Functional significance of tumor necrosis factor alpha in inducing retinal ganglion cell death by using gene targeting method

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We have first demonstrated that the ischemia-induced apoptosis of neurons in the ganglion cell layer of the mouse retina with cardiac arrest model. The mice were cardiac arrested for 5 min and reperfused after the ischemia. We found that the ganglion cells were degenerating with shrinkage of cells, nuclear condensations, DNA fragmentations but no disruptions of mitochondria, suggesting apoptotic changes in these cells. Tumor necrosis factor alpha (TNFα) is shown to induce neuronal cell death in the hippocampus and neocortex in brain and it is supposed to be involve in neuronal cell death in retina. Therefore, we used TNFα-deficient mice to demonstrate whether it induces a delayed neuronal cell death (apoptosis) in mice retina. Many apoptotic neuronal cell death in the ganglion cell layer was significantly observed in the wild-type ones as compared with TNFα-deficient ones. The caspase-3 activity in the ThF*-deficient ones was less than that of the wild-type ones. These results suggest that TNFa acts to stimulate the caspase-3 pathway, thereby inducing retinal ganglion cell death.