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Yasushi Kitaoka, Yuka Kitaoka, Jacky M. K. Kwong, Fred N. Ross-Cisneros, Jiantao Wang, Rong Kung Tsai, Alfredo A. Sadun, Tim T. Lam; TNF-α-Induced Optic Nerve Degeneration and Nuclear Factor-κB p65. Invest. Ophthalmol. Vis. Sci. 2006;47(4):1448-1457. doi: 10.1167/iovs.05-0299.
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purpose. To characterize a model of optic nerve axonal degeneration induced by tumor necrosis factor (TNF)-α and to determine the role of nuclear factor (NF)-κB 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-α. 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-κB p65 protein in retina and optic nerve were determined by Western blot analysis and immunohistochemistry. The effects of antisense oligodeoxynucleotide (AS ODN) against NF-κB p65 and helenalin, an inhibitor of NF-κB p65 activation, on TNF-α-induced optic nerve degeneration were determined by counting the number of axons.
results. Intravitreal injections of TNF-α 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-κB 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-κB p65 with AS ODN or helenalin significantly ameliorated the effects of TNF-α-mediated axonal loss.
conclusions. TNF-α causes axonal degeneration with probable delayed loss of retinal ganglion cell bodies. NF-κB p65 may play a pivotal role in axonal degeneration, with the possible involvement of microglial cells.
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