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  • Title: Deleterious role of TNF-alpha in retinal ischemia-reperfusion injury.
    Author: Berger S, Savitz SI, Nijhawan S, Singh M, David J, Rosenbaum PS, Rosenbaum DM.
    Journal: Invest Ophthalmol Vis Sci; 2008 Aug; 49(8):3605-10. PubMed ID: 18660426.
    Abstract:
    PURPOSE: Tumor necrosis factor (TNF)-alpha is a mediator of neuronal cell death and survival in ischemia-reperfusion injury. This study was conducted to further elucidate the role of TNF-alpha and its receptor in an in vivo model of retinal ischemia-reperfusion injury by investigating its effects on retinal histopathology and function. METHODS: Retinal ischemia-reperfusion injury was performed on p55 and p75 knockout (KO) mice and Sprague-Dawley rats using the high intraocular pressure METHOD: The temporal expression of TNF-alpha was ascertained with immunohistochemical staining. Separate rats received intravitreal recombinant TNF-alpha or neutralizing antibody before or after ischemia. TUNEL labeling was performed to assess for cell death, and electroretinography was performed to assess function. RESULTS: TNF-alpha expression peaked at 12 to 24 hours after ischemia-reperfusion injury. TUNEL staining was diminished after intravitreal TNF-alpha antibody. Both transgenic KOs demonstrated significantly less functional impairment. Rats receiving recombinant TNF-alpha 48 hours after ischemia showed exaggerated functional impairment. Animals treated with TNF-alpha antibody before ischemia displayed significant functional improvement. CONCLUSIONS: TNF-alpha plays a largely deleterious role in ischemia-reperfusion injury in an in vivo model of retinal injury. Direct neutralization of this cytokine partially preserves retinal function. The diverse characteristics of TNF-alpha are attributed in part to the timing of its expression after injury. TNF-alpha receptor expression and function, along with combination treatments targeting death receptor-mediated apoptosis, should be further explored to develop neuroprotective therapeutic strategies for acute retinal ischemic disorders.
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