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D.M. Rosenbaum, J. David, S. Berger, S. Nijhawan, M. Singh, S. Malhotra, P. Rosenbaum; TNF–Alpha and Caspase–3 Act Synergistically in Retinal Ischemia – Reperfusion Injury . Invest. Ophthalmol. Vis. Sci. 2006;47(13):498.
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© ARVO (1962-2015); The Authors (2016-present)
TNF–alpha is a pleiotrophic cytokine that may promote or inhibit neuronal survival in models of ischemia.Caspases are an integral constituents in cell death pathways in mammalian cells.The purpose of this study was to investigate the role of TNF–alpha in a model of retinal ischemia and to determine if there is a synergistic relationship with the downstream caspase–3.
Transient retinal ischemia was induced using a high intraocular pressure model in the rat.Immunohistochemistry for TNF–alpha was performed at different time points following reperfusion after 60 minutes of ischemia.TNF–alpha antibody ,rhTNF–alpha or a caspase–3 inhibitor were administered intravitreally before ischemia.Electrophysiology(ERG) was performed to assess functinal outcome.In a separate set of experiments,three groups of mice were subjected to 60 minutes od ischemia:TNFRp55 knockout,TNFRp75 knockput ,and wild–type.
TNF expression was increased in the GCL and INL as early as 3hrs and peaked at 6hrs of reperfusion following 60 minutes of ischemia.Intravitreal injection of rhTNF–alpha exacerbated ERG –b wave attenuation compared to vehicle.Conversely,intravitreal injection of TNF–alpha neutralizing antibody significantly preserved the ERG–b wave at 7 days following ischemia.The combination of neutralizing antibody and the caspase–3 inhibitor resulted in synergistic protection of the ERG–b wave.Both groups of mice showed significantly less morphological and functional impairment compared to the wild–types.
These data suggest that TNF–alpha plays a deleterious role in retinal ischemic injury.Furtheremore,TNF–alpha's role in the extrinsic cell death pathway and interaction with caspases indicate potential for retinal neuroprotection utilizing combination therapy.
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