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Protection of RGCs in optic nerve injury and glaucoma: Role of zinc and TNF-a.

Glaucoma is a leading cause of blindness worldwide, and although current treatments usually stem the progression of the disease, there are many cases in which this approach is unsuccessful. In two animal models of glaucoma, we elevated intraocular pressure by either episcleral vein cauterization (in rats) or angle closure (in mice) and observed a dramatic elevation of the cytokine TNF-a, activation of microglia1, 2, and a delayed, progressive loss of RGCs, thus mimicking key features of the disease. In one study, we showed that deletion of the gene for TNF-a or one of its receptors, or use of an antibody to TNF-a greatly slowed or arrested the loss of RGCs despite persistently elevated intraocular pressure1. In the second study, we showed that Etanercept, an FDA-approved, soluble decoy receptor for TNF-a, arrested microglial activation at the optic nerve head along and stemmed the loss of RGCs2. These studies have contributed to a growing awareness of the role of TNF-a and inflammation as potentially critical factors in the pathophysiology of glaucoma.

In other work, we have found that one of the earliest events to occur in the eye after the optic nerve is injured is a rise in ionic zinc (Zn2+) in the synaptic terminals that amacrine cells make onto the dendrites of RGCs. Within 2 days or so, the Zn2+ accumulates in RGCs. This effect requires the Zn2+ transporter ZnT3 and nitric oxide. Chelating Zn2+ leads to the enduring survival of many RGCs and extensive axon regeneration3. Ongoing projects in the lab are aimed at understanding the cellular and molecular events that underlie the presynaptic accumulation of zinc after optic nerve injury and the role that zinc plays in suppressing cell survival and axon regeneration.

  1. Nakazawa T, Nakazawa C, Matsubara A, Noda K, Hisatomi T, She H, Michaud N, Hafezi-Moghadam A, Miller JW, Benowitz LI. J Neurosci Tumor necrosis factor-alpha mediates oligodendrocyte death and delayed retinal ganglion cell loss in a mouse model of glaucoma 2006;26(49):12633-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17151265
  2. Roh M, Zhang Y, Murakami Y, Thanos A, Lee SC, Vavvas DG, Benowitz LI, Miller JW. PLoS One Etanercept, a widely used inhibitor of tumor necrosis factor-alpha (TNF-alpha), prevents retinal ganglion cell loss in a rat model of glaucoma 2012;7(7):e40065. http://www.ncbi.nlm.nih.gov/pubmed/22802951.3388998
  3. Li Y, Andereggen L, Yuki K, Omura K, Yin Y, Gilbert HY, Erdogan B, Asdourian MS, Shrock C, de Lima S, Apfel UP, Zhuo Y, Hershfinkel M, Lippard SJ, Rosenberg PA, Benowitz L. Proc Natl Acad Sci U S A Mobile zinc increases rapidly in the retina after optic nerve injury and regulates ganglion cell survival and optic nerve regeneration 2017;114(2):E209-E218. https://www.ncbi.nlm.nih.gov/pubmed/28049831.PMC5240690

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