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

Miin Roh, Yan Zhang, yusuke murakami, Aristomenis Thanos, Sung Chul Lee, Demetrios G. Vavvas, Larry I. Benowitz, Joan W. Miller

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Article numbere40065
JournalPloS one
Volume7
Issue number7
DOIs
Publication statusPublished - Jul 3 2012

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glaucoma
Retinal Ganglion Cells
tumor necrosis factors
Glaucoma
Rats
Tumor Necrosis Factor-alpha
animal models
Intraocular Pressure
cells
Cell death
optics
cell death
Optics
Ocular Hypertension
nerve tissue
Cell Death
Optic Disk
neuroglia
Microglia
axons

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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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. / Roh, Miin; Zhang, Yan; murakami, yusuke; Thanos, Aristomenis; Lee, Sung Chul; Vavvas, Demetrios G.; Benowitz, Larry I.; Miller, Joan W.

In: PloS one, Vol. 7, No. 7, e40065, 03.07.2012.

Research output: Contribution to journalArticle

Roh, Miin ; Zhang, Yan ; murakami, yusuke ; Thanos, Aristomenis ; Lee, Sung Chul ; Vavvas, Demetrios G. ; Benowitz, Larry I. ; Miller, Joan W. / Etanercept, a widely used inhibitor of tumor necrosis factor-α (TNF- α), prevents retinal ganglion cell loss in a rat model of glaucoma. In: PloS one. 2012 ; Vol. 7, No. 7.
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AU - Thanos, Aristomenis

AU - Lee, Sung Chul

AU - Vavvas, Demetrios G.

AU - Benowitz, Larry I.

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AB - 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.

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