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S. Berger, S. Nijhawan, P.S. Rosenbaum, D.M. Rosenbaum; TNF–alpha Plays a Deleterious Role in Ischemia–Reperfusion Injury in the Rat Retina . Invest. Ophthalmol. Vis. Sci. 2005;46(13):5314.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: TNF–alpha is a pleotrophic cytokine released by many cell types on diverse stimulation. There are conflicting data as to whether TNF–alpha acts to promote or inhibit neuronal survival in models of ischemia. The purpose of this study was to investigate the role of TNF–alpha in a model of ischemia–reperfusion in the rat retina. Methods: Transient retinal ischemia was induced using a high intraocular pressure (HIOP) model in Sprague–Dawley rats. Immunohistochemistry for TNF–alpha was performed at different time points following reperfusion after 60 minutes of ischemia. TNF–alpha neutralizing antibody or recombinant TNF–alpha was administered by intravitreal injection 1 hour before 45 minutes of ischemia. Electrophysiology(ERG) was performed to assess functional outcome. In a separate set of experiments, three groups of mice were subjected to 60 minutes of HIOP: TNFR p55 knockout, TNFR p75 knockout, and wild–type. Results: Immunohistochemistry demonstrated increased expression of TNF–alpha in the ganglion cell layer (GCL) and inner nuclear layer (INL) as early as 3 hours of reperfusion and peaked at 6 hours of reperfusion following 60 minutes of ischemia. Intravitreal injections of recombinant TNF–alpha 1 hour before 45 minutes of ischemia exacerbated ERG–b wave attenuation compared with the vehicle.Converesely,intravitreal administration of a TNF–alpha neutralizing antibody 1 hour before 45 minutes of ischemia demonstrated significant preservation of the ERG–b wave 7 days after ischemia. Seven days following 60 minutes of ischemia both transgenic knockout groups showed significantly less morphological and functional impairment as compared to wild–type controls. Conclusions: In aggregate these data suggest that TNF–alpha, a member of the death receptor family,plays a deleterious role in retinal ischemic injury. TNF–alpha's role in the death receptor–mediated (extrinsic) pathway of apoptosis and interaction with caspases indicates potential for further retinal preservation through combination with other inhibitors of the apoptotic pathway.
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