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Etanercept, a widely used inhibitor of tumor necrosis factor-α (TNF-α), prevents retinal ganglion cell loss in a rat model of glaucoma.
PLoS One. 2012; 7(7):e40065.Plos

Abstract

BACKGROUND

Visual loss in glaucoma is associated with pathological changes in retinal ganglion cell (RGC) axons and a slow decline in the RGC population. Age and elevated intraocular pressure (IOP) are the main risk factors for glaucomatous loss of vision. Several studies have implicated the proinflammatory cytokine tumor necrosis factor-α (TNF-α) as a link between elevated IOP and RGC death, but the cellular source of TNF-α and its causative role in RGC death remain uncertain. Here, using a rat model of glaucoma, we investigated the source of elevated TNF-α and examined whether Etanercept, a TNF-α blocker that is in common clinical use for other indications, is protective against RGC death.

METHODOLOGY/PRINCIPAL FINDINGS

Episcleral vein cauterization (EVC) caused intraocular pressure (IOP) to be elevated for at least 28 days. IOP elevation resulted in a dramatic increase in TNF-α levels within a few days, axonal degeneration, and a 38% loss of RGCs by 4 weeks. Immunostaining coupled with confocal microscopy showed that OHT induced robust induction of TNF-α in Iba-1-positive microglia around the optic nerve head (ONH). Despite persistent elevation of IOP, Etanercept reduced microglial activation, TNF-α levels, axon degeneration in the optic nerve, and the loss of RGCs.

CONCLUSIONS/SIGNIFICANCE

Ocular hypertension (OHT) triggers an inflammatory response characterized by the appearance of activated microglia around the ONH that express TNF-α. Blocking TNF-α activity with a clinically approved agent inhibits this microglial response and prevents axonal degeneration and loss of RGCs. These findings suggest a new treatment strategy for glaucoma using TNF-α antagonists or suppressors of inflammation.

Authors+Show Affiliations

Angiogenesis Laboratory and Retina Service, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, United States of America.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22802951

Citation

Roh, Miin, et al. "Etanercept, a Widely Used Inhibitor of Tumor Necrosis Factor-α (TNF-α), Prevents Retinal Ganglion Cell Loss in a Rat Model of Glaucoma." PloS One, vol. 7, no. 7, 2012, pp. e40065.
Roh M, Zhang Y, Murakami Y, et al. Etanercept, a widely used inhibitor of tumor necrosis factor-α (TNF-α), prevents retinal ganglion cell loss in a rat model of glaucoma. PLoS One. 2012;7(7):e40065.
Roh, M., Zhang, Y., Murakami, Y., Thanos, A., Lee, S. C., Vavvas, D. G., Benowitz, L. I., & Miller, J. W. (2012). Etanercept, a widely used inhibitor of tumor necrosis factor-α (TNF-α), prevents retinal ganglion cell loss in a rat model of glaucoma. PloS One, 7(7), e40065. https://doi.org/10.1371/journal.pone.0040065
Roh M, et al. Etanercept, a Widely Used Inhibitor of Tumor Necrosis Factor-α (TNF-α), Prevents Retinal Ganglion Cell Loss in a Rat Model of Glaucoma. PLoS One. 2012;7(7):e40065. PubMed PMID: 22802951.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Etanercept, a widely used inhibitor of tumor necrosis factor-α (TNF-α), prevents retinal ganglion cell loss in a rat model of glaucoma. AU - Roh,Miin, AU - Zhang,Yan, AU - Murakami,Yusuke, AU - Thanos,Aristomenis, AU - Lee,Sung Chul, AU - Vavvas,Demetrios G, AU - Benowitz,Larry I, AU - Miller,Joan W, Y1 - 2012/07/03/ PY - 2012/04/18/received PY - 2012/05/31/accepted PY - 2012/7/18/entrez PY - 2012/7/18/pubmed PY - 2012/12/10/medline SP - e40065 EP - e40065 JF - PloS one JO - PLoS One VL - 7 IS - 7 N2 - BACKGROUND: Visual loss in glaucoma is associated with pathological changes in retinal ganglion cell (RGC) axons and a slow decline in the RGC population. Age and elevated intraocular pressure (IOP) are the main risk factors for glaucomatous loss of vision. Several studies have implicated the proinflammatory cytokine tumor necrosis factor-α (TNF-α) as a link between elevated IOP and RGC death, but the cellular source of TNF-α and its causative role in RGC death remain uncertain. Here, using a rat model of glaucoma, we investigated the source of elevated TNF-α and examined whether Etanercept, a TNF-α blocker that is in common clinical use for other indications, is protective against RGC death. METHODOLOGY/PRINCIPAL FINDINGS: Episcleral vein cauterization (EVC) caused intraocular pressure (IOP) to be elevated for at least 28 days. IOP elevation resulted in a dramatic increase in TNF-α levels within a few days, axonal degeneration, and a 38% loss of RGCs by 4 weeks. Immunostaining coupled with confocal microscopy showed that OHT induced robust induction of TNF-α in Iba-1-positive microglia around the optic nerve head (ONH). Despite persistent elevation of IOP, Etanercept reduced microglial activation, TNF-α levels, axon degeneration in the optic nerve, and the loss of RGCs. CONCLUSIONS/SIGNIFICANCE: Ocular hypertension (OHT) triggers an inflammatory response characterized by the appearance of activated microglia around the ONH that express TNF-α. Blocking TNF-α activity with a clinically approved agent inhibits this microglial response and prevents axonal degeneration and loss of RGCs. These findings suggest a new treatment strategy for glaucoma using TNF-α antagonists or suppressors of inflammation. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/22802951/Etanercept_a_widely_used_inhibitor_of_tumor_necrosis_factor_α__TNF_α__prevents_retinal_ganglion_cell_loss_in_a_rat_model_of_glaucoma_ L2 - https://dx.plos.org/10.1371/journal.pone.0040065 DB - PRIME DP - Unbound Medicine ER -