title: Necroptosis, a novel form of caspase-independent cell death, contributes to neuronal damage in a retinal ischemia-reperfusion injury model.
abstract: Necroptosis is programmed necrosis triggered by death receptor signaling. We investigated whether necroptosis contributes to neuronal damage and functional impairment in a model of retinal ischemia.
  
  
  METHODS
  Sprague-Dawley rats were subjected to raised intra-ocular pressure for 45 min and received intravitreal injections of the specific necroptosis inhibitor, Nec-1, its inactive analogue (Nec-1i) or vehicle. Seven days after ischemia, ERGs were performed and then the eyes were enucleated for histological analysis. In other animals, retinas were subjected to propodium iodide, TUNEL staining or Western Blotting and probed with anti-LC-3 antibody.
  
  
  RESULTS
  Retinal ischemia resulted in selective neuronal degeneration of the inner layers. Pretreatment with Nec-1 led to significant preservation in thickness and histoarchitecture of the inner retina and functional improvement compared with vehicle-treated controls. Pretreatment with Nec-1i did not provide histological or functional protection. Post-treatment with Nec-1 also significantly attenuated the ERG b-wave reduction compared with ischemic vehicle controls. Nec-1 had no effect on the number of caspase or TUNEL-labelled cells in the ischemic retina but did inhibit the induction of LC-3 II and reduced the number of PI-labelled cells after ischemia.
  
  
  CONCLUSIONS
  Necroptosis is an important mode of neuronal cell death and involves autophagy in a model of retinal ischemia.
authors.affiliation: Department of Neurology, SUNY Downstate Medical Center, Brooklyn, New York, USA.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Rosenbaum
authors.forename: Alexei
authors.initials: A
authors.lastname: Degterev
authors.forename: Joel
authors.initials: J
authors.lastname: David
authors.forename: Pearl S
authors.initials: PS
authors.lastname: Rosenbaum
authors.forename: Steven
authors.initials: S
authors.lastname: Roth
authors.forename: James C
authors.initials: JC
authors.lastname: Grotta
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Cuny
authors.forename: Junying
authors.initials: J
authors.lastname: Yuan
authors.forename: Sean I
authors.initials: SI
authors.lastname: Savitz
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001343:Autophagy / Q000187:drug effects / Q000502:physiology; D020169:Caspases / Q000502:physiology; D004195:Disease Models, Animal; D004596:Electroretinography; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007429:Intraocular Pressure / Q000502:physiology; D008297:Male; D009336:Necrosis / Q000503:physiopathology*; D009410:Nerve Degeneration / Q000473:pathology / Q000503:physiopathology*; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000473:pathology / Q000503:physiopathology*; D012164:Retinal Diseases / Q000473:pathology / Q000503:physiopathology*
chemical_list: D007093:Imidazoles; D007211:Indoles; D018696:Neuroprotective Agents; C507699:necrostatin-1; D020169:Caspases