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The Journal of Neuroscience, December 1, 2000, 20(23):8693-8700
Increased Production of Tumor Necrosis Factor- by Glial Cells
Exposed to Simulated Ischemia or Elevated Hydrostatic Pressure Induces
Apoptosis in Cocultured Retinal Ganglion Cells
Gülgün
Tezel and
Martin
B.
Wax
Department of Ophthalmology and Visual Sciences, Washington
University School of Medicine, St. Louis, Missouri 63110
Although glial cells in the optic nerve head undergo a reactivation
process in glaucoma, the role of glial cells during glaucomatous neurodegeneration of retinal ganglion cells is unknown. Using a
coculture system in which retinal ganglion cells and glial cells are
grown on different layers but share the same culture medium, we studied
the influences of glial cells on survival of retinal ganglion cells
after exposure to different stress conditions typified by simulated
ischemia and elevated hydrostatic pressure. After the exposure to these
stressors, we observed that glial cells secreted tumor necrosis
factor- (TNF-) as well as other noxious agents such as nitric
oxide into the coculture media and facilitated the apoptotic death of
retinal ganglion cells as assessed by morphology, terminal
deoxynucleotidyl transferase-mediated dUTP nick end labeling, and
caspase activity. The glial origin of these noxious effects was
confirmed by passive transfer experiments. Furthermore, retinal ganglion cell apoptosis was attenuated ~66% by a neutralizing antibody against TNF- and 50% by a selective inhibitor of inducible nitric oxide synthase (1400W). Because elevated intraocular pressure and ischemia are two prominent stress factors identified in the eyes of
patients with glaucoma, these findings reveal a novel glia-initiated
pathogenic mechanism for retinal ganglion cell death in glaucoma. In
addition, these findings suggest that the inhibition of TNF- that is
released by reactivated glial cells may provide a novel therapeutic
target for neuroprotection in the treatment of glaucomatous optic neuropathy.
Key words:
apoptosis; glaucoma; glia; nitric oxide; retinal ganglion
cell; tumor necrosis factor-
Copyright © 2000 Society for Neuroscience 0270-6474/00/20238693-08$05.00/0
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