Necroptosis, a novel form of caspase-independent cell death, contributes to neuronal damage in a retinal ischemia-reperfusion injury model.

Abstract

UNLABELLED:

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.

CONCLUSION:

Necroptosis is an important mode of neuronal cell death and involves autophagy in a model of retinal ischemia.

• Authors: Daniel M Rosenbaum, Alexei Degterev, Joel David, Pearl S Rosenbaum, Steven Roth, James C Grotta, Gregory D Cuny, Junying Yuan, Sean I Savitz
• Journal: Journal of neuroscience research (J Neurosci Res) Vol. 88 Issue 7 Pg. 1569-76 (May 15 2010) ISSN: 1097-4547 [Electronic] United States
• PMID: 20025059 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: (c) 2009 Wiley-Liss, Inc.

Chemical References

• Imidazoles
• Indoles
• Neuroprotective Agents
• necrostatin-1
• Caspases

Topics

• Animals
• Apoptosis (physiology)
• Autophagy (drug effects, physiology)
• Caspases (physiology)
• Disease Models, Animal
• Electroretinography
• Imidazoles (pharmacology)
• Indoles (pharmacology)
• Intraocular Pressure (physiology)
• Male
• Necrosis (physiopathology)
• Nerve Degeneration (pathology, physiopathology)
• Neurons (drug effects, pathology, physiology)
• Neuroprotective Agents (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Reperfusion Injury (pathology, physiopathology)
• Retinal Diseases (pathology, physiopathology)