Etanercept, a widely used inhibitor of tumor necrosis factor-α (TNF-α), prevents retinal ganglion cell loss in a rat model of glaucoma

• Published in: PloS one Vol. 7; no. 7; p. e40065
• Main Authors: Roh, Miin, Zhang, Yan, Murakami, Yusuke, Thanos, Aristomenis, Lee, Sung Chul, Vavvas, Demetrios G, Benowitz, Larry I, Miller, Joan W
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 03.07.2012; Public Library of Science (PLoS)
• Subjects: Animals; Antagonists; Axons; Biology; Cell Death - drug effects; Cell Survival; Confocal microscopy; Death; Degeneration; Disease Models, Animal; Etanercept; Glaucoma; Glaucoma - drug therapy; Glaucoma - pathology; Hypertension; Immunoglobulin G - therapeutic use; Inflammation; Inflammatory response; Intraocular Pressure; Laboratories; Male; Medicine; Microglia; Microscopy; Mortality; Necrosis; Neurodegeneration; Neurosciences; Ocular Hypertension - physiopathology; Optic nerve; Rats; Receptors, Tumor Necrosis Factor - therapeutic use; Retina; Retinal ganglion cells; Retinal Ganglion Cells - drug effects; Retinal Ganglion Cells - pathology; Risk analysis; Risk factors; Rodents; Suppressors; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor necrosis factor-TNF; Tumor necrosis factor-α; United States > US; Massachusetts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0040065

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. 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. 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.