Purchase this article with an account.
Jorge Luis Cueva Vargas, Sr., Ingrid Osswald, Nicolas Unsain, Phil Barker, Derek Bowie, Adriana Di Polo; Tumor Necrosis Factor-α and Calcium Permeable AMPA Receptors Mediate Retinal Ganglion Cell Death in Experimental Glaucoma. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3934.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
The primary mechanism of retinal ganglion cell (RGC) damage in glaucoma is not well understood. Tumor Necrosis Factor Alpha (TNF-α) has emerged as a key regulator of neuronal glutamate receptors in the central nervous system. Here, we tested the hypothesis that TNF-α mediates RGC loss in experimental glaucoma by stimulating plasma membrane insertion of calcium-permeable AMPA receptors (CP-AMPAR) in these neurons.
RGC retrograde labeling was carried out by application of DiI onto the superior colliculus. Ocular hypertension (OHT) was induced a week later by injection of hypertonic saline into an episcleral vein in Brown Norway rats. The expression of TNF-α and its receptors, TNFR1 and TNFR2, was examined by RT-PCR, western blots and immunohistochemistry. Cell surface CP-AMPAR were visualized using a cobalt (Co2+) staining technique. The following agents were independently injected into the vitreous chamber: i) the TNF-α inhibitor Etanercept; ii) the CP-AMPAR blockers GYKI 52466 or Philantotoxin 343 (PhTX); or iii) the caspase-8 inhibitor Z-IETD-FMK. RGC neuroprotection was evaluated by quantification of RGC soma and axons.
Gene and protein expression of retinal TNF-α, TNFR1 and TNFR2 were rapidly upregulated following OHT surgery and prior to RGC death. Co2+ uptake, which occurs only through CP-AMPAR, was markedly increased in RGCs of glaucomatous eyes compared to control eyes; and was selectively blocked by GYKI or PhTX. Intraocular injection of the TNF-α inhibitor (Etanercept) or the CP-AMPAR blockers (GYKI, PhTX) led to RGC neuroprotection in experimental glaucoma. For example, GYKI and Etanercept promoted 82% and 81% RGC survival (n=8-10/group), respectively, compared to 68% in vehicle-treated controls (n=8) at 3 weeks of OHT. In contrast, caspase-8 inhibitors did not protect RGCs in this model.
Our data support a key role for TNF-α and CP-AMPAR in RGC loss in experimental glaucoma.
This PDF is available to Subscribers Only