be sensitive to oxidative stress, and zinc, causing loss of nicotinamide adenine dinucleotide (NAD+) and adenine triphosphate (ATP), which was prevented by pyruvate and nicotinamide. We previously showed similar results in cortical neurons exposed to oxidative stress or Zn(2+). In vivo, Zn(2+) is normally present in the inner and outer segments (associated with rhodopsin), Bruch's membrane and sclera (elastin), RPE, and the outer plexiform layer of the eye (synaptic). In this study, we examine the role of Zn(2+) in oxidative stress and light-induced damage in vitro and in vivo.
  
  
  METHODS
  We modeled retinal toxicity in cell-culture lines derived from retinal tissue: Müller and human retinal pigment epithelial (ARPE-19) cells and a cone photoreceptor-derived line (661W). These cultures were exposed to Zn(2+) and OS, and the therapeutic efficacy of pyruvate, nicotinamide, and NAD(+) was determined. Sprague Dawley albino rats were exposed to 18 kLux of white fluorescent light for 1-4 h in the presence and absence of pyruvate, nicotinamide, lactate, and cyclic light. The intracellular free zinc concentration ([Zn(2+)](i)) and cell damage were assessed 0.5 and 7 days later, respectively.
  
  
  RESULTS
  We show that Zn(2+) and oxidative stress results in increased [Zn(2+)](i) and that Zn(2+) therapeutic compounds (pyruvate, nicotinamide, and NAD(+)) and inhibitors of previously implicated pathways (sirtuin) are efficacious in vitro. Exposure to 18 kLux of cool white fluorescent light for 1 h induced a large increase in Zn(2+) staining 4-14 h later, particularly in the superior outer nuclear layer and RPE of dark-maintained Sprague Dawley albino rats; 4 h of light was required to induce similar damage in cyclic light-maintained rats. Photoreceptors and RPE cells died in untreated animals at 3-7 days. However, nicotinamide and pyruvate (intraperitoneal), but not lactate, attenuated this death in treated animals, as measured using optical coherence tomography and confirmed by counting photoreceptor nuclei.
  
  
  CONCLUSIONS
  Zn(2+) plays a role in this injury, as suggested by the increased Zn(2+) staining and the efficacy of Zn(2+) therapeutics. These results suggest that cyclic light maintenance, Zn(2+) chelation, pyruvate, and nicotinamide promote RPE and photoreceptor survival after injury and could be effective for various forms of retinal neurodegeneration. These results could have immediate clinical applications in surgery- or sun exposure- induced light damage to the retina.
authors.affiliation: Department of Ophthalmology and the Neuroscience Center of Excellence LSU Health Sciences Center, New Orleans, LA 70112, USA. csheli@lsuhsc.edu
authors.forename: Christian T
authors.initials: CT
authors.lastname: Sheline
authors.forename: Yongdong
authors.initials: Y
authors.lastname: Zhou
authors.forename: Shi
authors.initials: S
authors.lastname: Bai
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000528:radiation effects; D002460:Cell Line; D019610:Cytoprotection / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D008027:Light; D009536:Niacinamide / Q000494:pharmacology / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects / Q000528:radiation effects; D020419:Photoreceptor Cells, Vertebrate / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D019289:Pyruvic Acid / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012162:Retinal Degeneration / Q000188:drug therapy* / Q000473:pathology*; D012374:Rod Cell Outer Segment / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D041623:Tomography, Optical Coherence; D015032:Zinc / Q000633:toxicity*
chemical_list: D009536:Niacinamide; D019289:Pyruvic Acid; D015032:Zinc