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TNF--Induced Optic Nerve Degeneration and Nuclear Factor-B p65

¹From the Department of Ophthalmology, Doheny Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, California; the ²Department of Ophthalmology, St. Marianna University School of Medicine, Kanagawa, Japan; the ³Department of Ophthalmology, Jules Stein Eye Institute, University of California Los Angeles School of Medicine, Los Angeles, California; and the ⁴Department of Ophthalmology, Buddhist Tzu Chi Medical Center, Buddhist Tzu Chi University, Hualien, Taiwan.

PURPOSE. To characterize a model of optic nerve axonal degeneration induced by tumor necrosis factor (TNF)- and to determine the role of nuclear factor (NF)-B p65 in axonal degeneration.

METHODS. Groups of rats were euthanatized at 1 day, 1 or 2 weeks, or 1 or 2 months after intravitreal injection of TNF-. Morphometric analyses of neurofilament- or Thy-1-positive cells, retinal ganglion cells (flat preparations stained with cresyl violet or retrograde labeling with a neurotracer), the number of axons, immunostaining for myelin basic protein, and TUNEL assays were performed. Levels of NF-B p65 protein in retina and optic nerve were determined by Western blot analysis and immunohistochemistry. The effects of antisense oligodeoxynucleotide (AS ODN) against NF-B p65 and helenalin, an inhibitor of NF-B p65 activation, on TNF--induced optic nerve degeneration were determined by counting the number of axons.

RESULTS. Intravitreal injections of TNF- induced obvious axonal loss and extensive degeneration of the axons from 2 weeks to 2 months after injection, whereas significant retinal ganglion cell loss was noted only at 2 months after injection. NF-B p65 was increased in the optic nerve but not in the retina and was found to colocalize with ED-1 and Iba1, markers of microglia. Inhibition of NF-B p65 with AS ODN or helenalin significantly ameliorated the effects of TNF--mediated axonal loss.

CONCLUSIONS. TNF- causes axonal degeneration with probable delayed loss of retinal ganglion cell bodies. NF-B p65 may play a pivotal role in axonal degeneration, with the possible involvement of microglial cells.

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