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


RESULTS
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
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.
Angiogenesis Laboratory and Retina Service, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, United States of America.
Miin
M
Roh
Yan
Y
Zhang
Yusuke
Y
Murakami
Aristomenis
A
Thanos
Sung Chul
SC
Lee
Demetrios G
DG
Vavvas
Larry I
LI
Benowitz
Joan W
JW
Miller
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival; D004195:Disease Models, Animal; D000068800:Etanercept; D005901:Glaucoma / Q000188:drug therapy / Q000473:pathology*; D007074:Immunoglobulin G / Q000627:therapeutic use*; D007429:Intraocular Pressure; D008297:Male; D009798:Ocular Hypertension / Q000503:physiopathology; D051381:Rats; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use*; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept