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TNF--Mediated Death of Retinal Ganglion Cells Following Optic Nerve Crush Injury in Mice

¹ Ophthalmology & Visual Sciences, University Louisville School of Medicine, Louisville, KY, United States
² Ophthalmology Discovery Research, Pharmacia Corporation, Chesterfield, MO, United States

Commercial Relationships: G. Tezel, None; J. Yang, None; M.B. Wax, None.

Grant Identification: Glaucoma Foundation; Glaucoma Research Foundation, American Health Assistance Foundation

Abstract

Purpose: TNF- has recently been identified as one of the mediators of retinal ganglion cell death in glaucoma. To assess the specific role of TNF- signaling in the induction of retinal ganglion cell death, in vivo, we studied the loss of retinal ganglion cells and their axons following optic nerve crush injury in mice deficient for the TNF death receptor, TNF receptor-1.
Methods: Optic nerves of mice deficient for TNF receptor-1 (TNF-R1-/-, B6.129-Tnfrsf1a^tm1Mak), and age- and gender-matched wild type mice (C57BL/6J) were unilaterally subjected to crush injury. Retinal ganglion cell loss was estimated by comparing the counts of surviving retinal ganglion cells in experimental eyes relative to the control fellow eyes, using retinal sections obtained weekly for 6 weeks after the insult. Axon loss was similarly estimated weekly for 6 weeks after the insult by counting the retinal ganglion cell axons in optic nerve cross-sections, using an electron microscopic method. Data obtained from at least 4 animals for each time point, in a masked fashion, were statistically analyzed. In addition, time-dependent relationship of the retinal ganglion cell and axon loss with glial response was determined using immunohistochemistry.
Results: The counts of surviving retinal ganglion cells and their axons at 6-week after optic nerve crush injury demonstrated that their estimated loss was significantly less in TNF receptor-1 -/- mice compared to age- and gender-matched control or sham-operated mice (36% versus 70%, Mann-Whitney U test, p<0.001). The most prominent decrease in the loss of retinal ganglion cells and their axons detected in the TNF-R1-/- mice compared to control animals was beyond the initial 2-week period after the injury, and correlated with the period of glial activation and their increased TNF- expression.
Conclusions: These findings provide evidence that TNF--mediated cell death is involved in the loss of retinal ganglion cells following optic nerve injury, being predominantly associated with the secondary degeneration phase. Since the secondarily degenerating neurons are viable targets for neuroprotection, inhibition of TNF--mediated death signaling may be an effective strategy to protect retinal ganglion cells in glaucoma, in which spreading the damage by secondary degeneration of retinal ganglion cells is similar to optic nerve crush injury.

Keywords: neuroprotection • ganglion cells • animal model

© 2003, The Association for Research in Vision and Ophthalmology, Inc., all rights reserved. For permission to reproduce any part of this abstract, contact the ARVO Office at arvo{at}arvo.org.